Kazakh Ziziphora Species As Sources of Bioactive Substances

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Review Kazakh Ziziphora Species as Sources of Bioactive Substances

Karel Šmejkal 1,*, Milan Malaník 1, Karlygash Zhaparkulova 2, Zuriyadda Sakipova 2, Liliya Ibragimova 2, Galya Ibadullaeva 2 and Milan Žemliˇcka 3 1 Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno 61242, Czech Republic; [email protected] 2 Department of Pharmaceutical Technology, Faculty of Pharmacy, Kazakh National Medical University, Almaty 050000, Kazakhstan; [email protected] (K.Z.); [email protected] (Z.S.); [email protected] (L.I.); [email protected] (G.I.) 3 Department of Pharmacognosy and Botany, The University of Veterinary Medicine and Pharmacy in Košice, Košice 04181, Slovakia; [email protected] * Correspondence: [email protected]; Tel.: +420-72-424-3643

Academic Editor: Derek J. McPhee Received: 19 May 2016; Accepted: 18 June 2016; Published: 25 June 2016

Abstract: Ziziphora species represent the prototypical example of the Lamiaceae family. The phytochemicals present in Ziziphora include monoterpenic essential oils, triterpenes and phenolic substances belonging to the ﬂavonoids. In Kazakh traditional medicine, Ziziphora species possess several medicinal uses. In particular, Z. bungeana Lam. and Z. clinopodioides Lam. are used for the treatment of illnesses related to the cardiovascular system or to combat different infections. Unfortunately, the majority of the information about the complex Ziziphora species is only available in Russian and Chinese language, therefore, we decided gather all available information on Kazakhstan Ziziphora, namely its content compounds, medicinal uses and published patents, to draw the attention of scientists to this very interesting plant with high medicinal potential.

Keywords: Ziziphora; essential oil; ﬂavonoid; triterpene; cardiovascular; antibacterial

1. Introduction

1.1. Taxonomy of Ziziphora spp. and Their Typical Habitat Taxonomy of Ziziphora spp. is complicated, as its world population is represented by more than 30 different species. This genus belongs to a very large Lamiaceae family with very similar taxonomic signs. In the flora of Kazakhstan, this genus can be subdivided into six species: Z. bungeana Lam., Z. clinopodioides Lam., Z. interrupta Juz., Z. pamiroalaica Juz., Z. tenuior L., and Z. vichodceviana Tkatsch. ex Tuylaganova. It is not completely clear if Z. bungeana is not simply a subspecies derived from Z. clinopodioides [1]. Ziziphora plants are annual or perennial and herbaceous or sub-shrubby. Their leaves are short petiolate or sub-sessile; the leaf blade is abaxially glandular. Verticillasters are scattered on the leaf axils or crowded in a terminal capitulum; floral leaves occur as large as stem leaves or can be reduced. Ziziphora species blossom from June to September according to the surrounding conditions. The calyx of Ziziphora plants appears to be narrowly cylindric, straight to slightly curved, 13-veined, villous, annulated at throat, obscurely 2-lipped, with the upper lip 3-toothed and lower lip 2-toothed; the teeth are subequal, close together, rarely divergent after anthesis. The corolla limb of the flower is 2-lipped: upper lip straight, margin entire, apex emarginate; lower lip spreading, 3-lobed, and middle lobe narrower than suborbicular lateral lobes. The anterior stamens are fertile, reaching the upper corolla lip, and posterior stamens are rudimentary, short, or absent; anther cells are linear, with only

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1 or 2 of them developed, and the others tend to be reduced to an appendage or absent. The style apex is unequally 2-cleft, and the posterior lobe is short. The fruits are ovoid and smooth nutlets. As mentioned, around the world, there are about 25–30 species in Africa, Asia and Europe, and four different species in China. Kazakhstan flora is represented by six different species. The morphology of Z. bungeana and Z. clinopodioides is described in detail, and information about the phytochemically less explored species Z. tenuior, Z. pamiroalaica, Z. vichodceviana and Z. interupta can be found here [2,3]. Z. bungeana Lam. are aromatic subshrubs with woody roots. The stems are numerous, obliquely ascending to sub-erect, 12–30 cm long, woody at the base, branched, densely retrorse, pubescent, especially at apex. The petioles are pubescent; the leaves are narrowly lanceolate to ovate-lanceolate, rarely ovate, 5–15 mm ˆ 1.5–6 mm, sub-glabrous or pubescent, conspicuously glandular, base cuneate to attenuate, margin entire, apex acute to slightly obtuse. The verticillasters are crowded in globose or semiglobose terminal capitula; the floral leaves are reduced, mostly ascending or horizontal. The pedicel is 1–3 mm long. The calyx is tubular, 5(–7) mm, obscurely glandular; the teeth are subequal and acute. The corolla rose, ca. 8 mm, tube pubescent, and lateral lobes are circular. Usually, 2 stamens are fertile, and the posterior stamens are short or absent. The flowering period is typically in Aug-Sep. Z. bungeana grows in gravelly hillsides, semi-desert areas, or sandy beaches, at altitudes of 700–1100 m above sea level in the areas of Xinjiang (China), Kazakhstan, Kyrgyzstan, Mongolia, Russia, Tajikistan, Turkmenistan, and Uzbekistan [2]. Z. clinopodioides Lam. has a thick and woody rhizome. The stems are numerous, simple, erect, 8–40 cm long, rarely branched, but branching on the top, somewhat ascending, covered with short hairs bent down. The leaves are petiolate, ovate or oblong-ovate, 10–25 mm long, 3–10 mm wide, with entire or unclearly rarely toothed margin. The leaves are point-ferruginous, smooth or sparsely short-haired. The flowers are gathered in dense apical capitate inflorescences surrounded by small bracts. The calyx is covered with short hairs, corolla is 10–12 mm long, pink or light purple outside, short and fluffy, tubular, twice as long as the limb, with the upper lip oblong to oval and notched, the middle part of the lower lip almost formy and villous, and lateral lobes spit ovate. Z. clinopodioides Lam. grows typically on the open rocky and gravelly slopes of hills and mountains, on rocky riverbanks, and also on the steppe meadows [2].

1.2. The Traditional Utilization of Ziziphora spp. Z. clinopodioides is well known in Chinese traditional medicine as lip vanilla, leaflet mint or mountain mint. According to Chinese Materia Medica, it is used as a tranquilizing agent. It is also used to treat palpitations, insomnia, cold and fever, and oedema. It is usually administered orally as a decoction prepared by placing 15–18 g of the plant in boiling water to brew a tea. Z. clinopodioides is found to have been used in folk medicine to treat fevers and headaches in Xinjiang, China [4]. It is also a medicinal plant used in traditional Uighur medicine for many purposes, e.g., treatment of heart disease, high blood pressure, asthma, hyperhidrosis, palpitation, insomnia, edema, cough, bronchitis, lung abscess and other diseases [5,6]. Z. clinopodioides leaves, flowers and stems are frequently used as wild vegetables or additives in food to obtain a strong aroma and flavour [7]. Z. clinopodioides (known as blue mint bush in Turkish and Iranian traditional medicine) is well known for its antibacterial action [8]. Ziziphora species are used frequently also in Turkish and Iranian folk medicine, mainly as infusions for sedative, stomachic, carminative and other effects. Their antiseptic and wound healing effect is also well known [6,9]. In Anatolia, Z. clinopodioides is used as a wild vegetable or aroma and flavour adding spice. The plant is locally known as Kirnanesi and is prepared as an aromatic tea for treating gastrointestinal disorders and for its carminative, antiseptic and wound-healing properties [6]. Furthermore, it used as a culinary agent for manufacturing a special type of cheese [10,11]. Z. tenuior L. (known as raushangul in Kazakh language and kakuti in Persian language; kakuti-e kuhi is the Persian name of Z. clinopodioides according to Beikmohammadi [8]), is used in traditional medicine for treatment of fever, dysentery, uterus infection and as an analgesic. It is used also to combat Molecules 2016, 21, 826 3 of 54 different gastrointestinal disorders, especially as a carminative, or as a remedial agent for diarrhoea or nausea. The essential oils and main components pulegone (53), thymol (62), menthone/isomenthone (44) and piperitone (45) could be the compounds responsible for the above-mentioned medicinal properties [12]. Z. tenuior has high content of essential oil, meaning it is a good raw source of pulegone (53) which is widely used in the food and drug industry [13,14]. Sezik et al. found this plant (local name Chulhulva) to have hypotensive properties in their ethnopharmacological research on the medicinal plants of Uzbekistan [13]. Z. bungeana herb is used in Uygur medicine to prepare oral decoction which relieves respiratory distress, dizziness and other symptoms connected to cardiovascular diseases like coronary heart disease or hypertension [14].

2. Ziziphora Phytochemistry and Pharmacology The previous investigations which were carried out on the Ziziphora genus with aim to elucidate the phytochemical profiles were mainly focused on its essential oil composition, and this will be discussed in the following text. In addition to essential oils, the Ziziphora species can be sources of flavonoids, caffeic acid derivatives, fatty acids, triterpenes and sterols. Ding et al. attempted to determine the effect of growth stage of Z. clinopodioides on the content and composition of essential oils, terpenoids, phenolics and flavonoids, showing that essential oil content was higher during the flowering period from non-volatile compounds and only the total flavonoid content was strongly affected by the growth stage [15]. Similar results were shown by Razmjoue and Zarei, where the essential oil content was correlated to temperature, relative moisture and height above sea level [16]. The habitat was also a factor affecting the content of the compounds present in the essential oils of Z. clinopodioides [17]. Moreover, different chemovars were identified during the chemical analysis of Z. clinopodioides and Iranian Z. clinopodioides ssp. rigida. The content of main essential oils components varied and allowed authors to classify analyzed species into pulegone/neomenthol, pulegone, pulegone/1,8-cineol, neomenthol and 1,8-cineol/terpinen-4-ol chemotypes [18,19]. Water and ethanol extracts of Z. clinopodioides showed no activity against several bacterial species, but some activity against COX-1 was recorded [20]. When different extracts from Z. clinopodioides subsp. rigida were tested for antibacterial activity against several Gram-positive and Gram-negative bacterial strains, only low activity was noted (with the exception of deodorized hot water and water-soluble methanol extracts against Bacillus subtillis and methanol and water-insoluble methanol extract against E. coli)[21]. However, methanol-water extracts of Z. clinopodioides and Z. tenuior showed low activity against several Gram-positive and Gram-negative microbial species in other assays [22]. The efficacy of methanolic extract obtained from Z. clinopodioides for treating inflammatory bowel disease was tested using the dextran sulphate-induced colitis model in mice. The parameters of inflammatory process were observed and it was found that TNF-α and NO levels were decreased, and the level of antioxidative defence was restored to almost the normal level [23]. Promising results in mice model of acetic acid-induced collitis showed also the water soluble portion of methanolic extract of Z. clinopodioides, however, compounds responsible for effect were probably not the components of essential oil [24]. The effect observed in this assay could be connected with antioxidant activity, as myeloperoxidase and TBARS levels were decreased by pretreatment of mice with different Z. clinopodioides extract concentrations. All doses of Z. clinopodioides showed significantly lowered score values of macroscopic and microscopic evaluations of colons, the effect of Z. clinopodioides at concentration of 300 mg/kg was comparable to that of prednisolone. The anti-inflammatory potential of Ziziphora was confirmed also by further study which showed, that ethanolic extract of Z. tenuior is active in induction of CD40 expression on dendritic cells and it can modulate the immunity response by affection of cytokine secretion, what at least partially explaines the traditional usage of this plant in treatment of imunity related diseases [25]. Z. tenuior hydroalcoholic extract showed the antinociceptive activity (against visceral pain) in acetic acid-induced writhing assay in mice [26]. Molecules 2016, 21, 826 4 of 54

The methanolic extract of Z. clinopodioides subsp. rigida showed higher DPPH scavenging effect than the essential oil and other types of extracts [21]. Ziziphora extracts were tested for their potential cytotoxic effect in gastric cancer AGS cell line and showed promising cytotoxic activity [27]. Z. tenuior methanol and ethanol extracts showed the ability to decrease the bitterness of caffeine and showed some antioxidant activity, making Z. tenuior a promising food additive [28]. Some experiments also showed the reducing power of the water extract of Z. tenuior in the process of the formulation of silver nanoparticles [29]. The following chapters present an overview of the compounds identified from Kazakhstan Ziziphora species and their biological effects. Tables1–4 outline the Ziziphora compounds and their activities. The information pertaining to each single compound which was isolated or identified in Kazakhstan Ziziphora species is presented here to attract attention to these interesting plants with several possible uses. The data in this research were collected using the Scifinder portal, Web of Knowledge and Science Direct. The search included articles published till April 2016, which are written in English (with limited number of papers in Russian language). The search was conducted using each single compound detected in Ziziphora as keyword. The articles that presented results of compounds added to mixtures as well as those that appeared in congress abstracts were not considered in this review.

2.1. Patents There are several patents registered for the Ziziphora species and their application (or application of their isolated compounds) in the area of medicine. Capsules containing the mixture of dried aerial part extract Z. bungeana with Artemisia rupestris and Arctium lappa extracts are used to treat different viral infections of the upper respiratory tract. The patent applications also include the assays on the antipyretic activity of the extract in rabbits, anti-inflammatory activity in rats and antitussic activity in mice. The antiviral activity of the preparation was also evaluated in vitro [30]. The method for obtaining the flavonoid fraction of the Z. bungeana extract was also patented, combining the extraction of the Z. bungeana aerial part with organic solvent, with the dispersion of the extract into aqueous phase and filtration through macroporous resin, further washed with ethanol to get a flavonoid-rich extract [31]. This flavonoid fraction is believed to be useful in the treatment of cardiovascular diseases. Other patents cover the usage of Z. bungeana polyphenol and flavonoid fraction [32]. A flavonoid preparation from Z. bungeana to treat cardiovascular disorders is also patented [33]. Z. clinopodioides is also a component of Chinese traditional medicinal preparation for the treatment of paroxysmal supraventricular tachycardia [34]. Z. clinopodioides essential oil can be used as an oral spray to improve hygiene of oral cavity, suppress inflammation and suppress the growth of oral pathogenic bacteria [35]. Z. clinopodioides essential oil can be used in agriculture. The method for obtaining this oil and its application as an anti-fungal preparation against plant pathogenic fungus Sclerotinia sclerotiorum was patented [36]. The HPLC fingerprint for Z. clinopodioides compounds has also been developed using reversed-phase chromatography of diosmin (7), linarin (8) and pulegone (53)[37].

2.2. Phenolics Z. clinopodioides was extracted with aim to obtain extracts with different polarity compounds to determine the total polyphenol and flavonoid content. As shown, phenolic substances are concentrated in the ethyl acetate extract, similar to flavonoids, phenolic acids and some other phenolics [5]. However, the analysis of the literature on the isolation of flavonoids or further phenolics from Ziziphora showed the presence of mainly lipophilic compounds of aglycone type (Table1). From flavonoids, only a limited number of glycosides (diosmin (7) and linarin (8)) was isolated. Molecules 2016, 21, 826 5 of 54

MoleculesTable 2016 1., 21Phenolic, 826 substances isolated from Kazakhstan Ziziphora species. (N.f.—not found). 5 of 53

Table 1. Phenolic substances isolated from Kazakhstan Ziziphora species. (N.f.—not found). Flavonoids Flavonoids Chemical Structure Chemical Structure R4 R5 R3 Isolation/ Isolation/Detection Detection in R2 O Name of Compound and ID Biological Activity Name of Compound and ID in Kazakhstan spp. Kazakhstan spp.Biological of Activity of Ziziphora Ziziphora R6 R1 OH O R1 R2 R3 R4 R5 R6

Vasorelaxant activity (IC50 189.4 ± 12.4 µM) [39]; Some inhibitoryR1 activity R2 R3 R4 R5 R6 on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] Vasorelaxant activity (ICZ. tenuior50 189.4 [38];˘ 12.4 µM) [39]; Some inhibitory activity Review on apigenin (1) on breast cancer [41] Apigenin (1) Z. clinopodioides γ H OH H H OH H on NO production stimulated by LPS andAnticancer IFN- activityin RAW review 264.7 [42–44] cells [4] Z. tenuior [38]; Review on apigenin (1) on[4,39,40] breast cancer [41] Apigenin (1) Review on apigenin (1) impact on gastric cancer [45] H OH H H OH H Z. clinopodioides [4,39,40] Anticancer activity review [42–44] General review on the impact of apigenin (1) on health and disease [46] Review on apigenin (1) impact on gastricVasorelaxant cancer [45 activity] (IC50 347.8 ± 23.9 µM) [39] Neuroprotective activity reviewed [47] ChrysinGeneral (2) review on theZ. clinopodioides impact of [39] apigenin (1) on health and disease [46] H OH H H H H Anticancer activity reviewed [48,49] Vasorelaxant activity (IC50 347.8 ˘ 23.9 µRecentM) [ 39general] review on bioactivities of chrysin (2) and its derivatives [50] Neuroprotective activity reviewed [47] Some inhibitory activity on NO production stimulated by LPS and IFN-γ Chrysin (2) Z. clinopodioides [39] H OH H H H H Anticancer activity reviewed [48,49] in RAW 264.7 cells [4] Recent general review on bioactivities ofAnticancer chrysin [51,52] (2) and its derivatives [50] Review on anti-inflammatory and neuroprotective Some inhibitory activity on NO productioneffect stimulated [53,54] Luteolin (3) Z. clinopodioides [4] H OH H OH OH H by LPS and IFN-γ in RAW 264.7 cells [4]Neurotrophic effects [55] Anticancer [51,52] Anti-allergic [56] Review on anti-inﬂammatory and neuroprotectiveAnti-atherogenic effect [57] [53,54] Cardioprotective [58] Z. clinopodioides Luteolin (3) [4] Neurotrophic effects [55] General reviews on luteolin (3) [59,60] H OH H OH OH H

Anti-allergic [56] Low vasorelaxant activity (IC50 not calc.) [39] Anti-atherogenic [57] Toxicity against Artemia salina larvae [62] Thymonin (4) Z. clinopodioides [39,61] OH OCH3 OCH3 OCH3 OH H Cardioprotective [58] Antiradical [63] General reviews on luteolin (3)[59,60] Weak antibacterial effect [61] Low vasorelaxant activity (IC50 not calc.) [39] Low vasorelaxant activity (IC50 not calc.)Inhibition [39] of angiogenesis [64,65] Toxicity against Artemia salina larvae [62Induction] of apoptosis in different cancer cell lines [66–70] Thymonin (4) Z. clinopodioides [39,61] OH OCH OCH OCH OH H Antiradical [63] Inhibition of TNF-related apoptosis [71] 3 3 3 AcacetinWeak antibacterial(5) effectZ. clinopodioides [61] [39] Anticancer [72,73] H OH H H OCH3 H Induction of melanogenesis in B16F10 cells [74] Low vasorelaxant activity (IC50 not calc.)Cytotoxic [39] against HL-60 cells cells [75] Inhibition of angiogenesis [64,65] Interaction with telomeres [76] Induction of apoptosis in different cancerAntimetastatic cell lines [effect66–70 [77,78]] Inhibition of TNF-related apoptosis [71]

Acacetin (5) Z. clinopodioides [39] Anticancer [72,73] H OH H H OCH3 H Induction of melanogenesis in B16F10 cells [74] Cytotoxic against HL-60 cells cells [75] Interaction with telomeres [76] Antimetastatic effect [77,78] Molecules 2016, 21, 826 6 of 54

Molecules 2016, 21, 826 Table 1. Cont. 5 of 53

Table 1. Phenolic substances isolated from Kazakhstan Ziziphora species. (N.f.—not found). Flavonoids Flavonoids Chemical Structure Chemical Structure R4 R5 R3 Isolation/ Isolation/Detection in Detection in R2 O Name of Compound and ID Biological Activity Name of Compound and ID Kazakhstan spp. of Kazakhstan spp. of Biological Activity Ziziphora Ziziphora R6 R1 OH O R1 R2 R3 R4 R5 R6

Vasorelaxant activity (IC50 189.4 ± 12.4 µM) [39]; Some inhibitory activityR1 R2 R3 R4 R5 R6 on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] Some inhibitoryZ. tenuior activity [38]; on NO production stimulated Review on apigenin (1) on breast cancer [41] Apigenin (1) Z. clinopodioidesγ H OH H H OH H Molecules 2016, 21, 826by LPS and IFN- in RAW 264.7Anticancer cells [ 4activity] review [42–44] 6 of 53 [4,39,40] Diosmetin (6) Z. clinopodioides [4] Cytotoxic against HL-60 cells cellsReview [75 on] apigenin (1) impact on gastric cancer [45] H OH H OH OCH3 H Induction of melanogenesis inSomeGeneral B16F10 inhibitory review cells onactivity [73 the,74 impact on] NO of production apigenin (1 stimulated) on health byand LPS disease and IFN- [46] γ Review on bioactivity [79] inVasorelaxant RAW 264.7 activity cells [4] (IC 50 347.8 ± 23.9 µM) [39] Diosmetin (6) Z. clinopodioides [4] CytotoxicNeuroprotective against activity HL-60 reviewedcells cells [47][75] H OH H OH OCH3 H Chrysin (2) Z. clinopodioides [39] H OH H H H H Antidiabetic activity (reviewedInductionAnticancer by Abdurrazak of activity melanogenesis reviewed et al. in[48,49][ B16F1081]) cells [73,74] Diosmin (7) Z. clinopodioides [80] H O-Glc-Rha H OH OCH3 Hf Review on clinical use [82] ReviewRecent general on bioactivity review on[79] bioactivities of chrysin (2) and its derivatives [50] AntidiabeticSome inhibitory activity activity (reviewed on NO by production Abdurrazak stimulated et al. [81]) by LPS and IFN-γ Diosmin (7) InhibitionZ. of clinopodioides mucin production [80] and secretion in airways epithelial cells [83] H O-Glc-Rha H OH OCH3 Hf Reviewin RAW on 264.7 clinical cells use [4] [82] Hepatoprotective [84] InhibitionAnticancer of [51,52] mucin production and secretion in airways epithelial cells [83] Potential inhibitor of CDK4 inHepatoprotectiveReview retinoblastoma on anti-inflammatory [84] [ 85] and neuroprotective Linarin (8) Z. clinopodioides [44,80] Neuroprotective [86] Potentialeffect [53,54] inhibitor of CDK4 in retinoblastoma [85] H O-Glc-Rha H H OCH3 H Luteolin (3) Z. clinopodioides [4] H OH H OH OH H Linarin (8) InhibitionZ. ofclinopodioides acetylcholinesterase [44,80] NeuroprotectiveNeurotrophic [87] effects [86] [55] H O-Glc-Rha H H OCH3 H Anti-inflammatory [88]; Anti-inflammatoryInhibitionAnti-allergic of acetylcholinesterase[56] in vivo [89] [87] Depressant effect on CNS [90,Anti-inflammatory91Anti-atherogenic] [57] [88]; Anti-inflammatory in vivo [89] DepressantCardioprotective effect [58]on CNS [90,91] Ziziphorin A (9) Z. tenuior [39Ziziphorin] A (9) n.f. Z. tenuior [39] n.f.General reviews on luteolin (3) [59,60] HH OHOH HH HH OCO(CHOCO(CH2)217)CH17CH3 3 H H Low vasorelaxant activity (IC50 not calc.) [39] Ziziphorin B (10) Z. tenuior [39] n.f. Toxicity against Artemia salina larvae [62] H OH H H H OCO(CH2)25CH3) ZiziphorinThymonin B (410) ) Z. clinopodioidesZ. tenuior [39] [39,61] n.f. OHH OCHOH 3 OCHH 3 OCHH 3 OH H OCO(CH H2 )25CH3) 5,7,21-trihydroxyflavone-21- Antiradical [63] Z. clinopodioides [44] n.f. Weak antibacterial effect [61] H OH H H H O-Glc O-β-D-glucopyranoside (11) 5,7,2′-trihydroxyflavone-2′- Low vasorelaxant activity (IC50 not calc.) [39] Z. clinopodioides [44] n.f. H OH H H H O-Glc O-β-D-glucopyranoside (11) Inhibition of angiogenesisOther Phenolics [64,65] Induction of apoptosis in different cancerOther cell lines Phenolics [66–70] Inhibition of TNF-related apoptosis [71] Chemical Structure Chemical Structure H H OCH3 H Acacetin (5) Z. clinopodioides [39] Anticancer [72,73] H OH O Induction of melanogenesis in B16F10 cells [74] Cytotoxic against HL-60 cells cells [75] Isolation/Detection Isolation/Detection in Interaction with telomeres [76] Name of Compound and ID in KazakhstanName of spp. Compound andBiological ID Kazakhstan Activity spp. of BiologicalAntimetastatic Activity effect [77,78] of Ziziphora Ziziphora R2 R1

Low vasorelaxant activity (IC50 not calc.) [39] R1 R2 Acetovanillone (syn. Low vasorelaxantZ. clinopodioides activity [39] (ICReviewnot calc.)on its potential [39] in treatment of cardiovascular diseases [92] apocynin) (12) 50 R1OH OCH R23 Acetovanillone Z. clinopodioides [39] Review on its potential in treatmentReview on of its cardiovascular potential in treatment diseases of neurodegenerative [92] diseases [93] (syn. apocynin) (12) Review on its potential in treatment of neurodegenerative diseases [93] OH OCH3 4-Hydroxyaceto-phenone Z. clinopodioides [39] Low vasorelaxant activity (IC50 not calc.) [39] OH H 4-Hydroxyaceto-phenone (syn. piceol) (13) Z. clinopodioides [39] Low vasorelaxant activity (IC not calc.) [39] OH H (syn. piceol) (13) 50 Tyrosinase inhibition [95] Acetophenone (14) Z. tenuior [94] H H Acaricidal effect [96] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ Picein (15) Z. clinopodioides ([4,44] in RAW 264.7 cells [4] O-Glc H Glucosidase inhibitor (review by Benalla et al. [97])

Molecules 2016, 21, 826 6 of 53

Some inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] Diosmetin (6) Z. clinopodioides [4] Cytotoxic against HL-60 cells cells [75] H OH H OH OCH3 H Induction of melanogenesis in B16F10 cells [73,74] Review on bioactivity [79] Antidiabetic activity (reviewed by Abdurrazak et al. [81]) Diosmin (7) Z. clinopodioides [80] H O-Glc-Rha H OH OCH3 Hf Review on clinical use [82] Inhibition of mucin production and secretion in airways epithelial cells [83] Hepatoprotective [84] Potential inhibitor of CDK4 in retinoblastoma [85] Linarin (8) Z. clinopodioides [44,80] Neuroprotective [86] H O-Glc-Rha H H OCH3 H Inhibition of acetylcholinesterase [87] Molecules 2016, 21, 826 Anti-inflammatory [88]; Anti-inflammatory in vivo [89] 7 of 54 Depressant effect on CNS [90,91] Ziziphorin A (9) Z. tenuior [39] n.f. H OH H H OCO(CH2)17CH3 H

Ziziphorin B (10) Z. tenuior [39] n.f. Table 1. Cont. H OH H H H OCO(CH2)25CH3)

5,7,2′-trihydroxyflavone-2′- Z. clinopodioides [44] n.f. H OH H H H O-Glc O-β-D-glucopyranoside (11) Other Phenolics Other Phenolics Chemical Structure Chemical Structure O

Isolation/Detection in Isolation/Detection in Name of Compound and ID Kazakhstan spp. ofName of CompoundBiological and Activity ID Kazakhstan spp. of Biological Activity Ziziphora Ziziphora R2 R1

Low vasorelaxant activity (IC50 not calc.) [39] R1 R2 Acetovanillone (syn. Tyrosinase inhibitionZ. [clinopodioides95] [39] Review on its potential in treatment of cardiovascular diseases [92] Acetophenone (14) Z. tenuior [94] apocynin) (12) HHOH OCH3 Acaricidal effect [96] Review on its potential in treatment of neurodegenerative diseases [93] Weak inhibitory activity on NO production stimulated 4-Hydroxyaceto-phenone Picein (15) Z. clinopodioides ([4,44] by LPS and IFN-γ inZ. RAWclinopodioides 264.7 [39] cells [4] Low vasorelaxant activity (IC50 not calc.) [39] O-GlcOH H H Molecules(syn. 20162016 piceol),, 2121 ,,( 13826826) 77 ofof 5353 Molecules 2016Glucosidase,, 21,, 826826 inhibitor (review by Benalla et al. [97]) 7 of 53 Molecules 2016, 21, 826 7 of 53 Tyrosinase inhibition [95] Acetophenone (14) Z. tenuior [94] H OH H Acaricidal effect [96] OH O OH Weak inhibitory activity on NO production stimulated by LPS and IFN-γ O Picein (15) Z. clinopodioides ([4,44] in RAW 264.7 cells [4] O-Glc O H 2-Methoxy-4-vinylphenol 2-Methoxy-4-vinylphenol O Z. clinopodioides [15]2-Methoxy-4-vinylphenol2-Methoxy-4-vinylphenol n.f. Z. clinopodioides [15] Glucosidasen.f. inhibitor (review by Benalla et al. [97]) 2-Methoxy-4-vinylphenol(16) Z.Z. clinopodioidesclinopodioides [15][15][15] n.f.n.f. (16) 2-Methoxy-4-vinylphenol((1616)) (16) Z. clinopodioides [15] n.f. (16)

HO HO Anticancer potential reviewed [98] HO Anticancer potential reviewed [98] Anticancer potential reviewed [98] Caffeic acid (17) Z. clinopodioides [80] ProtectionAnticancer of potential endothelial reviewed cells (review [98] by Fuentes and Palomo [99]) OH Caffeic acid (17) Z. clinopodioides [80] CaffeicCaffeicProtection acidacid ((1717)) of endothelialZ.Z. clinopodioidesclinopodioides cells (review [80][80][80] byProtectionProtectionAnticancer Fuentes ofof potential and endothelialendothelial Palomo reviewed cellscells [ 99(review(review [98]]) byby FuentesFuentes andand PalomoPalomo [99])[99]) HO OH Caffeic acid (17) Z. clinopodioides [80] GeneralProtection review of endothelial on applications cells (review [100] by Fuentes and Palomo [99]) HO OH CaffeicGeneral acid (17 review) on applicationsZ. clinopodioides [ 100[80] ] GeneralGeneralProtection reviewreview of endothelial onon applicationsapplications cells (review [100][100] by Fuentes and Palomo [99]) HO General review on applications [100] HO O O O Weak inhibitory activity on NO productionWeakstimulated inhibitory activity on NO production stimulated by LPS and IFN-γ Weak inhibitory activity on NO production stimulated by LPS and IFN-γγ by LPS and IFN-γ in RAW 264.7 cells [4]inWeak RAW inhibitory 264.7 cells activity [4] on NO production stimulated by LPS and IFN-γ HO inininWeak RAWRAWRAW inhibitory 264.7264.7264.7 cellscellscells activity [4][4][4] on NO production stimulated by LPS and IFN-γ HO Antihypertensivein RAW 264.7 cells [101,102] [4] HO Antihypertensive [101,102] Antihypertensivein RAW 264.7 cells [101,102] [4] HO Ethyl ester of caffeic acid Anti-inflammatoryAntihypertensive [101,102] [103–105] EthylEthyl esteresterAnti-inﬂammatory ofof caffeiccaffeic acidacid [Z.103 clinopodioides–105] [4] Anti-inflammatoryAntihypertensive [101,102] [103–105] OCH CH Ethyl ester of caffeic acid (18) Z. clinopodioides [4] Ethyl ester( 18of) caffeic acid Z.Z. clinopodioidesclinopodioides [4][4] AntidiabeticAnti-inflammatory [106] [103–105] OCH22CH33 Ethyl esterAntidiabetic(( 1818of) )caffeic acid [106 ] Z. clinopodioides [4] AntidiabeticAnti-inflammatory [106] [103–105] HO OCH2 CH3 (18) Z. clinopodioides [4] InhibitoryAntidiabetic activity [106] against amyloidogenesis [107] HO OCH2CH3 (18) InhibitoryInhibitoryAntidiabetic activityactivity [106] againstagainst amyloidogenesisamyloidogenesis [107][107] HO Inhibitory activity against amyloidogenesisAntioxidativeInhibitory [107 ]activity [108–111] against amyloidogenesis [107] O AntioxidativeInhibitory activity [108–111] against amyloidogenesis [107] O Antioxidative [108–111] AnticancerAntioxidative [112] [108–111] O AnticancerAntioxidative [112] [108–111] O Anticancer [112] Anticancer [112] HO HHO Review on pharmaceutical and clinical usage [113] HO Review on pharmaceutical and clinical usageReviewReview [ onon113 pharmaceuticalpharmaceutical] andand clinicalclinical usageusage [113][113] HO Neuroprotective—reviewReview on pharmaceutical [114] and clinical usage [113] O OH RosmarinicNeuroprotective—review acid (19) Z. clinopodioides [114] [80] Neuroprotective—reviewReview on pharmaceutical [114] and clinical usage [113] HO O OH Rosmarinic acid (19) Z. clinopodioides [80] RosmarinicRosmarinic acidacid ((1919)) Z.Z. clinopodioidesclinopodioides [80][80][80] GeneralNeuroprotective—review review on applications [114] [115] HHO O OH Rosmarinic acid (19) Z. clinopodioides [80] GeneralGeneralNeuroprotective—review reviewreview onon applicationsapplications [114] [115][115] HO O OH RosmarinicGeneral acid review (19) on applicationsZ. clinopodioides [ 115[80] ] ReviewGeneral on review anticancer on applications potential [116] [115] HO O ReviewReviewGeneral on onreview anticanceranticancer on applications potentialpotential [116] [116][115] O O OH OH Review on anticancer potential [116] O O OH OH Review on anticancer potential [116] O O OH OH HO O OH OH HO Effect on cardiovascular system reviewed [117] HO Salicylic acid (20) Z. clinopodioides [80] EffectEffect onon cardiovascularcardiovascular systemsystem reviewedreviewed [117][117] SalicylicSalicylicEffect acidacid on ((2020 cardiovascular)) Z.Z. clinopodioidesclinopodioides system reviewed[80][80][80] PharmacologicalEffect [117 on] cardiovascular importance system reviewed reviewed [118] [117] Salicylic acid (20) Z. clinopodioides [80] Salicylic acid (20) Z. clinopodioides [80] PharmacologicalPharmacologicalEffect on cardiovascular importanceimportance system reviewedreviewed reviewed [118][118] [117] Salicylic acid (20) Z. clinopodioides [80] Pharmacological importance reviewed [118] HOOC Pharmacological importance reviewed [118Pharmacological] importance reviewed [118] HOOC HOOC Weak inhibitory activity on NO production stimulated by LPS and IFN-γ Weak inhibitory activity on NO production stimulated by LPS and IFN-γγ Benzoic acid (21) Z. clinopodioides [4] inWeak RAW inhibitory 264.7 cells activity [4] on NO production stimulated by LPS and IFN-γ BenzoicBenzoicWeak acidacid inhibitory ((2121)) activityZ.Z. clinopodioidesclinopodioides on NOproduction [4][4] inininWeak RAWRAWRAW stimulated inhibitory 264.7264.7264.7 cellscellscells activity [4][4][4] on NO production stimulated by LPS and IFN-γ Benzoic acid (21) Z. clinopodioides [4] Propertiesin RAW 264.7 reviewed cells [4] here [119] Benzoic acid (21) Z. clinopodioides [4] Benzoicby LPS acid and(21) IFN-γ inZ. RAW clinopodioides 264.7 cells[4] [4]PropertiesPropertiesin RAW 264.7 reviewedreviewed cells [4] herehere [119][119] HOOC Properties reviewed here [119] HOOC Properties reviewed here [119] Properties reviewed here [119] HOOC

O O (Z)-3-Hexen-1-ol benzoate OO OO ((ZZ)-3-Hexen-1-ol)-3-Hexen-1-ol benzoatebenzoate Z. tenuior [94] n.f. O O (Z)-3-Hexen-1-ol(22) benzoate Z.Z. tenuiortenuior [94][94][94] n.f.n.f. O (Z)-3-Hexen-1-ol((2222)) benzoate (22) Z. tenuior [94] n.f. (22)

Molecules 2016, 21, 826 7 of 53

OH O 2-Methoxy-4-vinylphenol Z. clinopodioides [15] n.f. (16) Molecules 2016, 21, 826 6 of 53

Some inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] HO Diosmetin (6) Z. clinopodioides [4] Cytotoxic against HL-60 cells cells [75] H OH H OH OCH3 H Anticancer potential reviewed [98] Induction of melanogenesis in B16F10 cells [73,74] Caffeic acid (17) Z. clinopodioides [80] Protection of endothelial cells (review by Fuentes and Palomo [99]) OH Review on bioactivity [79] General review on applications [100] HO Antidiabetic activity (reviewed by Abdurrazak et al. [81]) Diosmin (7) Z. clinopodioides [80] H O-Glc-Rha H OH OCH3 Hf Review on clinical use [82] O Inhibition of mucin production and secretion in airways epithelial cells [83] HepatoprotectiveWeak inhibitory activity [84] on NO production stimulated by LPS and IFN-γ Potentialin RAW 264.7inhibitor cells of [4] CDK4 in retinoblastoma [85] HO Linarin (8) Z. clinopodioides [44,80] NeuroprotectiveAntihypertensive [86] [101,102] H O-Glc-Rha H H OCH3 H Ethyl ester of caffeic acid InhibitionAnti-inflammatory of acetylcholinesterase [103–105] [87] Molecules 2016, 21, 826 Z. clinopodioides [4] OCH2CH3 8 of 54 (18) Anti-inflammatoryAntidiabetic [106] [88]; Anti-inflammatory in vivo [89] HO DepressantInhibitory activity effect on against CNS [90,91] amyloidogenesis [107] Ziziphorin A (9) Z. tenuior [39] n.f. H OH H H OCO(CH2)17CH3 H Antioxidative [108–111] O Anticancer [112]

Ziziphorin B (10) Z. tenuior [39] n.f. H OH H H H OCO(CH2)25CH3) Table 1. Cont. HO Review on pharmaceutical and clinical usage [113] Neuroprotective—review [114] O OH 5,7,2Rosmarinic′-trihydroxyflavone-2 acid (19) ′- Z. clinopodioides [80] Z. clinopodioides [44] n.f.General review on applications [115] H OH HO H H H O-Glc O-β-D-glucopyranoside (11) Other Phenolics Review on anticancer potential [116] O Other Phenolics Chemical StructureO OH OH ChemicalHO Structure O Effect on cardiovascular system reviewed [117] Salicylic acid (20) Z. clinopodioides [80] Isolation/Detection in Pharmacological importance reviewed [118] Isolation/Detection in HOOC Name of Compound and ID Kazakhstan spp. ofName of CompoundBiological and Activity ID Kazakhstan spp. of Biological Activity Ziziphora Ziziphora Weak inhibitory activity on NO production stimulated by LPS and IFN-γ Benzoic acid (21) Z. clinopodioides [4] in RAW 264.7 cells [4] R2 Properties reviewed here [119] HOOCR1

Low vasorelaxant activity (IC50 not calc.) [39] R1 R2 Acetovanillone (syn. Z. clinopodioides [39] Review on its potential in treatment of cardiovascular diseases [92] apocynin) (12) OH OCH3 Review on its potential in treatment of neurodegenerative diseases [93] O O (Z)-3-Hexen-1-ol benzoate (Z)-3-Hexen-1-ol benzoate Z. tenuior [94] n.f. Z. tenuior [94] n.f.(22) (22) 4-Hydroxyaceto-phenone Z. clinopodioides [39] Low vasorelaxant activity (IC50 not calc.) [39] OH H (syn. piceol) (13) Molecules 2016, 21, 826 8 of 53 Molecules 2016, 21, 826 8 of 53 Weak inhibitory activity on NO productionTyrosinase stimulated inhibition [95] MoleculesAcetophenone 2016, 21, 826(14) Z. tenuior [94] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ H H 8 of 53 by LPS and IFN-γ in RAW 264.7 cells [4]Acaricidal effect [96] WeakWeakin RAW inhibitory inhibitory 264.7 cells activity activity [4] on on NO NO production production stimulated stimulated by by LPS LPS and and IFN- IFN-γγ Glc O Antihypertensive effect [120] Antihypertensive effect [120] Benzylalcohol glucoside (23) Z. clinopodioides [4] BenzylalcoholPicein glucoside(15) (23) Z. Z.clinopodioides clinopodioides ([4,44] [4] inWeakin RAW RAW inhibitory 264.7 264.7 cells cells activity [4] [4] on NO production stimulated by LPS and IFN-γ O-Glc Glc O H Low anti-inflammatory activity [121] Low anti-inﬂammatory activity [121] GlucosidaseinAntihypertensive RAW 264.7 inhibitor cells effect [4] (review [120] by Benalla et al. [97]) Glc O Benzylalcohol glucoside (23) Z. clinopodioides [4] Neuroprotective effect [122] Neuroprotective effect [122] AntihypertensiveLow anti-inflammatory effect [120]activity [121] Benzylalcohol glucoside (23) Z. clinopodioides [4] Weak inhibition of TPA-induced EBV-EA activation [123] Weak inhibition of TPA-induced EBV-EALowNeuroprotective activation anti-inflammatory [123 effect] [122]activity [121] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ NeuroprotectiveWeak inhibition ofeffect TPA-induced [122] EBV-EA activation [123] Weak inhibitory activity on NO productionin RAW stimulated 264.7 cells [4] Glc O Phenethylalcohol glucoside Weak inhibitioninhibitory of activity TPA-induced on NO production EBV-EA activation stimulated [123] by LPS and IFN-γ γ Z. clinopodioides [4] Neuroprotective effect [122] Glc O by( LPS24) and IFN- in RAW 264.7 cells [4]Weakin RAW inhibitory 264.7 cells activity [4] on NO production stimulated by LPS and IFN-γ Phenethylalcohol glucoside Phenethylalcohol glucoside Antiradical activity, weak ACE-inhibitory activity [124] Glc O Z. clinopodioides [4] Neuroprotective effectZ. clinopodioides [122] [4] inNeuroprotective RAW 264.7 cells effect [4] [122] (24) Phenethylalcohol(24) glucoside Inhibition of osteoclast differentiation [125] Z. clinopodioides [4] NeuroprotectiveAntiradical activity, effect weak [122] ACE-inhibitory activity [124] Antiradical(24) activity, weak ACE-inhibitory activity [124] AntiradicalInhibitionInsecticidal of activity,(against osteoclast weakL. serricornedifferentiation ACE-inhibitory) [126] [125] activity [124] Inhibition of osteoclast differentiation [125] OH InhibitionInsecticidalAcaricidal of activity (against osteoclast [127] L. serricornedifferentiation ) [126] [125] Antibacterial [128] OH Insecticidal (against L. serricorne)[126] InsecticidalAcaricidal activity (against [127] L. serricorne ) [126] OMe Inhibition of tyrosine kinase [129] OH Acaricidal activity [127] AcaricidalAntibacterial activity [128] [127] OMe Review on possible antidepressive activity [130] Antibacterial [128] AntibacterialInhibition of tyrosine[128] kinase [129] Eugenol (25) Z. tenuior [94] Review on antibacterial effect against cariogenic OMe InhibitionReview on of possible tyrosine antidepressive kinase [129] activity [130] Inhibition of tyrosine kinase [129] bacteria [131] Eugenol (25) Z. tenuior [94] ReviewReview onon possibleantibacterial antidepressive effect against activity cariogenic [130] Review on possible antidepressive activityReview [130 on] possible synergy of eugenol containing essential oils and Eugenol (25) Z. tenuior [94] Eugenol (25) Z. tenuior [94] Reviewbacteria on [131] antibacterial effect against cariogenic eugenol (25) with antibiotics [132] Review on antibacterial effect against cariogenicbacteriaReview [131]on bacteriapossible synergy [131] of eugenol containing essential oils and Review on antioxidative effect [133] Review on possible synergy of eugenol containingRevieweugenol on (25) possible with essential antibiotics synergy oils of [132] eugenol containing essential oils and General properties reviewed here [134] and eugenol (25) with antibiotics [132] eugenolReview on(25) antioxidative with antibiotics effect [132] [133]

Review on antioxidative effect [133] ReviewGeneral on properties antioxidative reviewed effect here [133] [134]

General properties reviewed here [134] General properties reviewed here [134]

Molecules 2016, 21, 826 9 of 54

Several aglycons, which can be called as dietary aglycons (like apigenin (1) and luteolin (3)) were also obtained. Typically, from Lamiaceae plants, lipophilic methoxylated aglycons were extracted, e.g., thymonin (4) or acacetin (5). Some relatively uncommon fatty acid-substituted flavones ziziphorin A and B (9 and 10) were isolated from Z. tenuior [38]. Furthermore, several phenolic acids and their esters, like caffeic acid (17) and its ethyl ester (18) and rosmarinic acid (19), salicylic acid (20) and benzoic acid (21), and derivatives of benzyl alcohol were detected in Ziziphora species (Table1). The bioactivity of Ziziphora flavonoids was studied for several single compounds; therefore, we will mention the activities in connection to possible Ziziphora use. Generally, flavonoids from Ziziphora species showed antioxidant, anti-inflammatory, venoprotective and anticancer activity. Several lipophilic flavonoids showed also antibacterial properties. The antioxidant activity of flavonoid substances depends on the arrangement of the functionalities on the skeleton. Especially, the substitution and number of hydroxyl groups affects the antioxidant activity mediated by radical scavenging and metal ion chelation. As the substitution of Ziziphora-isolated flavonoids is not entirely favourable for scavenging and chelation, the antioxidant effect may be more related with suppression of ROS formation either by inhibition of enzymes or by upregulation or protection of antioxidant defences. Flavonoids contribute to ROS generation inhibition by the affection of the enzymes involved in their production, like microsomal monooxygenase, glutathione S-transferase, mitochondrial succinoxidase, NADH oxidase, and others. The antioxidant activity of Z. clinopodioides was tested by several methods (DPPH, superoxide, and hydroxyl radical scavenging activity). Given the high polyphenol and flavonoid content, the greatest activity was observed in ethyl acetate extract [5]. Monoterpenic glucoside shizonepetoside A (83) and simple flavonoids apigenin (1), luteolin (3) and diosmetin (6) showed potent inhibitory effects on NO production. The stereochemistry of monoterpenic glucosides is important for this effect according to these results [4]. Vasorelaxant activity was shown by those Z. clinopodioides extracts that had high concentration of polyphenolic substances [135]. The mechanism of its vasorelaxant action was also elucidated. The bioactivity guided separation of CH2Cl2 part of a hydroalcoholic extract of the whole plant, using an in vitro model of rat-isolated thoracic aortic rings led to isolation of several compounds, from which apigenin (1) and chrysin (2) showed the greatest activity [39]. Therefore, some structure-activity relationships can be assumed: the presence of 41-hydroxy group of flavonoid, no methyl substitution at C-41 and absence of continual substitution at positions 5, 6 and 7 of the flavonoid skeleton [39]. These results should be interpreted carefully, as these tests were carried out ex vivo on normal rat aortas, and differences can be observed after application of compounds or extracts to hypertonic animals or human. In general, lipophilic flavonoids (flavonoids aglycons or methoxylated and prenylated flavonoids) are synthesized by plants as a part of defence against microbial infection; therefore, they can be used for antimicrobial therapy in humans. Lipophilic flavonoids isolated from Ziziphora species like chrysin (2), acacetin (5) or thymonin (4) have antimicrobial effects and are components of, for example, propolis, a well-known antimicrobial active material [50,61]. Antibacterial flavonoids probably possess multiple cellular targets rather than one specific site of action. One of their actions at the molecular level is to form a complex with proteins through nonspecific forces such as hydrogen bonding and hydrophobic effects as well as by covalent bond formation. Thus, their mode of antimicrobial action may be related to their ability to inactivate microbial adhesins, enzymes, cell envelope transport proteins, and others [136]. Lipophilic flavonoids can also kill microbes by causing disruption of the microbial membranes [136]. Therefore, the presence of a number of lipophilic flavonoids can contribute to overall antibacterial effect of the traditional medicinal usage of Ziziphora extracts. As it is well known, inflammation is a normal biological process in response to tissue injury, microbial pathogen infection, and chemical irritation. Inflammation is initiated by migration of immune cells from the blood vessels and release of mediators at the site of damage. This process is followed by further recruitment of inflammatory cells and release of reactive oxygen and nitrogen species and pro-inflammatory cytokines to combat the cause of inflammation, and later to repair Molecules 2016, 21, 826 10 of 54 caused damage. Acute inflammatory process is rapid and self-limiting, but prolonged inflammation triggers chronic disorders. Natural products are often used to combat diseases connected with chronic inflammation [137,138]. The effectiveness of methanolic extract obtained from Z. clinopodioides for treating inflammatory bowel disease was tested in dextran sulphate-induced colitis model in mice. The parameters of inflammatory process were observed and it was found that the TNF-α level and NO level were decreased and level of antioxidative defence was restored to almost normal level [23]. Ziziphora is relatively rich in flavonoids, which can be considered responsible for the anti-inflammatory potential of this plant. Flavonoids like apigenin (1)[46], luteolin (3)[53,54], diosmin (7)[82], its aglycone diosmetin (6)[79] and linarin (8)[88,89] are reported to possess anti-inflammatory effects. Caffeic acid (17) and its derivatives are often connected with different therapeutical applications: their potential anticancer activity was well reviewed [98], their effects on the cardiovascular system were reviewed by Fuentes and Palomo [99] and a large review on general applications of caffeic acid (17) was published recently [100]. Similar activities were observed for caffeic acid ethylester (18). This compound showed antihypertensive, antioxidant and anti-inflammatory activities that can be connected with usage of Ziziphora against diseases of cardiovascular system [101–112]. Similarly, rosmarinic acid (19) possesses various activities, also connected with civilization diseases like cardiovascular system illnesses, chronic inflammations and cancer [113–116].

2.3. Triterpenes and Steroids There is not much information about triterpenes obtained from Ziziphora species, however, their presence is confirmed and some unpublished results showed their relatively high concentrations. The main triterpenic compounds identified till date in Ziziphora spp. are oleanolic acid (26), ursolic acid (27) and maslinic acid (28), together with daucosterol (29) as a representative of plant steroids. The bioactivity of all these compounds was well reviewed (with the exception of 29)[139,140]. Oleanolic acid (26) and maslinic acid (28) are representatives of β-amyrin type of pentacyclic triterpenes with the carboxyl group at position C-17 of the triterpenic skeleton. Both these compounds are relatively abundant in nature and are active components of many plants with medicinal properties. Oleanolic (26) and maslinic (28) acids and their derivatives are often used as components in medical drugs with effect on the cardiovascular system. These compounds help combat different so-called “civilization” diseases, for example cardiovascular diseases including atherosclerosis and diabetes, and even cancer. This could be because they have anti-inflammatory and antioxidative properties, and both cytoprotective and cytotoxic activity depending on the conditions and type of cells. Albeit, their activity is relatively indistinctive, and the multiple potentials of these triterpenes makes them good candidates for semi-synthesis and synthesis of potent drugs [141]. Ursolic acid (27) is an α-amyrin type of triterpene, again with carboxylic function at C-17. Similarly to oleanolic (26) and maslinic (28) acid, it can be isolated from several plant species with potent medicinal properties [142]. Similar to previously mentioned triterpenic acids, it shows activities beneficial in the treatment of civilization diseases like for example cancer, cardiovascular diseases or chronic inflammations [142]. Concerning the folk usage and effects of Ziziphora, oleanolic acid (26) and maslinic (28) acid have been found to affect the cardiovascular system. Both these compounds work against LDL oxidation, thus showing antiatherogenic properties. Oleanolic acid (27) also causes vascular smooth muscle relaxation. 28 acts as a strong antioxidant and possesses hypoglycemic properties; it was found to reduce the insulin resistance in the mouse model of genetic type 2 diabetes. 26 is also a potent antioxidant interfering with the glutathione redox cycle, affecting the Fenton reaction, NADPH oxidase, Nrf2 and others [142]. Its anti-inflammatory effects are connected mainly with interaction with NF-κB, STAT3 dimerization and overall inhibition of gene expression of pro-inflammatory factors (COX, iNOS) [142]. Molecules 2016, 21, 826 11 of 54

Table 2.MoleculesTriterpenic 2016, 21, 826 substances isolated from Kazakhstan Ziziphora species. (N.f.—not found). 11 of 53 Molecules 2016, 21, 826 11 of 53 Molecules 2016, 21, 826 11 of 53 Table 2. Triterpenic substances isolated from Kazakhstan Ziziphora species. (N.f.—not found). TableTriterpenes 2. Triterpenic and substances Sterols isolated from Kazakhstan Ziziphora species. (N.f.—not found). Molecules 2016, 21, 826 Table 2. Triterpenic substances isolated from Kazakhstan Ziziphora species. (N.f.—not found). 11 of 53 Triterpenes and Sterols Isolation/Detection in Triterpenes and Sterols Name of Compound and ID Name of Compound Isolation/Detection in Biological ActivityTriterpenes and Sterols Chemical Structure Kazakhstan spp. of ZiziphoraName of Compound Isolation/Detection in Biological Activity Chemical Structure Name ofand Compound ID KazakhstanIsolation/Detection spp. of Ziziphora in Table 2. Triterpenic substances isolated fromBiological Kazakhstan Activity Ziziphora species. (N.f.—not found). Chemical Structure and ID Kazakhstan spp. of Ziziphora Biological Activity Chemical Structure and ID Kazakhstan spp. of Ziziphora Triterpenes and Sterols Name of Compound Isolation/Detection in Biological Activity Chemical Structure and WeakID inhibitoryKazakhstan activity spp. of on Ziziphora NO production Weak inhibitory stimulated activity on by NO LPS production and IFN- stimulatedγ in RAWby LPS and 264.7 IFN- cellsγ in RAW [4] 264.7 cells [4] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] OH Oleanolic acid (26) Z. clinopodioides [4,80,143] WeakReview inhibitory on effect activityon vascular on NO functions production [140] stimulated by LPS and IFN-γ in RAW 264.7 cells [4] H OH Oleanolic acid (26) Z. clinopodioides [4,80,143]Oleanolic acidReview (26) on effectZ. clinopodioides on vascular [4,80,143] functions Review [140 on] effect on vascular functions [140] H OH Oleanolic acid (26) Z. clinopodioides [4,80,143] ReviewGeneral onreview effect on on bioactivity vascular functions and mechanisms [140] of effect [143,144] H General review on bioactivity and mechanismsGeneral review ofon bioactivity effect [143 and,144 mechanisms] of effect [143,144] O General review on bioactivity and mechanisms of effect [143,144] H H O Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] H H O HO H H OH Oleanolic acid (26) Z. clinopodioides [4,80,143] Review on effect on vascular functions [140] H HO General review on bioactivity and mechanisms of effect [143,144] HO O H H Weak inhibitory activity on NO production stimulatedγ by LPS and IFN-γ in RAW 264.7 cells [4] HO Weak inhibitory activity on NO productionWeak inhibitory stimulated activity on by NO LPS production and IFN- stimulatedin RAWby LPS and 264.7 IFN- cellsγ in RAW [4] 264.7 cells [4] WeakCytotoxicity inhibitory against activity HL-60 on andNO LLCproduction cell line stimulated [145] by LPS and IFN-γ in RAW 264.7 cells [4] Cytotoxicity against HL-60 and LLCCytotoxicity cell line [against145] HL-60 and LLC cell line [145] OH Ursolic acid (27) Z. clinopodioides [4,80,143] CytotoxicityRecent general against review HL-60 on bioactivity and LLC cell[142] line [145] H OH Ursolic acid (27) Z. clinopodioides [4,80,143] Ursolic acidRecent (27) generalZ. clinopodioides review on [4,80,143] bioactivity Recent [142 ]general review on bioactivity [142] H OH Ursolic acid (27) Z. clinopodioides [4,80,143] RecentGeneral general review review on bioactivity on bioactivity [146] [142] H GeneralWeak inhibitory review on activity bioactivity on NO [146] production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] O General review on bioactivity [146] GeneralReview onreview anticancer on bioactivity potential [146] [147,148] H O ReviewCytotoxicity on anticancer against HL-60 potential and [147,148] LLC cell line [145] H O Review on anticancer potential [147,Review148] on anticancer potential [147,148] H OH Ursolic acid (27) Z. clinopodioides [4,80,143] Recent general review on bioactivity [142] HO H HO General review on bioactivity [146] HO O Review on anticancer potential [147,148] H HO Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells [4] Weak inhibitory activity on NO productionWeakCytotoxicity inhibitory stimulated against activity HL-60 on by andNO LPS LLCproduction andcell line IFN- stimulated [145]γ in RAWby LPS and 264.7 IFN- cellsγ in RAW [4] 264.7 cells [4] OH Maslinic acid (28) Z. clinopodioides [4] Cytotoxicity against HL-60 and LLC cell line [145] H OH Maslinic acidCytotoxicity (28) againstZ. clinopodioides HL-60 [4] and LLCCytotoxicityRecent cell line review [against145 on bioactivity] HL-60 and [139,144] LLC cell line [145] HO H OH Maslinic acid (28) Z. clinopodioides [4] Recent review on bioactivity [139,144] H Maslinic acid (28) Z. clinopodioides [4] RecentReview review on anti-inflammatory on bioactivity [139,144] potential [149] HO O Recent review on bioactivity [139,144Review] on anti-inflammatory potential [149] HO H H O ReviewWeak inhibitory on anti-inflammatory activity on NO potential production [149] stimulated by LPS and IFN-γ in RAW 264.7 cells [4] O Review on anti-inflammatory potential [149] H H OH Cytotoxicity against HL-60 and LLC cell line [145] HO H H Maslinic acid (28) Z. clinopodioides [4] HO H Recent review on bioactivity [139,144] HHOO ImmunoregulatoryReview on anti-inflammatory effect [150] potential [149] O Immunoregulatory effect [150] H H ImmunoregulatoryAnti-inflammatory activityeffect [150] [151]; anti-inflammatory in ear edema assay [152]; topical anti-inflammatory activity in the Anti-inflammatory activity [151]; anti-inflammatory in ear edema assay [152]; topical anti-inflammatory activity in the Immunoregulatory effect [150] Anti-inflammatorymouse ear edema model activity [153]; [151]; weak anti-inflammatory 5-LOX inhibitory in activityear edema [154] assay [152]; topical anti-inflammatory activity in the mouse ear edema model [153]; weak 5-LOX inhibitory activity [154] HO mouseDPPH andear edemaABTS; modelscavenging [153]; effect weak [155]; 5-LOX antioxidant inhibitory [156]activity; inhibitory [154] effect on nitric oxide production in Anti-inflammatory activity [151]; anti-inflammatoryDPPH and ABTS; scavenging in ear effect edema [155]; assay antioxidant [152 [156]]; topical; inhibitory anti-inflammatory effect on nitric oxide production in DPPHLPS-activatedImmunoregulatory and ABTS; RAW264.7 scavenging effect cells[150] effect [157] [155]; antioxidant [156]; inhibitory effect on nitric oxide production in activity in the mouse ear edema modelLPS-activated [153]; weak RAW264.7 5-LOX cells [157] inhibitory activity [154] LPS-activatedAntinociceptiveAnti-inflammatory RAW264.7 [158] activity cells [151]; [157] anti-inflammatory in ear edema assay [152]; topical anti-inflammatory activity in the Antinociceptive [158] DPPH and ABTS; scavenging effect [AntinociceptiveSomemouse155]; anticomplementary ear antioxidant edema [158] model [[153];156 activity]; weak inhibitory [159] 5-LOX inhibitory effect activity on nitric [154] Some anticomplementary activity [159] oxide production in LPS-activated RAW264.7SomeNeuroprotectiveDPPH anticomplementary and ABTS; cells [160,161]; scavenging [157 ]activity promotion effect [159] [155]; of proliferation antioxidant of[156] neural; inhibitory stem cells effect [162]; on Inhibitionnitric oxide of production acetylcholinesterase in [163] Neuroprotective [160,161]; promotion of proliferation of neural stem cells [162]; Inhibition of acetylcholinesterase [163] NeuroprotectiveInhibitionLPS-activated of cancer RAW264.7 [160,161]; cell proliferation cells promotion [157] [164], of proliferation induction ofof apoptosisneural stem [165], cells antiproliferative [162]; Inhibition [166], of acetylcholinesterase cytotoxic [167]; [163] DaucosterolAntinociceptive (29) Z. clinopodioides [158] [44] Inhibition of cancer cell proliferation [164], induction of apoptosis [165], antiproliferative [166], cytotoxic [167]; Daucosterol (29) Z. clinopodioides [44] InhibitionantiproliferativeAntinociceptive of cancer activity[158] cell proliferation against HL-60, [164], K562, induction HepG2 of and apoptosis CNE-1 cell[165], lines antiproliferative [168] inhibition [166], of MDA-MB-231 cytotoxic [167]; cancer cell DaucosterolSome (29) anticomplementaryZ. clinopodioides [44] activity [159antiproliferative] activity against HL-60, K562, HepG2 and CNE-1 cell lines [168] inhibition of MDA-MB-231 cancer cell antiproliferativemigrationSome anticomplementary [169]; Abilityactivity to against activateactivity HL-60, [159]PPAR K562,γ and HepG2 PPARβ and [170] CNE-1 cell lines [168] inhibition of MDA-MB-231 cancer cell migration [169]; Ability to activate PPARγ and PPARβ [170] Neuroprotective [160,161]; promotionmigrationInhibitionNeuroprotective of proliferation [169];of α-glucosidase Ability [160,161]; to of activate [171]promotion neural PPAR stem of γproliferation and cells PPAR [162β of[170] neural]; Inhibition stem cells [162]; of acetylcholinesterase Inhibition of acetylcholinesterase [163] [163] Inhibition of α-glucosidase [171] Inhibition of cancer cell proliferationInhibitionAntibacterialInhibition [164], induction ofof αcancereffect-glucosidase against cell ofproliferation apoptosisE.[171] coli [172], [164], against [165 induction ],H. antiproliferativepylori of andapoptosis [165], antiproliferative [166], cytotoxic [166], [ 167cytotoxic]; [167]; GlcO Daucosterol (29) Z. clinopodioides [44] Daucosterol (29) Z. clinopodioides [44] Antibacterial effect against E. coli [172], against H. pylori and GlcO AntibacterialS.antiproliferative aureus [173]; effect against activity against E. againstcoli E. and coli HL-60,[172],S. aureus against K562, [174]; HepG2 H. against pylori and andBacillus CNE-1 subtilis cell lines and [168] S. aureus inhibition [175] of MDA-MB-231 cancer cell GlcO antiproliferative activity against HL-60,S. aureus K562, [173]; HepG2 against E. and coli and CNE-1 S. aureus cell [174]; lines against [168 Bacillus] inhibition subtilis and of S. aureus [175] S.Inhibitorymigration aureus [173]; effect[169]; against onAbility reverse E. to coli activate transcriptase and S. PPARaureus [176]γ [174]; and PPAR againstβ [170] Bacillus subtilis and S. aureus [175] MDA-MB-231 cancer cell migration [Inhibitory169]; Ability effect on to reverse activate transcriptase PPAR [176]γ and PPARβ [170] InhibitorySuppressionInhibition effectof ofα-glucosidase HCl/ethanol-induced on reverse transcriptase[171] gastric [176] lesions [177] α Suppression of HCl/ethanol-induced gastric lesions [177] Inhibition of -glucosidase [171] SuppressionInhibitoryAntibacterial activity of effect HCl/ethanol-induced against against osteoclast E. coli [172], differentiationgastric against lesions H. pylori by[177] suppressing and TRAP activity in RANKL-induced RAW 264.7 GlcO Inhibitory activity against osteoclast differentiation by suppressing TRAP activity in RANKL-induced RAW 264.7 Antibacterial effect against E. coli [172InhibitorymacrophageS.], aureus against [173]; activity cells H.against [178] against pylori E. coliosteoclastand and S.S. aureusdifferentiation aureus [174];[173 against by]; suppressing Bacillus subtilis TRAP and activity S. aureus in RANKL-induced [175] RAW 264.7 macrophage cells [178] against E. coli and S. aureus [174]; againstmacrophageInhibitoryBacillus effect cells on [178] subtilis reverse andtranscriptaseS. aureus [176] [175] Suppression of HCl/ethanol-induced gastric lesions [177] Inhibitory effect on reverse transcriptase [176] Inhibitory activity against osteoclast differentiation by suppressing TRAP activity in RANKL-induced RAW 264.7

Suppression of HCl/ethanol-inducedmacrophage gastric lesions cells [178] [ 177] Inhibitory activity against osteoclast differentiation by suppressing TRAP activity in RANKL-induced RAW 264.7 macrophage cells [178] Molecules 2016, 21, 826 12 of 54

Ziziphora species extracts are also connected with antibacterial effect, and the activity of ursolic acid (27) was proven against numerous Gram-positive and Gram-negative bacteria, including vancomycin-resistant Enterococcus and different Mycobacterium tuberculosis strains. Some antiviral, anti-parasitic and antifungal activity was also observed [142]. However, the authors of the majority of the cited papers are right in that more studies should be carried out to prove these effects in vivo in humans [144]. Daucosterol (29) is a natural phytosterol—a glucoside derived form β-sitosterol. As we did not find relevant information about its bioactivity, we tried to summarise its effects in Table2. Several activities of daucosterol (29) are again in accordance with therapeutic potential of Ziziphora species observed both in folk medicine and scientific studies. The anti-inflammatory effect of daucosterol (29) was observed both in vitro and in vivo [152,153] and a 5-LOX inhibitory effect was observed [154]. Daucosterol (29) also acts as scavenger of free radicals in vitro [155] and as an antioxidant [156] and it inhibits nitric oxide production in LPS-activated RAW264.7 cells [157]. Furthermore, 29 showed antiproliferative [164,166] and cytotoxic [167] activity against different cancer cell lines; it induces apoptosis [165] and inhibits MDA-MB-231 cancer cell migration [169]. Some antimicrobial activities of 29 were observed, mainly against E. coli, S. aureus and H. pylori. The inhibition of H. pylori growth can be beneficial in the treatment of gastric ulcer lesions, because daucosterol (29)-mediated suppression of HCl/ethanol-induced gastric lesions was observed by Jeong et al. [177].

2.4. Essential Oil The essential oils are probably the most studied part of Ziziphora phytochemical components (Table3). As could be expected for Lamiaceae, these essential oils are predominantly composed of monoterpenic compounds; however, several sesquiterpenic substances and some other compounds were also identified by GC-MS analysis (see Table3). The hydrodistillation is the commonly used method for obtaining Ziziphora essential oils, but the method used for obtaining Z. tenuior essential oil by supercritical fluid extraction (SFE) with higher yield was also published [179]. It is clear that the relative ratios of components vary according to the frequently occurring chemotypes in the family Lamiaceae, environmental factors, geographic origin and also extraction method [180–182]. For example, although we can see biochemical convergence among the Z. clinopodioides from different locations, owing to the frequent occurrence of chemotypes, different patterns in the composition of the oils are common. As mentioned above, the variability of essential oils components in Ziziphora species is really high and chemovars of one species can be found in very related habitats, as showed for example by Khodaverdi-Samani et al., who identified several chemovars of Z. clinopodioides ssp. rigida in limited area of southwestern Iran (Alpine type mountains). The essential oils obtained by hydro-distillation (content ranged from 0.12 to 0.98 mL/100 g of dry weight) were analyzed by GC and GC/MS to prove that the main chemical compositions were pulegone (53) (5.19% to 57.85%), limonene (38) (0.26% to 12.79%), 1,8-cineole (72) (0.00% to 27.4%), bornyl acetate (69) (0.47% to 9.37%), piperitenone (46) (0.70% to 9.05%) and menthol derivatives (for example 58)[19]. Other study revealed Z. clinopodioides as plant rich in carvacrol (73) 52.7%, linalool (66) 15.9% and menthol (56) 14% [183]. Further literature survey indicated that the oils of Ziziphora species have been found to be rich in pulegone (53) and thymol (62), but there are also analysis showing low or no concentration of these substances in Z. clinopodioides essential oil [184]. The composition of Z. clinopodioides essential oil is strongly influenced by flowering stage [182]. Also, the composition of Z. tenuior and Z. pamiroalaica essential oil may vary strongly [185]. Z. bungeana and Z. clinopodioides were analysed by the same group [185], same as Z. vychodceviana [186]. Molecules 2016, 21, 826 13 of 54

Table 3. Mono and sesquiterpenic substances isolated from Kazakhstan Ziziphora species (N.f.—not found). Molecules 2016, 21, 826 13 of 53 Molecules 20162016,, 2121,, 826826 1313 ofof 5353 Monoterpenes Table 3. Mono and sesquiterpenic substances isolated from Kazakhstan Ziziphora species (N.f.—not found). Isolation/Detection in Kazakhstan Table 3. MonoMono andand sesquiterpenicsesquiterpenic substasubstances isolated from Kazakhstan Ziziphora speciesspecies (N.f.—not(N.f.—not found).found). Name of Compound and ID spp. of Ziziphora (Percentage Biological ActivityMonoterpenes Chemical Structure Monoterpenes Content when Given) Isolation/Detection in Kazakhstan Isolation/DetectionIsolation/Detection inin KazakhstanKazakhstan Name of Compound and ID Moleculesspp. of 2016 Ziziphora, 21, 826 (Percentage Biological Activity Chemical Structure 13 of 53 Name of Compound and ID spp.spp. ofof Ziziphora (Percentage(Percentage Biological Activity Chemical Structure Content when Given) Z. clinopodioides (0.6%–1.9%) Content when Given) Antibacterial,Z. clinopodioides antitermitic, (0.6%–1.9%) antifungal Table [187Antibacterial, 3. ]Mono and antitermitic,sesquiterpenic antifungal substances [187] isolated from Kazakhstan Ziziphora species (N.f.—not found). [9,15,185] Z. clinopodioides (0.6%–1.9%)(0.6%–1.9%) Antibacterial, antitermitic, antifungal [187] Antioxidant (DPPH)[9,15,185] [188] Antioxidant (DPPH) [188] [9,15,185][9,15,185] Antioxidant (DPPH) [188] Monoterpenes Some cytotoxic activity [189] Isolation/DetectionSomeSome cytotoxiccytotoxic in Kazakhstan activityactivity [189][189] Name of Compound and ID spp. ofSome Ziziphora cytotoxic (Percentage activity [189] Biological Activity Chemical Structure Low fumigantZ. clinopodioides activity subsp.subsp. against rigidarigida various (0.2%)(0.2%) speciesLowLow fumigantfumigant of insects activityactivity [ 190 againstagainst,191 variousvarious] speciesspecies ofof insectsinsects [190,191][190,191] Z. clinopodioides Z. clinopodioides subsp. rigida (0.2%) ContentLow whenfumigant Given) activity against various species of insects [190,191] subsp. [21][21] Sedative and motor relaxant effects in mice [192] Sedative and motor relaxant[21] effectsZ. in clinopodioides miceSedativeSedative [192 (0.6%–1.9%) andand] motormotor relaxantrelaxantAntibacterial, effectseffects antitermitic, inin micemice [192][192] antifungal [187] rigida (0.2%) [21] Anti-inflammatory activity in the mouse model of pleurisy induced by LPS [193] Anti-inflammatory activity in the mouseAnti-inflammatory model[9,15,185] of pleurisy activityAntioxidant induced in the (DPPH)mouse by [188] LPSmodel [193 of pleurisy] induced by LPS [193] Myrcene (syn. β-myrcene) (30) Myrcene (syn. ProtectiveProtective effecteffect againstagainstSome tt-BOOH-BOOH cytotoxic inducedinduced activity mutagenesismutagenesis[189] [194][194] Myrcene (syn. Protective effect against t-BOOH inducedZ. clinopodioidesProtective mutagenesis subsp. effectrigida (0.2%) against [ 194Low t-BOOH] fumigant induced activity againstmutagenesis various species [194] of insects [190,191] ββ-myrcene)-myrcene) ((3030)) Z. clinopodioides subsp. bungeana ImmunomodulatoryImmunomodulatory andand protectiveprotective effectseffects agaiagainstnst thethe immunotoxicityimmunotoxicity inducedinduced byby TCDDTCDD inin β-myrcene) (30) Z. clinopodioides subsp.subsp. bungeanabungeana Immunomodulatory[21] and protective effects against the immunotoxicity induced by TCDD in Immunomodulatory(0.3%) and [201] protective effectsrats [195]; against antioxidant the immunotoxicity activitySedative againstand motor TCDD-induced relaxant induced effects byin miceoxidative TCDD [192] stress in rats in rats [195 liver]; [196]; Z. clinopodioides subsp. (0.3%) [201] ratsrats [195];[195]; antioxidantantioxidant activityactivityAnti-inflammatory againstagainst TCDD-inducedTCDD-induced activity in the mouse oxidativeoxidative model of pleurisystressstress in ininduced ratsrats liverliver by LPS [196];[196]; [193] antioxidant activity(0.3%) against [201] TCDD-inducedneuroprotective oxidative after stress global in cerebral rats liver ischemia [196/reperfusion-mediated]; neuroprotective oxidative after and neuronal bungeana (0.3%) [201] Myrcene (syn. neuroprotectiveneuroprotective afterafter globalglobalProtective cerebralcerebral effect againstischemiaischemia t-BOOH/reperfusion-mediated/reperfusion-mediated induced mutagenesis [194] oxidativeoxidative andand neuronalneuronal β-myrcene) (30) Z. clinopodioidesdamage subsp. in mouse bungeana [197] Immunomodulatory and protective effects against the immunotoxicity induced by TCDD in global cerebral ischemia/reperfusion-mediateddamagedamage inin oxidative mousemouse [197][197] and neuronal damage in mouse [197] Gastroprotective(0.3%) [201] effect againstrats [195]; various antioxidant ulcerogenic activity against agents TCDD-induced [198] oxidative stress in rats liver [196]; Gastroprotective effect against various ulcerogenicGastroprotective agents effect against [198] various ulcerogenic agents [198] Z. tenuior (0.1%)(0.1%) [179,202][179,202] Analgesic activity reviewedneuroprotective [199] after global cerebral ischemia/reperfusion-mediated oxidative and neuronal Z. tenuior (0.1%) [179,202] Analgesic activity revieweddamage [199] in mouse [197] Analgesic activity reviewed [199] Review on metabolism and toxicity [200] Z. tenuior (0.1%) [179,202] Review on metabolism andGastroprotective toxicity [200] effect against various ulcerogenic agents [198] Review on metabolism and toxicity [Z.200 tenuior] (0.1%) [179,202] Analgesic activity reviewed [199] Review on metabolism and toxicity [200] Z. clinopodioides (1.1%)(1.1%) [184][184] Z. clinopodioides (1.1%) [184] Antibacterial [187] Z. clinopodioidesAntibacterial (1.1%) [187][184] Z. clinopodioides (1.1%) [184] Antifungal (Candida strains, Cryptococcus neoformans, Epidermophyton floccosum, Microsporum (Z)-β-Ocimene (31Antibacterial) [187] Antifungal (Candida strains,strains,Antibacterial Cryptococcus [187] neoformans,, EpidermophytonEpidermophyton floccosumfloccosum,, Microsporum (Z)-(Z)-ββ--Ocimene (3131)) canis and M. gypseum, TrychophytonAntifungal (Candida mentagrophytes strains, Cryptococcus and T. neoformans verrucosum, Epidermophyton, Aspergillus floccosum flavus, ,Microsporum A Antifungal (Candida(Z)-β-Ocimenestrains, (31) Cryptococcuscanis neoformans and M. gypseum, Epidermophyton, Trychophyton mentagrophytes floccosum, Microsporum and T. verrucosum canis, Aspergillusand M. flavus gypseum, A , (Z)-β-Ocimene (31) Z. clinopodioides subsp. bungeana canis and M. gypseum, Trychophytoncanis and M. gypseum mentagrophytes, Trychophyton and mentagrophytes T. verrucosum and T., verrucosumAspergillus, Aspergillus flavus, A flavus , A Z. clinopodioides subsp.subsp. bungeanabungeana fumigatusfumigatus,, A. niger)) [203,204][203,204] Trychophyton mentagrophytes[201] and T.Z. verrucosum clinopodioidesfumigatus subsp., ,Aspergillus A. bungeana niger) [203,204]fumigatus flavus ,, A.A niger fumigatus) [203,204] , A. niger)[203,204] Z. clinopodioides subsp. bungeana [201] [201][201] [201]

Antifungal (Candida strains, Cryptococcus neoformans, Epidermophyton floccosum, Microsporum Antifungal (Candida strains, Cryptococcus neoformans, Epidermophyton floccosum, Microsporum (E)-β-Ocimene (32) Z. clinopodioidesAntifungal (1.2%) (Candida [184] strains,strains,canis and Cryptococcus M. gypseum, neoformansTrychophyton ,,mentagrophytes EpidermophytonEpidermophyton and T. floccosumfloccosum verrucosum,, , Microsporum Aspergillus flavus , A (E)-β-Ocimene (32Antifungal) (Z.Candida clinopodioidesstrains, (1.2%)Cryptococcus [184] canis neoformans and M. gypseum, Epidermophyton, Trychophytonfumigatus, A. niger mentagrophytes ﬂoccosum) [203,204] , Microsporumand T. verrucosum canis, Aspergillusand M. flavus gypseum, A , (E)-β-Ocimene (32) Z. clinopodioides (1.2%)(E)-(E)- [184ββ-Ocimene-Ocimene] ((3232)) Z. clinopodioides (1.2%)(1.2%) [184][184] caniscanis andand M. gypseum,, TrychophytonTrychophyton mentagrophytesmentagrophytes andand T.T. verrucosumverrucosum,, Aspergillus flavus,, A Trychophyton mentagrophytes and T. verrucosumfumigatus, ,Aspergillus A. niger) [203,204] ﬂavus , A fumigatus, A. niger)[203,204] fumigatusfumigatus,, A. niger)) [203,204][203,204]

3,7-Dimethyl-1,3,7-octa-triene Z. tenuior [94] n.f. (33)

3,7-Dimethyl-1,3,7-octa-triene3,7-Dimethyl-1,3,7-octa-triene 3,7-Dimethyl-1,3,7-octa-triene Z. tenuior [94][94] n.f.n.f. 3,7-Dimethyl-1,3,7-octa-triene (33) Z. tenuior [94]((3333)) n.f. Z. tenuior [94] n.f. (33) Z. clinopodioides (0.1%–1.2%) α-Thujene (34) n.f. [15,184]

Molecules 2016, 21, 826 14 of 53 Z. clinopodioides (0.1%–1.2%)(0.1%–1.2%) α-Thujene-Thujene ((3434)) Z. clinopodioides (0.1%–1.2%) n.f.n.f. Z. clinopodioides (0.1%–1.2%)α-Thujene [15,184 ](34) Z. clinopodioides[15,184][15,184] subsp. rigida (0.1%) n.f. [15,184][21] Z. clinopodioides subsp. Z. clinopodioides subsp. bungeana rigida (0.1%) [21] [201] α-Thujene (34) n.f. Z. clinopodioides subsp. bungeana [201] Z. tenuior (0.48%) [94,179] Z. tenuior (0.48%) [94,179]

Insecticidal activity against various species of insects [192,193]; larvicidal activity against various mosquito species [205,206] Antinociceptive activity assessed in various chemical-induced nociception models in rodents [207,208] α-Phellandrene (35) Z. clinopodioides (0.3%) [184] Antidepressant activity in rats [208] Induction of autophagy in human liver tumour cells [209]; induction of necrosis [210]; induction of apoptosis in mice leukaemia WEHI-3 cells in vitro [211]; promotion of the immune response by increasing the level of T-cells, monocytes and macrophages in BALB/c mice in vivo [212] Z. clinopodioides (2.0%) [184] Inhibition of P-glycoprotein-mediated transport of different substances [213] Z. clinopodioides subsp. rigida [21] Suppression of CNS in mice [214,215] Some topical anti-inflammatory activity in carrageenan-induced paw edema in rats [216] Antioxidant activity in various free radical scavenging tests [217,218] α-Terpinene (36) Antifungal activity tested against some food spoilage yeasts [219] Z. clinopodioides subsp. bungeana Larvicidal activity against mosquitoes Aedes aegypti and A. albopictus [206] (0.1%) [201] Antiviral activity against herpes simplex virus type 1 in vitro [220] Review on some effects on cardiovascular system [221] Trypanocidal activity against Trypanosoma evansi [222] Z. clinopodioides (0.1%–0.2 %) [184] Inhibition of P-glycoprotein-mediated transport of different substances [213] Z. clinopodioides subsp. rigida (0.5%) Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 [21] macrophages) [223] Z. clinopodioides subsp. bungeana Terpinolene (37) Inhibition of acetylcholinesterase and butyrylcholinesterase [224] (0.1%) [201] Suppression of CNS in mice [214,215,225] Antiproliferative (tested on primary rat neurons and N2a neuroblastoma cells) [226]; Z. tenuior (0.19%) [94,179] antiproliferative effect on K562 cells [227]; some cytotoxic activity [190]

Insecticidal activity against Callosobruchus chinensis and Sitophilus oryzae [228]; larvicidal activity tested against various mosquito species [205,206,229] Antioxidant activity in various free radical scavenging tests [217,218]; protective effect

against LDL-oxidation [230] Review on some effects on cardiovascular system [221] Antiviral activity against inﬂuenza A⁄PR⁄8 virus subtype H1N1 [231] Limonene (38) Z. tenuior (0.51%–7.82%) [232]

Molecules 2016, 21, 826 14 of 54

Molecules 2016, 21, 826 14 of 53 Molecules 2016, 21, 826 14 of 53 Z. clinopodioides subsp.Table rigida (0.1%) 3. Cont. Molecules 2016, 21, 826 [21] 14 of 53 Z. clinopodioides subsp. rigida (0.1%) Z. clinopodioides subsp. bungeana [21] Z. clinopodioides[201] subsp. rigida (0.1%) Z. clinopodioides subsp.Monoterpenes bungeana [21] [201] Isolation/Detection in Kazakhstan Z. clinopodioides subsp. bungeana Z. tenuior (0.48%) [94,179] Name of Compound and ID spp. of Ziziphora (Percentage [201] Biological Activity Chemical Structure Content when Given) Z. tenuior (0.48%) [94,179] Insecticidal activity against various species of insects [192,193]; larvicidal activity against Z. tenuior (0.48%) [94,179] Insecticidal activity against various speciesvarious of mosquito insects [species192,193 [205,206]]; Insecticidal activity against various species of insects [192,193]; larvicidal activity against larvicidal activity against various mosquitoAntinociceptive species [activity205,206 assessed] in various chemical-induced nociception models in various mosquito species [205,206] Antinociceptive activity assessed in variousInsecticidalrodents chemical-induced [207,208] activity against various nociception species ofmodels insects [192,193]; in rodents larvicidal [207 activity,208] against Antinociceptive activity assessed in various chemical-induced nociception models in α α-Phellandrene (35) Z. clinopodioides (0.3%) [184] variousAntidepressant mosquito activity species in [205,206] rats [208] -Phellandrene (35) Z. clinopodioides (0.3%) [184] Antidepressant activity in rats [208] rodents [207,208] AntinociceptiveInduction of autophagy activity inassessed human in liver variou tumours chemical-induced cells [209]; induction nociception of necrosis models [210]; in α-Phellandrene (35Induction) ofZ. autophagy clinopodioides in(0.3%) human [184] liverAntidepressant tumour cells activity [209]; in induction rats [208] of necrosis [210]; induction of apoptosis in inductionrodents [207,208] of apoptosis in mice leukaemia WEHI-3 cells in vitro [211]; promotion of the mice leukaemia WEHI-3 cells in vitro [211Induction]; promotion of autophagy of the in huma immunen liver responsetumour cells by [209]; increasing induction of the necrosis level [210]; of T-cells, α-Phellandrene (35) Z. clinopodioides (0.3%) [184] immuneAntidepressant response activity by increasing in rats [208] the level of T-cells, monocytes and macrophages in BALB/c monocytes and macrophages in BALB/cinduction mice in of vivoapoptosis [212 in] mice leukaemia WEHI-3 cells in vitro [211]; promotion of the miceInduction in vivo of [212] autophagy in human liver tumour cells [209]; induction of necrosis [210]; immune response by increasing the level of T-cells, monocytes and macrophages in BALB/c Z. clinopodioides (2.0%) [184] inductionInhibition ofof apoptosisP-glycoprotein-mediated in mice leukaemia transport WEHI-3 of cellsdifferent in vitro substances [211]; promotion [213] of the mice in vivo [212] Z. clinopodioides (2.0%) [184] InhibitionZ. of clinopodioides P-glycoprotein-mediated subsp. rigida [21] transportimmuneSuppression response of of differentCNS by in increasing mice substances [214,215] the level [of213 T-cells,] monocytes and macrophages in BALB/c Z. clinopodioides (2.0%) [184] Inhibition of P-glycoprotein-mediated transport of different substances [213] Suppression of CNS in mice [214,215] miceSome in topical vivo [212] anti-inflammatory activity in carrageenan-induced paw edema in rats [216] Z. clinopodioides subsp. rigida [21] Suppression of CNS in mice [214,215] Some topicalZ. anti-inflammatoryclinopodioides (2.0%) [184] activity AntioxidantInhibition in carrageenan-induced of activityP-glycoprotein-mediated in various free paw radical transport edema scavenging inof different rats tests [216 [217,218]substances] [213] Some topical anti-inflammatory activity in carrageenan-induced paw edema in rats [216] α-Terpinene (36) Z. clinopodioides subsp. rigida [21] AntifungalSuppression activity of CNS tested in mice against [214,215] some food spoilage yeasts [219] Z. clinopodioides subsp. rigida [21] AntioxidantZ. clinopodioides activity in subsp. various bungeana free radicalAntioxidant scavenging activity testsin various [217 free,218 radical] scavenging tests [217,218] LarvicidalSome topical activity anti-inflammatory against mosquitoes activity Aedes in carrageenan-induced aegypti and A. albopictus paw [206] edema in rats [216] α-Terpinene (36) α-Terpinene (36) Antifungal activity(0.1%) tested [201] against someAntifungal food spoilage activity yeasts tested against [219] some food spoilage yeasts [219] Z. clinopodioides subsp. bungeana AntiviralAntioxidant activity activity against in various herpes free simplex radical virus scavenging type 1 in tests vitro [217,218] [220] Larvicidal activity against mosquitoes AedesLarvicidal aegypti activityand againstA. albopictus mosquitoes[ Aedes206] aegypti and A. albopictus [206] α-Terpinene (36) (0.1%) [201] ReviewAntifungal on someactivity effects tested on against cardiovascular some food system spoilage [221] yeasts [219] Z. clinopodioides subsp. bungeana Antiviral activity against herpes simplex virus type 1 in vitro [220] Z. clinopodioides subsp. Antiviral activity against herpes simplexTrypanocidalLarvicidal virus type activity activity 1 inagainst vitroagainst mosquitoes [220 Trypanosoma] Aedes evansi aegypti [222] and A. albopictus [206] (0.1%) [201] Review on some effects on cardiovascular system [221] bungeana (0.1%) [201] Review onZ. someclinopodioides effects (0.1%–0.2 on cardiovascular %) [184] Antiviral system activity [221 against] herpes simplex virus type 1 in vitro [220] TrypanocidalInhibition of P-glycoprotein-mediated activity against Trypanosoma transport evansi of [222] different substances [213] TrypanocidalZ. clinopodioides activity subsp. against rigidaTrypanosoma (0.5%) Review evansi on some[222 effects] on cardiovascular system [221] Z. clinopodioides (0.1%–0.2 %) [184] Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 [21] InhibitionTrypanocidal of P-glycoprotein-mediated activity against Trypanosoma transport evansi of [222] different substances [213] Z. clinopodioides subsp. rigida (0.5%) macrophages) [223] Z. clinopodioides (0.1%–0.2 %) [184] Z.Z. clinopodioides clinopodioides (0.1%–0.2 subsp. bungeana %) [184] Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 Terpinolene (37) Inhibition of P-glycoprotein-mediated[21] transportInhibition of of P-glycoprotein-mediatedacetylcholinesterase different substances and butyrylcholinesterase transport [213] of different [224]substances [213] Z. clinopodioides(0.1%) subsp. [201] r igida (0.5%) macrophages) [223] Z. clinopodioides subsp. Anti-inflammatoryZ. clinopodioides (inhibition subsp. bungeana of NO productionSuppressionAnti-inflammatory inof CNS LPS-stimulated (inhibition in mice [214,215,225] of NO RAW-264.7 production in macrophages)LPS-stimulated RAW-264.7 [223] Terpinolene (37) [21] Inhibition of acetylcholinesterase and butyrylcholinesterase [224] (0.1%) [201] Antiproliferativemacrophages) [223] (tested on primary rat neurons and N2a neuroblastoma cells) [226]; rigida (0.5%) [21] InhibitionZ. of clinopodioidesZ. acetylcholinesterase tenuior (0.19%) subsp. [94,179] bungeana and butyrylcholinesteraseSuppression of CNS in mice [224 [214,215,225]] Terpinolene (37) Terpinolene (37) antiproliferativeInhibition of acetylcholinesterase effect on K562 cells and [227]; butyrylcholinesterase some cytotoxic activity [224] [190] Suppression of CNS(0.1%) in mice[201] [214,215,225Antiproliferative] (tested on primary rat neurons and N2a neuroblastoma cells) [226]; Z. clinopodioides subsp. Z. tenuior (0.19%) [94,179] Suppression of CNS in mice [214,215,225] Antiproliferative (tested on primary ratantiproliferativeInsecticidal neurons andactivity effect N2a against on neuroblastoma K562 Callosobruchus cells [227]; chinensissome cells) cytotoxic[ and226 Sitophilus]; activity oryzae[190] [228]; larvicidal bungeana (0.1%) [201] Antiproliferative (tested on primary rat neurons and N2a neuroblastoma cells) [226]; antiproliferativeZ. tenuior effect (0.19%) on K562 [94,179] cells [227activity]; some tested cytotoxic against various activity mosquito [190] species [205,206,229] Insecticidalantiproliferative activity effect against on K562 Callosobruchus cells [227]; chinensissome cytotoxic and Sitophilus activity oryzae[190] [228]; larvicidal Z. tenuior (0.19%) [94,179] Antioxidant activity in various free radical scavenging tests [217,218]; protective effect activity tested against various mosquito species [205,206,229] againstInsecticidal LDL-oxidation activity against [230] Callosobruchus chinensis and Sitophilus oryzae [228]; larvicidal Insecticidal activity against CallosobruchusAntioxidant chinensis activityand inSitophilus various free oryzae radical[ 228scavenging]; tests [217,218]; protective effect activityReview testedon some against effects various on cardiovascular mosquito species system [205,206,229] [221] against LDL-oxidation [230] larvicidal activity tested against variousAntioxidantAntiviral mosquito activity activity species against in various [ 205influenza,206 free, 229Aradical⁄PR]⁄8 virus scavenging subtype tests H1N1 [217,218]; [231] protective effect Review on some effects on cardiovascular system [221] Limonene (38) AntioxidantZ. activity tenuior (0.51%–7.82%) in various [232] free radicalagainst scavenging LDL-oxidation tests [230] [217 ,218]; protective effect against LDL-oxidation [230] Antiviral activity against influenza A⁄PR⁄8 virus subtype H1N1 [231] Review on some effects on cardiovascularReview system on some [221 effects] on cardiovascular system [221] Limonene (38) Z. tenuior (0.51%–7.82%) [232] Antiviral activity against influenza A⁄PR⁄8Antiviral virus activity subtype against H1N1 influenza [231 A] ⁄PR⁄8 virus subtype H1N1 [231] Limonene (38) Z. tenuior (0.51%–7.82%) [232]

Molecules 2016, 21, 826 15 of 54

Table 3. Cont.

Monoterpenes Isolation/Detection in Kazakhstan Name of Compound and ID spp. of Ziziphora (Percentage Biological Activity Chemical Structure Content whenMolecules Given) 2016, 21, 826 15 of 53 Molecules 2016, 21, 826 15 of 53 Molecules 2016,, 21,, 826826 15 of 53 Insecticidal (against red imported ﬁre ant)Insecticidal [233] (against red imported fire ant) [233] Z. tenuior (0.51%–7.82%) [232] Fumigation activity against stored-productFumigation pestinsects activity against [234] stored-product pest insects [234] Insecticidal (against red imported fire ant) [233] AnxiolyticInsecticidal effect (against in mice red imported[225] fire ant) [233] Anxiolytic effect in mice [225] Fumigation activity against stored-product pest insects [234] GastroprotectiveFumigation activity in ratsagainst [235] stored-product pest insects [234] GastroprotectiveZ. clinopodioides in rats [235 [11,15]] Anxiolytic effect in mice [225] Limonene (38) PharmacologicalAnxiolytic effect inimportance mice [225] and properties reviewed [190,236,237] Pharmacological importance and propertiesGastroprotective reviewed in [rats190 [235],236 ,237] Z. clinopodioides [11,15][11,15] AnalgesicGastroprotective activity in reviewed rats [235] [199] Analgesic activityZ. clinopodioides reviewed [11,15][11,15] [199 ] Pharmacological importance and properties reviewed [190,236,237] ReviewPharmacological on some effectsimportance on cardiovascular and properties system reviewed [221] [190,236,237] Z. clinopodioides [11,15] Analgesic activity reviewed [199] Review on some effects on cardiovascularReviewAnalgesic system on activity metabolism [221 reviewed] and toxicity[199] [200] Review on some effects on cardiovascular system [221] Review on metabolism and toxicity [200Review] on some effects on cardiovascular system [221] Review on metabolism and toxicity [200] Review on metabolism and toxicity [200]

p-Mentha-1(7,8)-diene (syn. Z. tenuior (0.04%) [179] n.f. pseudolimonene) (39) p-Mentha-1(7,8)-diene p-Mentha-1(7,8)-diene (syn. Z. tenuior (0.04%)p-Mentha-1(7,8)-diene [179] n.f.(syn. Z. tenuior (0.04%)(0.04%) [179][179] n.f. pseudolimonene) (39) Z. tenuior (0.04%)(0.04%) [179][179] n.f. (syn. pseudolimonene) (39) pseudolimonene) (39)

Z. tenuior (1.65%) [179]

Z. tenuior (1.65%)(1.65%) [179][179] Z. tenuior (1.65%)(1.65%) [179][179] Z. tenuior (1.65%) [179] p-Mentha-3,8-diene (40) Z. clinopodioides subsp. bungeana n.f. [201] p-Mentha-3,8-diene (40) Z. clinopodioides subsp.subsp. bungeana n.f. p-Mentha-3,8-diene (40) p-Mentha-3,8-diene (n.f.40) Z. clinopodioides subsp.subsp. bungeana n.f. [201] Z. clinopodioides subsp. bungeana [201] [201]

4-Methyl-1-(1-methyl-ethenyl)- cyclohexene (syn. 3,8-p- Z. tenuior [94] n.f. 4-Methyl-1-(1-methyl-ethenyl)- 4-Methyl-1-(1-methyl-ethenyl)- 4-Methyl-1-(1-methyl-ethenyl)-menthadiene) (41) cyclohexene (syn. 3,8-p- Z. tenuior [94][94] n.f. cyclohexene (syn. Z. tenuior [94cyclohexene] (syn. 3,8- n.f.p- Z. tenuior [94][94] n.f. menthadiene) (41) 3,8-p-menthadiene) (41) menthadiene) (41)

3-Methyl-6-(1-methylethylidene)-cyclohexene (syn. 3-Methyl-6-(1-methyl- Z. tenuior [94] n.f. 3-Methyl-6-(1-methyl-Isoterpinolene, 2,4-p- 3-Methyl-6-(1-methyl-ethylidene)- ethylidene)-cyclohexene (syn. ethylidene)-cyclohexenementhadiene) (42) (syn. Z. tenuior [94][94] n.f. cyclohexene (syn. Isoterpinolene, Z. tenuior [94]Isoterpinolene, 2,4- n.f.p- Z. tenuior [94][94] n.f. Isoterpinolene, 2,4-p- p 42 menthadiene) (42) 2,4- -menthadiene) ( ) menthadiene) (42)

3-Isopropenyl-5,5-di-methyl- Z. tenuior [94] n.f. cyclopentene (43) 3-Isopropenyl-5,5-di-methyl- 3-Isopropenyl-5, 3-Isopropenyl-5,5-di-methyl- Z. tenuior [94][94] n.f. Z. tenuior [94]cyclopentene (43)n.f. Z. tenuior [94][94] n.f. 5-di-methyl-cyclopentene (43) cyclopentene (43)

Molecules 2016, 21, 826 16 of 54

Table 3. Cont.

Monoterpenes Isolation/Detection in Kazakhstan Molecules 2016,, 21,, 826826 16 of 53 Name of Compound and ID spp. of ZiziphoraMolecules(Percentage 2016, 21, 826 Biological Activity Chemical Structure 16 of 53 Content when Given) Molecules 2016, 21, 826 16 of 53 Antifungal effect against C. albicans,, synergysynergy withwith fluconazolfluconazol [239];[239]; antimicrobialantimicrobial activityactivity Antifungal effect against C. albicans, synergyAntifungalagainst withtested effect ﬂuconazolstrains against of bacteria, C. albicans [239 yeast];, antimicrobialsynergy and pathogenic with fluconazol activity fungi [240,241][239]; antimicrobial activity Antifungal effect against C. albicans, synergy with fluconazol [239]; antimicrobial activity against tested strains of bacteria, yeast andagainstInsecticidal pathogenic tested activity strains tested fungi of bacteria, against [240 ,yeast 241various] and st pathogenicored grain fungipests and[240,241] vectors [242]; moderate Menthone (44) Z. clinopodioides (6.2%–13.3%)(6.2%–13.3%) [238][238] against tested strains of bacteria, yeast and pathogenic fungi [240,241] Insecticidalinsecticidalinsecticidal activityactivity againsttestedagainst against Sitophilus various zeamais stored [243][243] grain pests and vectors [242]; moderate Menthone (44) Z. clinopodioides (6.2%–13.3%)Menthone [238] (44) InsecticidalZ. clinopodioides activity tested (6.2%–13.3%) against [238] various storedInsecticidal grain pests activity and tested vectors against various stored grain pests and vectors [242]; moderate O Menthone (44) Z. clinopodioides (6.2%–13.3%)insecticidalAntidepressant-like [238] activity againsteffects inSitophilus an unpredic zeamaistable [243] chronic mild stress mouse model of O [242]; moderate insecticidal activity againstAntidepressant-likeSitophilusinsecticidal zeamais effects activity in[ 243againstan unpredic] Sitophilustable zeamais chronic [243] mild stress mouse model of O depression [244]Antidepressant-like effects in an unpredictable chronic mild stress mouse model of O Antidepressant-like effects in an unpredictabledepression chronic [244] mild stress mouse model of depression [244] depression [244] Z. clinopodioides (4.18%) [11] Z. clinopodioides (4.18%) [11] Z. clinopodioides subsp.subsp.Z. clinopodioides rigida (1.4%)(1.4%) (4.18%) [11] Z. clinopodioides (4.18%) [11] Repellent activity against ants of the genus Crematogaster [245];[245]; insecticidalinsecticidal activityactivity againstagainst RepellentZ. activity clinopodioides against [21]Z.subsp. clinopodioides ants rigida of (1.4%) subsp. the genus rigidaRepellent (1.4%)Crematogaster activity against[245 ants]; of insecticidal the genus Crematogaster activity against [245]; insecticidal activity against [21] Repellent activityRepellent against activity ants against of the ants genus of the Crematogaster genus Crematogaster [245]; insecticidal[245]; insecticidal activity activity against against Z. clinopodioides subsp. larvae of Spodoptera littoralis[21] [246[21]] and againstlarvaelarvae ofof Callosobruchus Spodoptera littoralismaculatus [246][246] andand againstagainst[247 ]Callosobruchus maculatus [247][247] Piperitone (45) larvaeIncrease of inSpodoptera antimicrobiallarvae of littoralisSpodoptera activity [246] littoralis of and furazolidone [246] against and Callosobruchusagainst and Callosobruchusnitrofurantoin maculatus maculatus against [247] [247] bacteria of the Piperitone (45) rigida (1.4%) [21] Piperitone (45) IncreasePiperitone in (45 antimicrobial) activity of furazolidoneIncrease in antimicrobialIncrease and nitrofurantoin in antimicrobial activity of activity furazolidone against of furazolidone and nitrofurantoin and nitrofurantoin against against bacteria bacteria of the of the Z. clinopodioides subsp.subsp. bungeana family Enterobacteriaceaeiaceae [248,249][248,249] O bacteria of the family EnterobacteriaceaeZ. clinopodioides subsp. bungeanafamily [248 Enterobacter ,249family] Enterobacteriaceae [248,249]iaceae [248,249] O Z. clinopodioides subsp. Z. clinopodioides(0.6%) subsp. [201] bungeana Fungicidal activity against Aspergillus flavus [250][250] O Fungicidal activity(0.6%) against [201]Aspergillus (0.6%) [201] ﬂavusFungicidal[250 activity]Fungicidal against activity Aspergillus against Aspergillus flavus [250] flavus [250] bungeana (0.6%) [201]

Z. clinopodioidesZ. (5.3%)(5.3%) clinopodioides [11][11] (5.3%) [11] Z. clinopodioides (5.3%) [11] Z. clinopodioides (5.3%) [11]

AntibacterialAntibacterial activity against activity 52 against Gram-positiv 52 Gram-positive and Gram-negativee and Gram-negative bacterial bacterial species, species, disc disc Antibacterial activity against 52 Gram-positiveAntibacterial and activity Gram-negative against 52 Gram-positiv bacteriale and species, Gram-negative disc diffusion bacterial methodspecies, disc [11 ] Piperitenone (46) Piperitenone (46) Piperitenone (46Z.) clinopodioidesZ. subsp.subsp. clinopodioides rigida subsp.diffusion rigida methoddiffusion [11] method [11] Piperitenone (46) Insecticidal activity against Sitophilus(17.4%) [21] zeamaisdiffusion[243 methodInsecticidal] [11] activity against Sitophilus zeamais [243] Z. clinopodioides subsp. Z. clinopodioides(17.4%) subsp.[21] rigida Insecticidal activity against Sitophilus zeamais [243][243] OO Insecticidal activity against Sitophilus zeamais [243] O rigida (17.4%) [21] (17.4%) [21] O

p-Menth-4-en-3-one (47) Z. tenuior (0.5%) [202] n.f. p-Menth-4-en-3-one (47) Z. tenuior (0.5%)p- [Menth-4-en-3-one202] ( n.f.47) Z. tenuior (0.5%) [202] n.f. O p-Menth-4-en-3-one (47) Z. tenuior (0.5%) [202] n.f. O O

O O Piperitone oxide (48) Z. persica (0.32%) [251] Antibacterial activity against 19 Gram-positive and Gram-negative bacterial species [252] O O Piperitone oxide (48) Z. persica (0.32%) [Piperitone251] oxide (48 Antibacterial) activityZ. persica (0.32%)(0.32%) against [251][251] 19 Gram-positiveAntibacterial and activity Gram-negative against 19 Gram-positiv bacteriale and species Gram-negative [252] bacterial species [252] Piperitone oxide (48) Z. persica (0.32%) [251] Antibacterial activity against 19 Gram-positive and Gram-negative bacterial species [252] O O Molecules 2016, 21, 826 17 of 53

O Antimicrobial activity against strains ofAntimicrobial bacteria, yeast activity and against pathogenic strains of bacteria, fungi [yeast241,252 and] pathogenic fungi [241,252] Insecticidal activity against the West NileInsecticidal virus mosquito activity againstCulex the pipiensWest Nilelarvae virus mosquito [253] Culex pipiens larvae [253] and against various stages of Anopheles stephensi [254] Piperitenone oxide (49) Z. clinopodioides (0.16%) [11] Piperitenone oxide (49) Z. clinopodioides (0.16%) [11] and against various stages of AnophelesAntinociceptive stephensi [254 activity] in acetic acid-induced writhing test and in the second phase of

Antinociceptive activity in acetic acid-inducedformalin test writhing [255] test and in the second phase of formalin test [255] O Antiviral activity against herpes simplexAntiviral virus activity type 1 against [256] herpes simplex virus type 1 [256]

O Antifungal activity against Botrytis cinerea [257] Z. clinopodioides subsp. rigida (0.2%) Verbenone (50) Fumigation activity against stored-product pest insects [234] [21] Insecticidal activity against Acanthoscelides obtectus [258]

O 2-Acetyl-4,4-dimethyl-cyclopent- Z. tenuior (2.49%) [94] n.f. 2-enone (51) O O

2-Isopropyl-5-methyl-3- Z. tenuior [94], n.f. cyclohexen-1-one (52) Z. tenuior (1.6%) [179] O

Z. tenuior (86.29%–87.06%) [259] Insecticidal [260] Fumigation activity against stored-product pest insects [234] Pulegone (53) Anti-inflammatory activity reviewed [261] Analgesic activity reviewed [199] O Z. clinopodioides (45.8%) [21] Review on metabolism and toxicity [200]

3-Methyl-6-(1-methyl-ethenyl)-2- cyclohexen-1-one (syn. Z. tenuior (0.3%–1%) [259,94] n.f. Isopiperitenone) (54) O

Molecules 2016, 21, 826 17 of 54

Molecules 20162016,, 2121,, 826826 1717 ofof 5353

Molecules 2016, 21, 826 Table 3. Cont. 17 of 53 O Molecules 2016, 21, 826 Antimicrobial activity against strains of bacteria, yeast and pathogenic fungi [241,252] O 17 of 53 InsecticidalInsecticidal activityactivity againstagainst thethe WestWest NileNile virusvirus mosquitomosquito Culex pipiens larvaelarvae [253][253] andand Monoterpenesagainst various stages of Anopheles stephensi [254] O Piperitenone oxide (49) Z. clinopodioides (0.16%) [11] against variousAntimicrobial stages of activityAnopheles against stephensi strains [254] of bacteria, yeast and pathogenic fungi [241,252] Piperitenone oxide (49) Z. clinopodioides (0.16%) [11] Antinociceptive activity in acetic acid-induced writhing test and in the second phase of O Isolation/Detection in Kazakhstan AntinociceptiveInsecticidalAntimicrobial activity activity inactivity acetic against against acid-induced the strains West Nileof writhing bacteria, virus mosquito yeasttest and and Culex inpathogenic the pipiens second larvaefungi phase [241,252] [253] of and O formalinformalin testtestagainstInsecticidal [255][255] various activity stages against of Anopheles the West stephensi Nile virus [254] mosquito Culex pipiens larvae [253] and O Piperitenone oxide (49) Z. clinopodioides (0.16%) [11] Name of Compound and ID spp. of Ziziphora (Percentage Antiviral activityBiologicalAntinociceptiveagainst against various Activity herpes stages activity ofsimplex in Anopheles acetic virus acid-induced stephensi type [254]1 [256]writhing test and in the second phase of Chemical Structure Piperitenone oxide (49) Z. clinopodioides (0.16%)Antiviral [11] activity against herpes simplex virus type 1 [256] Content when Given) formalinAntinociceptive test [255] activity in acetic acid-induced writhing test and in the second phase of O Antiviralformalin testactivity [255] against herpes simplex virus type 1 [256] O Antiviral activity against herpes simplex virus type 1 [256] O Antifungal activity against Botrytis cinereaAntifungal[257] activity against Botrytis cinerea [257] Z. clinopodioides subsp. Z. clinopodioides subsp. rigida (0.2%) Antifungal activity against Botrytis cinerea [257] O Verbenone (50) Z. clinopodioides subsp. rigida (0.2%) Fumigation activity against stored-product pest insects [234] Verbenone (50) Verbenone (50) Fumigation activity against[21] stored-productFumigation pestinsectsAntifungal activity against [ 234activity] stored-product against Botrytis cinereapest insects [257] [234] O rigida (0.2%) [21] Z.[21] clinopodioides subsp. rigidaInsecticidal (0.2%) activity against Acanthoscelides obtectus [258] InsecticidalVerbenone (50) activity against AcanthoscelidesInsecticidalInsecticidal obtectus FumigationactivityAntifungalactivity[258 againstagainst] activity activity Acanthoscelides against against Botrytis stored-product obtectus cinerea [257] [258]pest[258] insects [234] Z. clinopodioides [21]subsp. rigida (0.2%) Verbenone (50) InsecticidalFumigation activityactivity againstagainst Acanthoscelidesstored-product obtectus pest insects [258] [234] [21] Insecticidal activity against Acanthoscelides obtectus [258]

O 2-Acetyl-4,4-dimethyl-cyclopent- 2-Acetyl-4,4-dimethyl- 2-Acetyl-4,4-dimethyl-cyclopent- Z. tenuior (2.49%) [94] n.f. O Z. tenuior (2.49%) [942-enone] (2-Acetyl-4,4-dimethyl-cyclopent-51) n.f. Z. tenuior (2.49%) [94] n.f. cyclopent-2-enone (51) 2-enone2-enone ((5151)) Z. tenuior (2.49%) [94] n.f. O 2-Acetyl-4,4-dimethyl-cyclopent-2-enone (51) O Z. tenuior (2.49%) [94] n.f. O O 2-enone (51) O O O

2-Isopropyl-5-methyl-3- Z. tenuior [942-Isopropyl-5-methyl-3-2-Isopropyl-5-methyl-3-], 2-Isopropyl-5-methyl-3- Z. tenuior [94][94],, Z. tenuior [94], n.f. n.f. cyclohexen-1-one 2-Isopropyl-5-methyl-3-(52cyclohexen-1-onen.f.) (52)Z. tenuior (1.6%)Z. [179] tenuiorZ. tenuior (1.6%) [94] [179], n.f. cyclohexen-1-one (52) Z. tenuior (1.6%) [cyclohexen-1-one179] (52) Z. tenuior (1.6%) [179] n.f. cyclohexen-1-one (52) Z. tenuior (1.6%) [179] OO O

Z. tenuior (86.29%–87.06%) [259] Insecticidal [260] Z. tenuior (86.29%–87.06%) [259] Z. tenuior (86.29%–87.06%) [259] Insecticidal [260] InsecticidalZ. [tenuior260] (86.29%–87.06%)(86.29%–87.06%)Z. tenuior (86.29%–87.06%) [259][259] InsecticidalInsecticidal [259] FumigationInsecticidal[260][260] [260]activity against stored-product pest insects [234] FumigationPulegone (53) activity against stored-productFumigationFumigation pest insectsAnti-inflammatory Fumigationactivityactivity againstagainst [234 activity] stored-productstored-product activity against reviewedstored-product pestpest [261] insectsinsects pest insects[234][234] [234] Pulegone (53) PulegonePulegone ((5353)) Anti-inﬂammatoryPulegone (53) activity reviewed [261Anti-inflammatory] AnalgesicAnti-inflammatory activity activity reviewed reviewed activity reviewed [199][261] [261] O Analgesic activity reviewed [199] Analgesic activity reviewedZ. clinopodioides [199] (45.8%)Analgesic [21] activityReviewAnalgesic reviewed on activity metabolism [199]reviewed and toxicity [199] [200] OO Z. clinopodioides (45.8%) [21] Z. clinopodioides (45.8%)Review [21] on metabolismReview on metabolism and toxicity and [200] toxicity [200] Review on metabolismZ. clinopodioides and (45.8%)(45.8%) toxicity [21][21] [200Review] on metabolism and toxicity [200]

3-Methyl-6-(1-methyl-ethenyl)-2- 3-Methyl-6-(1-methyl-ethenyl)-2-cyclohexen-1-one (syn. Z. tenuior (0.3%–1%) [259,94] n.f. 3-Methyl-6-(1-methyl-ethenyl)- 3-Methyl-6-(1-methyl-ethenyl)-2- 3-Methyl-6-(1-methyl-ethenyl)-2-3-Methyl-6-(1-methyl-ethenyl)-2-cyclohexen-1-oneIsopiperitenone) (syn.(54) Z. tenuior (0.3%–1%) [259,94] n.f. O cyclohexen-1-one (syn. Z. tenuior (0.3%–1%) [259,94] n.f. 2-cyclohexen-1-one (syn. Z. tenuior (0.3%–1%)cyclohexen-1-onecyclohexen-1-one [94,259] (syn.(syn.Isopiperitenone) n.f. Z.(54 tenuior) (0.3%–1%)(0.3%–1%) [259,94][259,94] n.f.n.f. O Isopiperitenone) (54) Isopiperitenone)Isopiperitenone) ((5454)) O Molecules 2016, 21, 826 18 of 53

Cytotoxic activity against MCF-7 and Hep-G2Cytotoxic cells activity [262 against] MCF-7 and Hep-G2 cells [262] Carvotanacetone (55) Z. tenuior [94]Carvotanacetone (55) Z. tenuior [94] Antifungal activity against tested phytopathogenicAntifungal activity fungi against [263 tested] phytopathogenic fungi [263]

Antifungal effect against Candida albicans, synergy with fluconazol [239] Fumigant activity [264] Z. clinopodioides (9.13%) [11] Analgesic, antifungal, antibacterial, antipruritic, anticancer, anti-inflammatory, antitussive, antiviral, insecticidal activity reviewed in Kamatou et al. [265] Gastroprotective effect in gastric ulcers induced by ethanol or indomethacin in Wistar male Menthol (56) rats and also antidiarrheal and antiperistaltic effect; anti-apoptotic, antioxidant and anti- inflammatory activities [266,267] OH Z. clinopodioides subsp. rigida (0.1%) Allosteric modulation of human α3β4 nicotinic acetylcholine receptors [268] [21] Analgesic activity reviewed [199] Review on some effects on cardiovascular system [221] Review on metabolism and toxicity [200]

Menthofuran (57) Z. tenuior (0.1%) [182] Acetyl and butyrylcholinesterase inhibitory activity [269] O

Z. clinopodioides subsp. rigida (2.1%) [21] Antibacterial activity against Escherichia coli [270] Neomenthol (58) Acaricidal activity against Tyrophagus putrescentiae [271] Sedative in the pentobarbital-induced sleep test in mice [272] Z. clinopodioides subsp. bungeana OH [201]

Z. clinopodioides subsp. bungeana (0.3%) [201] Neo-iso-menthol (59) n.f. OH Z. clinopodioides (0.12%–0.25%) [15]

Molecules 2016, 21, 826 18 of 54

Molecules 2016, 21, 826 18 of 53 Table 3. Cont. Molecules 2016, 21, 826 18 of 53 Molecules 2016, 21, 826 O 18 of 53 Molecules 2016, 21, 826 Monoterpenes 18 of 53 Cytotoxic activity against MCF-7 and Hep-G2 cells [262] Carvotanacetone (55) Z. tenuior [94] Isolation/Detection in Kazakhstan Antifungal activity against tested phytopathogenic fungi [263] O Name of Compound and ID spp. of Ziziphora (Percentage Biological Activity Chemical StructureO Cytotoxic activity against MCF-7 and Hep-G2 cells [262] O Content when Given) Carvotanacetone (55) Z. tenuior [94] Cytotoxic activity against MCF-7 and Hep-G2 cells [262] Carvotanacetone (55) Z. tenuior [94] Antifungal activity against tested phytopathogenic fungi [263] AntifungalCytotoxic activity activity against against MCF-7 tested andphytopathogenic Hep-G2 cells [262]fungi [263] Carvotanacetone (55) Z. tenuior [94] Antifungal effect against Candida albicansAntifungal, synergy effectAntifungal with against fluconazol activity Candida against albicans [ 239tested], synergyphytopathogenic with fluconazol fungi [263] [239] Fumigant activity [264] Fumigant activity [264] Z. clinopodioides (9.13%) [11] Z. clinopodioides (9.13%) [11] Analgesic, antifungal, antibacterial, antipruritic,Analgesic, antifungal, anticancer,Antifungal effectantibacterial, anti-inflammatory, against Candida antipruritic, albicans anticancer,, synergy with anti-inflammatory, fluconazol [239] antitussive, antiviral, insecticidalAntifungalFumigant activityactivity effect against [264] reviewed Candida in Kamatoualbicans, synergy et al. [265] with fluconazol [239] FumigantAntifungal activity effect against [264] Candida albicans, synergy with fluconazol [239] antitussive, antiviral, insecticidalZ. clinopodioides activity (9.13%)Gastroprotective [11] reviewed Analgesic, in effect Kamatou antifungal, in gastric etantibacterial, ulcers al. [ 265indu] antipruritic,ced by ethanol anticancer, or indomethacin anti-inflammatory, in Wistar antitussive, male Z. clinopodioides (9.13%) [11] Fumigant activity [264] Gastroprotective effect in gastric ulcers induced byAnalgesic,antiviral, ethanol insecticidal antifungal, or indomethacin activity antibacterial, reviewed antipruritic, in in Kamatou Wistar anticancer, et maleal. [265] anti-inflammatory,rats and also antitussive, Menthol (56) Menthol (56) Z. clinopodioides (9.13%)rats [11] and alsoAnalgesic, antidiarrheal antifungal, and antiperistaltic antibacterial, antipruritic, effect; anti-apoptotic, anticancer, anti-inflammatory, antioxidant and antitussive,anti- antiviral,Gastroprotective insecticidal effect activity in gastric reviewed ulcers inindu Kamatouced by ethanolet al. [265] or indomethacin in Wistar male antidiarrheal and antiperistaltic effect; anti-apoptotic,inflammatoryantiviral, activities antioxidant insecticidal [266,267] activity and reviewed anti-inflammatory in Kamatou et al. [265] activities [266,267] Menthol (56) Gastroprotectiverats and also antidiarrheal effect in gastric and antiperistaltic ulcers induced effect; by ethanol anti-apoptotic, or indomethacin antioxidant in Wistarand anti- male OH Z. clinopodioides subsp. rigida (0.1%)α β Allosteric modulationGastroprotective of human effect αin3 gastricβ4 nicotinic ulcers acetylcholineinduced by ethanol receptors or indomethacin [268] in Wistar male Z. clinopodioides subsp. AllostericMenthol (56 modulation) of human 3 4 nicotinic acetylcholineratsinflammatory and also antidiarrheal activities receptors [266,267] and antiperistaltic [ 268] effect; anti-apoptotic, antioxidant and anti- Menthol (56) [21] Analgesic activityrats and reviewed also antidiarrheal [199] and antiperistaltic effect; anti-apoptotic, antioxidant and anti- OH rigida (0.1%) [21] Analgesic activity reviewedZ. clinopodioides [199 ]subsp. rigida (0.1%) inflammatoryAllosteric modulation activities of [266,267] human α3β4 nicotinic acetylcholine receptors [268] OH Z. clinopodioides subsp. rigida (0.1%) inflammatory activities [266,267] [21] Review on someAllostericAnalgesic effects modulationactivity on cardiovascular reviewed of human [199] α system3β4 nicotinic [221] acetylcholine receptors [268] OH Review on some effectsZ. clinopodioides on cardiovascular [21]subsp. rigida (0.1%) system Allosteric [221] modulation of human α3β4 nicotinic acetylcholine receptors [268] Review on metabolismAnalgesicReview on activity some and effects toxicity reviewed on [200]cardiovascular [199] system [221] Review on metabolism and toxicity[21] [200] Analgesic activity reviewed [199] Review on metabolismsome effects and on cardiovascular toxicity [200] system [221] Review on metabolismsome effects and on cardiovascular toxicity [200] system [221] Review on metabolism and toxicity [200]

Menthofuran (57) Z. tenuior (0.1%) [182] Acetyl and butyrylcholinesterase inhibitory activity [269] Menthofuran (57) Z. tenuior (0.1%) [182] AcetylMenthofuran and (57 butyrylcholinesterase) Z. tenuior (0.1%) inhibitory [182] activityAcetyl [269 and ]butyrylcholinesterase inhibitory activity [269] Menthofuran (57) Z. tenuior (0.1%) [182] Acetyl and butyrylcholinesterase inhibitory activity [269] O O Menthofuran (57) Z. tenuior (0.1%) [182] Acetyl and butyrylcholinesterase inhibitory activity [269] O O

Z. clinopodioides subsp. Z. clinopodioides Z.subsp. clinopodioides rigida (2.1%) subsp. rigida (2.1%) Z.[21] clinopodioides [21]subsp. rigida (2.1%) rigida (2.1%) [21] Z. clinopodioides [21]subsp. rigidaAntibacterial (2.1%) Antibacterial activity against activity Escherichia against Escherichia coli [270] coli [270] Antibacterial activity against Escherichia coli [270]Antibacterial activity against Escherichia coli [270] Neomenthol (58) Neomenthol (58) [21] Acaricidal activity against Tyrophagus putrescentiae [271] Neomenthol (58) Acaricidal activityAcaricidalAntibacterial against activity activity Tyrophagus against against Tyrophagus putrescentiaeEscherichia putrescentiae coli [271] [270] [271] Neomenthol (58) Acaricidal activity against Tyrophagus putrescentiaeSedative[271 ]in the pentobarbital-induced sleep test in mice [272] OH Neomenthol (58) Z. clinopodioides subsp. bungeanaSedative in theSedativeAcaricidal pentobarbital-induced in activity the pentobarbital-induced against Tyrophagus sleep test putrescentiaesleep in mice test in [272] mice[271] [272] OH Sedative inZ. theclinopodioides pentobarbital-induced Z.subsp. clinopodioides bungeana subsp. sleepbungeana test in mice [272] OH Z. clinopodioides subsp. [201] Sedative in the pentobarbital-induced sleep test in mice [272] OH bungeana [201] [201]Z. clinopodioides [201] subsp. bungeana [201]

Z. clinopodioides subsp. bungeana Z. clinopodioides subsp. Z. clinopodioides Z.subsp. clinopodioides bungeana(0.3%) subsp. [201] bungeana Z. clinopodioides(0.3%) subsp. [201] bungeana bungeana (0.3%) [201] Neo-iso-menthol (59) (0.3%) [201] n.f. Neo-iso-menthol (59) (0.3%) [201] n.f. Neo-iso-menthol (59) n.f. OH Neo-iso-menthol (59) Neo-ison.f. -menthol (59) n.f. OH Z. clinopodioides (0.12%–0.25%) [15] OH Z. clinopodioides (0.12%–0.25%) [15] Z. clinopodioides (0.12%–0.25%) [15] MoleculesZ. clinopodioides 2016, 21, 826 Z.(0.12%–0.25%) clinopodioides (0.12%–0.25%) [15] [15] 19 of 53

Menthyl acetate (60) Z. clinopodioides (0.1%) [184] n.f. Menthyl acetate (60) Z. clinopodioides (0.1%) [184] n.f. O

O Z. clinopodioides subsp. rigida (0.5%) Z. clinopodioides subsp. Isomenthyl acetate (61) n.f. Isomenthyl acetate (61) n.f. [21] rigida (0.5%) [21] O

Antibacterial (Bacillus cereus, Micrococcus flavus, S. aureus, Listeria monocytogenes, E. coli, P. aeruginosa, Proteus mirabilis, Salmonella typhimurium) [261,273,274] Z. clinopodioides (0.17%–53.6%) aeruginosa, Proteus mirabilis, Salmonella typhimurium) [261,273,274] Antifungal (Trichophyton mentagrophytes, T. interdigitale, T. rubrum, T. erinaceum, T. [15,184] Antifungal (Trichophyton mentagrophytes, T. interdigitale, T. rubrum, T. erinaceum, T. soudanense, T. violaceum, Microsporum canis, M. gypseum, Epidermophyton flocosum, A. fumigatus, Scopulariopsis brevicaulis, Scytalidium dimidiatum, C. albicans, Cryptococcus neoformans, Malassezia pachydermatis [273]); against Botrytis cinerea [275]; against Penicillium funiculosum and P. ochrochloron, Aspergillus fumigatus, A. niger, A. flavus, A. ochraceus, C. albicans, Trichoderma viride) [187]; antifungal (Candida albicans, C. tropicalis, Saccharomyces cerevisiae, Cryptococcus neoformans, Microsporum gypseum, Trichophyton rubrum, T. Thymol (62) Z. clinopodioides subsp. rigida (8%) mentagrophytes), antimicrobial (E. coli, P. aeruginosa, Yersinia enterocolitica, Salmonella [21] enteritidis) activity [276]; antifungal (yeasts, dermatophyte and Aspergillus strains) [277] OH Antifungal activity against various Candida strains and synergy with fluconazole [278] Review on possible synergy of 62 containing essential oils and thymol (62) with antibiotics [132]

Antileshmanial (against L. chagasi) [279] Antimalarial (P. falciparum) [280] Low antinematocidal activity [281] Antiviral (HSV-1) [282] Z. tenuior [94] Z. tenuior [94] Cytotoxic (HeLa, B16, MCF-7, 3T3, MRC-5 cells) [283]; against P815 and PBMC [284]; induction of apoptosis [285]; cytotoxic effects on acute promyelotic cancer cell line HL-60 [286] Anti-genotoxic (bleomycin-induced DNA damage) [287] Anti-inflammatory activity in carrageenan-induced paw edema, MPO activity and peritonitis in rats [288]; anti-inflammatory activity in LPS-stimulated mouse mammary epithelial cells via inhibition of the NF-κB and MAPKs signalling pathways [289]; anti- inflammatory effect in ovoalbumin-induced mouse asthma, possibly through inhibiting NF-κB activation [290]; inhibition of S. aureus internalization into bovine mammary epithelial cells by inhibiting NF-κB activation [291] Review on anti-inflammatory, antioxidant, and immunological effects [292] Protective effect on radiation-induced apoptosis in Chinese hamster lung fibroblast V79 cells [293]; DNA-protective effects against H2O2-induced DNA lesions in human hepatoma [293]; DNA-protective effects against H2O2-induced DNA lesions in human hepatoma HepG2 cells [294]; hepatoprotective effect against t-BHP-induced oxidative damage in Chang liver cells [84]; protective effect against cisplatin-induced nephrotoxicity in rats [295]; protective effect against UVA- and UVB-induced lipid peroxidation in NCTC 2544 cell line

Molecules 2016, 21, 826 19 of 53

Molecules 2016, 21, 826 19 of 54 O Menthyl acetate (60) Z. clinopodioides (0.1%) [184] n.f. O Table 3. Cont.

Monoterpenes Isolation/Detection in Kazakhstan O Z. clinopodioides subsp. rigida (0.5%) Name of Compound and ID spp. of Ziziphora (PercentageIsomenthyl acetate (61) n.f. Biological Activity Chemical Structure [21] Content when Given) O

Antibacterial (Bacillus cereus, Micrococcus flavus, S. aureus, Listeria monocytogenes, E. coli, P. aeruginosa, Proteus mirabilis, Salmonella typhimurium)[261,273,274] Z. clinopodioides (0.17%–53.6%) Antibacterial (Bacillus cereus, Micrococcus flavus, S. aureus, Listeria monocytogenes, E. coli, P. Antifungal (Trichophyton mentagrophytes, T. interdigitale, T. rubrum, T. erinaceum, T. soudanense, T. violaceum, [15,184] Z. clinopodioides (0.17%–53.6%) aeruginosa, Proteus mirabilis, Salmonella typhimurium) [261,273,274] Microsporum canis, M.[15,184] gypseum , EpidermophytonAntifungal flocosum (Trichophyton, A. mentagrophytes fumigatus, Scopulariopsis, T. interdigitale, T. brevicaulis rubrum, T. erinaceum, Scytalidium, T. dimidiatum, C. albicans, Cryptococcus neoformanssoudanense, ,Malassezia T. violaceum, pachydermatisMicrosporum canis[, 273M. gypseum]); against, EpidermophytonBotrytis cinereaflocosum,[ 275A. ]; against Penicillium funiculosum and P. ochrochloronfumigatus, Scopulariopsis, Aspergillus brevicaulis fumigatus, Scytalidium, A. niger dimidiatum, A. flavus, C. albicans, A. ochraceus, Cryptococcus, C. albicans, Trichoderma viride)[187]; antifungal (Candidaneoformans albicans, Malassezia, C. tropicalis pachydermatis, Saccharomyces [273]); against Botrytis cerevisiae cinerea, Cryptococcus [275]; against Penicillium neoformans , funiculosum and P. ochrochloron, Aspergillus fumigatus, A. niger, A. flavus, A. ochraceus, C. Microsporum gypseum, Trichophyton rubrumalbicans, T., mentagrophytesTrichoderma viride) ),[187]; antimicrobial antifungal (Candida (E. coli albicans, P. aeruginosa, C. tropicalis,, Saccharomyces Thymol (62) Z. clinopodioides subsp. Yersinia enterocolitica, Salmonella enteritidiscerevisiae) activity, Cryptococcus [276]; neoformans, Microsporum gypseum, Trichophyton rubrum, T. rigida (8%) [21] Thymol (62) antifungalZ. (yeasts,clinopodioides dermatophyte subsp. rigida (8%) and Aspergillusmentagrophytesstrains)), antimicrobial [277] (E. coli, P. aeruginosa, Yersinia enterocolitica, Salmonella Antifungal activity against[21] various Candidaenteritidisstrains) activity and [276]; synergy antifungal with (yeasts, fluconazole dermatophyte [278 and] Aspergillus strains) [277] OH Review on possible synergy of 62 containingAntifungal essential activity oilsagainst and various thymol Candida (62 strains) with and antibiotics synergy with [132 fluconazole] [278] Antileshmanial (against L. chagasi)[279]Review on possible synergy of 62 containing essential oils and thymol (62) with antibiotics [132] Antileshmanial (against L. chagasi) [279] Antimalarial (P. falciparum)[280] Antimalarial (P. falciparum) [280] Low antinematocidal activity [281] Low antinematocidal activity [281] Z. tenuior [94] Antiviral (HSV-1) [282] Antiviral (HSV-1) [282] Cytotoxic (HeLa,Z. B16, tenuior MCF-7, [94] 3T3, MRC-5Cytotoxic cells) (HeLa, [283 B16,]; against MCF-7, 3T3, P815 MRC-5 and cells) PBMC [283]; [against284]; P induction815 and PBMC of [284]; apoptosis induction [ 285of ]; cytotoxic effects on acute promyelotic cancerapoptosis cell [285]; line cytotoxic HL-60 effects [286 on] acute promyelotic cancer cell line HL-60 [286] Anti-genotoxic (bleomycin-induced DNA damage) [287] Anti-genotoxic (bleomycin-induced DNAAnti-inflammatory damage) [287 activity] in carrageenan-induced paw edema, MPO activity and Anti-inflammatory activity in carrageenan-inducedperitonitis in rats paw [288]; edema, anti-inflammatory MPO activity activity andin LPS-stimulated peritonitis mouse in rats mammary [288]; anti-inflammatory activity in LPS-stimulatedepithelial mouse cells via mammary inhibition of the epithelial NF-κB and cells MAPKsvia inhibitionsignalling pathways of the [289]; NF-κ anti-B and MAPKs signalling pathways [289]; anti-inflammatoryinflammatory effect effect in ovoalbumin-induced in ovoalbumin-induced mouse asthma, mouse possibly asthma, through inhibiting possibly through inhibiting NF-κB activation [290NF-];κ inhibitionB activation [290]; of S. inhibition aureus internalization of S. aureus internalization into bovine into bovine mammary mammary epithelial cells by inhibiting NF-κB activation [291] epithelial cells by inhibiting NF-κB activation [291] Review on anti-inflammatory, antioxidant, and immunological effects [292] Review on anti-inflammatory, antioxidant,Protective and immunologicaleffect on radiation-induced effects apoptosi [292] s in Chinese hamster lung fibroblast V79 cells Protective effect on radiation-induced apoptosis[293]; DNA-protective in Chinese effects hamster against lung H2O2 fibroblast-induced DNA V79 lesions cells in [ 293human]; DNA-protective hepatoma effects against H2O2-induced DNA lesionsHepG2 in cells human [294]; hepatomahepatoprotective HepG2 effect cellsagainst [294 t-BHP-induced]; hepatoprotective oxidative damage effect in against t-BHP-induced oxidative damage in ChangChang liver liver cells [84]; [84 protective]; protective effect effectagainst againstcisplatin-induced cisplatin-induced nephrotoxicity in rats [295]; nephrotoxicity in rats [295]; protective effectprotective against effect against UVA- UVA- and UVB-inducedand UVB-induced lipidlipid peroxidation peroxidation in NCTC 2544 cell line Moleculesin 2016 NCTC, 21, 826 2544 cell line [296]; antioxidant [273,297–299] 20 of 53 Review on some effects on cardiovascular system [221] Gastroprotective effects in the acute and chronic ulcer[296]; antioxidant models [273,297–299] in rats [300 ] Positive allosteric modulator of the GABA receptorsReview inon some primary effects cultureson cardiovascular of mouse system cortical[221] neurons [301] A Gastroprotective effects in the acute and chronic ulcer models in rats [300] Anti-hyperglycemic and anti-hyperlipidemic activityPositive in allosteric high fat-inducedmodulator of the typeGABA 2A receptors in primary cultures of mouse cortical diabetic C57BL/6J mice [302] and protective effectneurons in nephropathy [301] [303] Analgesic activity reviewed [199] Anti-hyperglycemic and anti-hyperlipidemic activity in high fat-induced type 2 diabetic C57BL/6J mice [302] and protective effect in nephropathy [303] Review on metabolism and toxicity [200]; generalAnalgesic review activity on thyme reviewed and [199]62 [304] Review on metabolism and toxicity [200]; general review on thyme and 62 [304] Z. clinopodioides (0.3%–2.2%) [184] OH Z. clinopodioides (0.3%–2.2%) [184] H

cis-Sabinene hydrate (63) cis-AntiviralSabinene hydrate (HSV-1) (63) [282]Z. clinopodioides subsp. bungeana Antiviral (HSV-1) [282] Z. clinopodioides subsp. bungeana [201] [201]

Z. clinopodioides subsp. rigida (0.1%) [21] Antiviral (HSV-1) [282] trans-Sabinene hydrate (64) Moderate repellent (against tick Amblyomma americanum) [305] Z. tenuior [94] OH

Z. clinopodioides (2.7%) [185]

Z. clinopodioides subsp. rigida p-Menth-3-en-8-ol (65) (12.5%) [21] n.f.

Z. tenuior (53.97%) [179] OH

Antibacterial [128,187,306] Antimycotic (Candida albicans) [307], against M. ramamnianus [308] Repellent against mosquitoes [309] Molluscicidal (against snail Oncomelania hupensis) and cercarcicidal (against Schistosoma Z. clinopodioides (1.8%–7.9%) [184] japonicum) [310] Anti-inflammatory (in carrageenan-induced edema and inhibition of hyperalgesia induced OH by L-glutamate and prostaglandin E2 in rats) [311]; anti-inflammatory (through inhibition of the expression of TNF-α and IL-6 in LPS-stimulated RAW 264.7 cells) [312]; anti- Linalool (66) inflammatory (in cigarette smoke-induced ALI in mice through inhibiting NF-κB activation) [313] Cytotoxic (human amelanotic melanoma cell line C32, renal cell adenocarcinoma ACHN, hormone-dependent prostate carcinoma LNCaP) [314]; induction of apoptosis (variety of human leukaemia cells) [315–317] Z. clinopodioides subsp. rigida [21] Hypocholesterolemic (through inhibition of HMG-CoA reductase and conversion of lanosterol to cholesterol) [318,319] Protective effect against t-BOOH induced mutagenesis [194] Review on some effects on cardiovascular system [221] Sedative and anxiolytic [320]; antidepressant [321]; GABAA receptor modulation [322]

Molecules 2016,, 21,, 826826 20 of 53

[296];[296]; antioxidantantioxidant [273,297–299][273,297–299] Molecules 2016, 21, 826 Review on some effects on cardiovascular system [221] 20 of 53 Molecules 2016, 21, 826 Gastroprotective effects in the acute and chronic ulcer models in rats [300] 20 of 54 Positive allosteric modulator of the GABAA receptors in primary cultures of mouse cortical Positive[296]; antioxidant allosteric modulator[273,297–299] of the GABAA receptors in primary cultures of mouse cortical neuronsReview on[301] some effects on cardiovascular system [221] Anti-hyperglycemicGastroprotective effects and inanti-hyperlipidemic the acute and chronic activity ulcer in models high fat-induced in rats [300] type 2 diabetic C57BL/6J mice [302] and protective effect in nephropathy [303] C57BL/6JPositive allosteric mice [302] modulator and protecti of theve effectGABA inA nephropathyreceptors in primary [303] cultures of mouse cortical Table 3. Cont.Analgesicneurons [301] activity reviewed [199] ReviewAnti-hyperglycemic on metabolism and and anti-hyperlipidemic toxicity [200]; general activity review in high on thyme fat-induced and 62 type [304][304] 2 diabetic Z. clinopodioides (0.3%–2.2%)(0.3%–2.2%) [184][184] C57BL/6J mice [302] and protective effect in nephropathy [303] OH H MonoterpenesAnalgesic activity reviewed [199] H Review on metabolism and toxicity [200]; general review on thyme and 62 [304] cis-Sabinene hydrate (63) Antiviral (HSV-1) [282] Isolation/Detection incis- KazakhstanSabinene hydrate (63) Z.Z. clinopodioidesclinopodioides (0.3%–2.2%)subsp.subsp. bungeanabungeana [184] Antiviral (HSV-1) [282] OH Name of Compound and ID spp. of Ziziphora (Percentage [201][201] Biological Activity ChemicalH Structure Content when Given) cis-Sabinene hydrate (63) Z. clinopodioides subsp. bungeana Antiviral (HSV-1) [282] Z. clinopodioides [201]subsp.subsp. rigidarigida (0.1%)(0.1%) Z. clinopodioides subsp. [21] rigida (0.1%) [21] [21] Antiviral (HSV-1) [282] Antiviral (HSV-1) [282] trans-Sabinene hydrate (64) trans-trans-Sabinene hydrate (64)) ModerateZ. repellent clinopodioides (against subsp. rigida tick (0.1%)Amblyomma Moderate americanum repellent (against)[305 tick] Amblyomma americanum)) [305][305] Z. tenuior [94][94] OH Z. tenuior [94] [21] Antiviral (HSV-1) [282] trans-Sabinene hydrate (64) Moderate repellent (against tick Amblyomma americanum) [305] Z. clinopodioides (2.7%) [185] Z. clinopodioidesZ. tenuior (2.7%)(2.7%) [94] [185][185] OH

Z. clinopodioides subsp. Z. clinopodioides subsp.subsp. rigidarigida p-Menth-3-en-8-ol (65) n.f. p-Menth-3-en-8-ol (65) rigida (12.5%) [21p-Menth-3-en-8-ol] (65n.f.) Z. clinopodioides(12.5%)(12.5%) [21] [21](2.7%) [185] n.f.

Z. clinopodioides subsp. rigida Z. tenuior (53.97%) [179] Z. tenuior (53.97%) [179] OH p-Menth-3-en-8-ol (65) Z. tenuior(12.5%) (53.97%) [21] [179] n.f. OH Antibacterial [128,187,306] Antibacterial [128,187,306] Antibacterial [128,187,306] Antimycotic (Candida albicans)) [307],[307], againstagainst M. ramamnianus [308][308] Antimycotic (CandidaZ. tenuior (53.97%) albicans [179])[307 ], against M. ramamnianus [308] OH Repellent against mosquitoes [309] Repellent against mosquitoes [309] MolluscicidalAntibacterial (against[128,187,306] snail Oncomelania hupensis)) andand cercarcicidalcercarcicidal (against(against Schistosoma Z. clinopodioides (1.8%–7.9%)(1.8%–7.9%) [184][184] japonicum) [310] Z. clinopodioides (1.8%–7.9%) [184] Molluscicidal (against snail OncomelaniajaponicumAntimycotic hupensis) [310]) ( andCandida cercarcicidal albicans) [307], (against against M.Schistosoma ramamnianus [308] japonicum )[310] Anti-inflammatory (in carrageenan-inducedAnti-inflammatoryRepellent edema against and mosquitoes (ininhibition carrageenan-induced [309] of hyperalgesia edema andinduced inhibition of by hyperalgesia L-glutamate induced OH by L-glutamate and prostaglandin E2 in rats) [311]; anti-inflammatory (through inhibition of by L-glutamate and prostaglandin E2 in rats) [311]; anti-inflammatory (through inhibition of and prostaglandin E2 in rats) [311]; anti-inflammatoryMolluscicidal (against (through snail Oncomelania inhibition hupensis of the) and expression cercarcicidal of(against TNF- Schistosomaα and Z. clinopodioides (1.8%–7.9%) [184] the expression of TNF-α and IL-6 in LPS-stimulated RAW 264.7 cells) [312]; anti- IL-6 in LPS-stimulated RAW 264.7 cells)thejaponicum [312 expression]; anti-inflammatory) [310] of TNF-α and IL-6 (inin LPS-stimulated cigarette smoke-induced RAW 264.7 cells) [312]; anti- Linalool (66)) inflammatoryinflammatoryAnti-inflammatory (in(in cigarettecigarette (in carrageenan-induced smoke-inducedsmoke-induced ALIALI in inedem micemicea through throughand inhibition inhibitinginhibiting of NF-hyperalgesiaNF-κB activation) induced [313] OH ALI in mice through inhibiting NF-κB activation)Cytotoxic (human [313 ]amelanotic melanoma cell line C32, renal cell adenocarcinoma ACHN, Cytotoxicby L-glutamate (human and amelanotic prostaglandin melanoma E2 in rats) cell line[311]; C32, anti-inflammatory renal cell adenocarcinoma (through inhibition ACHN, of Linalool (66) Cytotoxic (human amelanotic melanomahormone-dependentthe cell expression line C32, of TNF- renal prostateα and cell IL-6carcinoma adenocarcinoma in LPS-stimulated LNCaP) [314];[314]; RAW ACHN, inductioninduction 264.7 hormone-dependentcells) ofof apoptosisapoptosis [312]; anti- (variety(variety ofof human leukaemia cells) [315–317] Linalool (66) prostate carcinoma LNCaP) [314]; inductionhumaninflammatory ofleukaemia apoptosis (in cigarette cells) (variety [315–317] smoke-induced of human ALI in leukaemiamice through inhibiting cells) [315 NF-–κ317B activation)] [313] Hypocholesterolemic (through inhibition of HMG-CoA reductase and conversion of HypocholesterolemicZ. clinopodioides (through subsp.subsp. rigidarigida inhibition [21][21] HypocholesterolemicCytotoxic of HMG-CoA (human amelanotic reductase(through melanoma inhibition and ofcell HMG-CoA line C32, renal reductase cell adenocarcinoma and conversion ACHN,of conversion of lanosterol to cholesterol)lanosterollanosterol [hormone-dependent318,319 to]to cholesterol)cholesterol) prostate [318,319][318,319] carcinoma LNCaP) [314]; induction of apoptosis (variety of Protective effect against t-BOOH induced mutagenesis [194] Protective effect against t-BOOH inducedProtectivehuman mutagenesis leukaemia effect against cells) [194 t[315–317]-BOOH] induced mutagenesis [194] Z. clinopodioides subsp. rigida [21] Review on some effects on cardiovascular system [221] Z. clinopodioides subsp. rigida [21] ReviewHypocholesterolemic on some effects (through on cardiovascular inhibition ofsystem HMG-CoA [221] reductase and conversion of Review on some effects on cardiovascularSedative system and anxiolytic [221] [320]; antidepressant [321]; GABAA receptor modulation [322] Molecules 2016, 21, 826 Sedativelanosterol and to anxiolyticcholesterol) [320]; [318,319] antidepressant [321]; GABAA receptor modulation [322] 21 of 53 Sedative and anxiolytic [320]; antidepressantProtective [321 effect]; GABA againstA t-BOOHreceptor induced modulation mutagenesis [322 [194]] Analgesic activity reviewed [199] Review on some effects on cardiovascular system [221] Analgesic activity reviewed [199] Review on metabolism and toxicity [200Sedative] and anxiolytic [320]; antidepressant [321]; GABAA receptor modulation [322] Review on metabolism and toxicity [200] Inhibition of nicotinic acetylcholine receptorInhibition [323 of ]nicotinic acetylcholine receptor [323] DNA-protective effects against H2O2 in primary rat hepatocytes and testicular cells [324] DNA-protective effects against H2O2 in primary rat hepatocytes and testicular cells [324] Anti-inflammatory in an ALI model in miceAnti-inflammatory through inhibition in an ALI ofmodel the in NF- miceκB through and MAPKs inhibition signalling of the NF-κB pathways and MAPKs [ 325]; signalling pathways [325]; suppression of expression of IL-1β and IL-6 in TNBS-induced OH 67 Z. clinopodioides Borneol (67) Z. clinopodioides (0.9%–1.2%) [184]β Borneol ( ) (0.9%–1.2%) [184] suppression of expression of IL-1 andcolitis IL-6 in mice TNBS-induced [326] colitis in mice [326] Penetration enhancer [327]; increasing ofPenetration the brain enhancer bioavailability [327]; increasing of different of the brain drugs bioavailability [328] of different drugs [328] Antibacterial (multi-drug resistant E. coliAntibacterial)[329] (multi-drug resistant E. coli) [329] Antiviral (HSV-1) [282] Antiviral (HSV-1) [282]

Vasorelaxant effect on rat thoracic aorta artery rings [330] HO Positive modulation of the activation of GABAA receptors [331] endo-Borneol (68) Z. tenuior (0.14%) [202] Potentiation of SeC-induced apoptosis in human hepatocellular carcinoma cells [332] Prolonging anaesthesia time of propofol by inhibiting its glucuronidation [333]

Antifungal (against Pyrenophora avenae) [334] Insecticidal (against Callosobruchus chinensis and Sitophilus oryzae) [228] Anti-inflammatory in an ALI model in mice [335] and in human chondrocytes [336] O Bornyl acetate (69) Z. clinopodioides (3.3%) [184] Antiabortive in pregnant mice [337] Cytotoxic ((Eca-109, HepG2, HT29, MDA-MB-231, PC-3, SGC7901, SW1990 and U2-OS) and O a normal cell line (HL-7702) [338] Sedative and anaesthetic (on silver catfish juveniles) [339]; depressant effect on the CNS and Z. clinopodioides (0.36%–18.2%) significant anticonvulsant activity probably due to interaction with GABA receptors [15,184] [340,341] Low inhibition of acetylcholinesterase and butyrylcholinesterase [224] Relaxant effect on vascular smooth muscle [342] Review on some effects on cardiovascular system [221] Z. clinopodioides subsp. rigida (0.4%) Anticancer (melanoma) [343]; antiproliferative activity in two murine cancer cell lines [21] through induction of necrosis and cell cycle arrest [344]; induction of apoptosis in human non-small cell lung cancer [345]; anti-tumoral activity in human melanoma cells by induction of caspase-dependent form of apoptosis [346] Terpinen-4-ol (70) Antiviral activity against inﬂuenza A⁄PR⁄8 virus subtype H1N1 [231] Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 OH macrophages) [223]; anti-inflammatory [216]; anti-inflammatory activity in a murine model Z. clinopodioides subsp. bungeana of oral candidiasis [347]; suppression of the production of TNFα, IL-1β, IL-8, IL-10 and PGE2

(0.6%) [201] by LPS-activated monocytes [348] Antibacterial against MRSA and CoNS [349] Low antinematocidal activity [281] Antimycotic (C. albicans) [307,350] Insecticidal (against L. serricorne) [351] Z. tenuior (0.08%) [202] Trypanocidal activity against Trypanosoma evansi [222]

Molecules 2016, 21, 826 21 of 54 Molecules 2016, 21, 826 21 of 53 Molecules 2016, 21, 826 21 of 53

Molecules 2016, 21, 826 Analgesic activity reviewed [199] 21 of 53 Table 3. Cont.AnalgesicReview on activity metabolism reviewed and toxicity[199] [200] AnalgesicReviewInhibition on activity ofmetabolism nicotinic reviewed acetylcholine and toxicity[199] [200]receptor [323] ReviewInhibitionDNA-protective on ofmetabolism nicotinic effects acetylcholine and against toxicity H2O [200]receptor2 in primary [323] rat hepatocytes and testicular cells [324] InhibitionDNA-protectiveAnti-inflammatory of nicotinic effects in acetylcholinean against ALI model H2O receptor2 in miceprimary through[323] rat hepatocytes inhibition ofand the testicular NF-κB and cells MAPKs [324] MonoterpenesAnti-inflammatory in an ALI model in mice through inhibition of the NF-κB and MAPKs OH DNA-protectivesignalling pathways effects [325]; against suppression H2O2 in primaryof expression rat hepatocytes of IL-1β and and IL-6 testicular in TNBS-induced cells [324] Borneol (67) Z. clinopodioides (0.9%–1.2%) [184] signalling pathways [325]; suppression of expression of IL-1β and IL-6 in TNBS-induced OH Isolation/Detection in KazakhstanBorneol (67) Z. clinopodioides (0.9%–1.2%) [184] Anti-inflammatorycolitis in mice [326] in an ALI model in mice through inhibition of the NF-κB and MAPKs signallingcolitisPenetration in mice pathways enhancer [326] [325]; [327]; suppression increasing ofof theexpression brain bioavailability of IL-1β and ofIL-6 different in TNBS-induced drugs [328] OH Name of Compound and ID spp. of Ziziphora (PercentageBorneol (67) Z. clinopodioides (0.9%–1.2%) [184] Biological Activity Chemical Structure colitisPenetrationAntibacterial in mice enhancer (multi-drug[326] [327]; resistant increasing E. coli of )the [329] brain bioavailability of different drugs [328] Content when Given) PenetrationAntibacterialAntiviral (HSV-1) enhancer (multi-drug [282] [327]; resistant increasing E. coli of )the [329] brain bioavailability of different drugs [328] Antiviral (HSV-1) [282] Antibacterial (multi-drug resistant E. coli) [329] Vasorelaxant effect on rat thoracic aortaAntiviralVasorelaxant artery rings(HSV-1) effect [330 [282] on] rat thoracic aorta artery rings [330] Vasorelaxant effect on rat thoracic aorta artery rings [330] HO Positive modulation of the activation ofPositive GABA modulationreceptors of the [331 activation] of GABAA receptors [331] endo-Borneol (68) Z. tenuior (0.14%) [202] A HO endo-Borneol (68) Z. tenuior (0.14%) [202] Positive modulation of the activation of GABAA receptors [331] endo-Borneol (68) Potentiation ofZ. SeC-inducedtenuior (0.14%) [202] apoptosis inVasorelaxantPotentiation human hepatocellular ofeffect SeC-induced on rat thoracic apoptosis carcinoma aorta in artery human cells rings hepatocellular [[330]332] carcinoma cells [332] Potentiation of SeC-induced apoptosis in human hepatocellular carcinoma cells [332] HO PositiveProlonging modulation anaesthesia of the time activation of propofol of GABA by inhibitingA receptors its glucuronidation [331] [333] endo-Borneol (68) Prolonging anaesthesiaZ. tenuior (0.14%) time [202] ofpropofol by inhibiting its glucuronidation [333] PotentiationProlonging anaesthesia of SeC-induced time apoptosisof propofol in by human inhibiting hepatocellular its glucuronidation carcinoma [333] cells [332] Antifungal (against Pyrenophora avenae)[ProlongingAntifungal334] anaesthesia(against Pyrenophora time of propofol avenae) [334] by inhibiting its glucuronidation [333] AntifungalInsecticidal (against (against Pyrenophora Callosobruchus avenae chinensis) [334] and Sitophilus oryzae) [228] Insecticidal (against Callosobruchus chinensis and Sitophilus oryzae)[228] AntifungalInsecticidalAnti-inflammatory (against(against in PyrenophoraCallosobruchus an ALI model avenae chinensis in) mice[334] and [335] Sitophilus and in human oryzae )chondrocytes [228] [336] O Bornyl acetate (69Anti-inflammatory) Z. clinopodioides in an (3.3%) ALI model[184] in miceAnti-inflammatory [335] and inin an human ALI model chondrocytes in mice [335] and [336 in] human chondrocytes [336] O Bornyl acetate (69) Z. clinopodioides (3.3%)Bornyl [184 acetate] (69) Z. clinopodioides (3.3%) [184] InsecticidalAntiabortive (against in pregnant Callosobruchus mice [337] chinensis and Sitophilus oryzae) [228] Antiabortive in pregnant mice [337] Anti-inflammatoryAntiabortiveCytotoxic ((Eca-109, in pregnant in HepG2, an ALImice HT29,model [337] MDA-MB- in mice [335]231, and PC-3, in humanSGC7901, chondrocytes SW1990 and [336] U2-OS) and O O Bornyl acetate (69) Z. clinopodioides (3.3%) [184] Cytotoxic ((Eca-109, HepG2, HT29, MDA-MB-231,AntiabortiveCytotoxica normal cell((Eca-109, inline PC-3, pregnant (HL-7702) HepG2, SGC7901, mice [338]HT29, [337] MDA-MB- 231, PC-3, SGC7901, SW1990 and U2-OS) and O CytotoxicaSedative normal and cell((Eca-109, lineanaesthetic (HL-7702) HepG2, (on [338]HT29, silver MDA-MB-catfish juven231,iles) PC-3, [339]; SGC7901, depressant SW1990 effect and on theU2-OS) CNS and and O SW1990 andZ. U2-OS)clinopodioides and (0.36%–18.2%) a normal cell line (HL-7702) [338] aSedativesignificant normal andcell anticonvulsant lineanaesthetic (HL-7702) (on activity [338] silver probablycatfish juven dueiles) to interaction [339]; depressant with GABA effect receptors on the CNS and Z. clinopodioides[15,184] (0.36%–18.2%) Sedative and anaesthetic (on silver catfishSedativesignificant[340,341] juveniles) and anticonvulsant anaesthetic [339]; depressant(on activity silver probably catfish effect juven due oniles) to theinteraction [339]; CNS depressant with GABA effect receptors on the CNS and Z. clinopodioides[15,184] (0.36%–18.2%) Z. clinopodioides and significant anticonvulsant activity probablysignificant[340,341]Low inhibition anticonvulsant due of to acetylcholinesterase interaction activity probably with and GABA butyrylcholinesterase due to receptorsinteraction with [340 [224] GABA,341 ] receptors [15,184] Low inhibition of acetylcholinesterase and butyrylcholinesterase [224] (0.36%–18.2%) [15,184] Low inhibition of acetylcholinesterase and[340,341]Relaxant butyrylcholinesterase effect on vascular smooth [224 muscle] [342] RelaxantReview on effect some on effects vascular on cardiovascularsmooth muscle system[342] [221] RelaxantZ. effect clinopodioides on vascular subsp. rigida smooth (0.4%) muscle Low [inhibition342] of acetylcholinesterase and butyrylcholinesterase [224] ReviewAnticancer on some(melanoma) effects on[343]; cardiovascular antiproliferativ systeme activity [221] in two murine cancer cell lines Z. clinopodioides [21]subsp. rigida (0.4%) Relaxant effect on vascular smooth muscle [342] Review on some effects on cardiovascularReviewAnticancerthrough system on induction some(melanoma) [221 effects ]of necrosis on[343]; cardiovascular antiproliferativand cell cycle system aerrest activity [221] [344]; in induction two murine of apoptosiscancer cell in lines human Z. clinopodioides [21]subsp. rigida (0.4%) Anticancer (melanoma) [343]; antiproliferativeAnticancerthroughnon-small activityinduction cell(melanoma) lung inof cancer necrosis two [343]; [345]; murine antiproliferativand anti-tumor cell cancer cycle alaerrest cellactivity activity [344]; lines in in inductionhuman two through murine melanoma of induction apoptosiscancer cells cell in bylines ofhuman necrosis Z. clinopodioides subsp. [21] and cell cycle arrest [344]; induction of apoptosisthroughnon-smallinduction induction ofcell in caspase-dependen lung human of cancer necrosis non-small [345]; andt formanti-tumor cell cell ofcycle apoptosis lung alarrest activity cancer [344]; [346] in inductionhuman [345]; melanoma anti-tumoral of apoptosis cells in by human activity in rigida (0.4%) [21]Terpinen-4-ol (70) induction of caspase-dependent form of apoptosis [346] Terpinen-4-ol (70)human melanoma cells by induction ofnon-smallAntiviral caspase-dependent activity cell lung against cancer formin [345];fluenza ofanti-tumor A apoptosis⁄PR⁄8 virusal activity subtype [346 in] human H1N1 [231]melanoma cells by Antiviral activity against influenza A⁄PR⁄8 virus subtype H1N1 [231] Terpinen-4-ol (70) Antiviral activity against influenza A⁄PR⁄8inductionAnti-inflammatory virus of subtype caspase-dependen (inhibition H1N1 [oft231 form NO] productionof apoptosis in [346] LPS-stimulated RAW-264.7 Terpinen-4-ol (70) Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 OH Anti-inflammatory (inhibition of NO productionAntiviralmacrophages) activity in [223]; LPS-stimulated against anti-inflammatory influenza A RAW-264.7⁄PR [216];⁄8 virus anti-inflammatory subtype macrophages) H1N1 [231] activity [223 in ];a murine model OH Z. clinopodioides subsp. bungeana macrophages)of oral candidiasis [223]; [347]; anti-inflammatory suppression of [216]; the production anti-inflammatory of TNFα ,activity IL-1β, IL-8, in a murineIL-10 and model PGE 2 Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 anti-inflammatoryZ. clinopodioides [216 subsp.]; anti-inflammatory bungeana of oral activity candidiasis in [347]; a murine suppression model of the of oralproduction candidiasis of TNFα,[ IL-1347β];, IL-8, IL-10 and PGE2 OH Z. clinopodioides subsp. (0.6%) [201] macrophages)by LPS-activated [223]; monocytes anti-inflammatory [348] [216]; anti-inflammatory activity in a murine model (0.6%) [201] αby LPS-activatedβ monocytes [348] bungeana (0.6%) [201] suppressionZ. clinopodioides of the production subsp. bungeana of TNF of,Antibacterial IL-1 oral candidiasis, IL-8, against IL-10 [347]; MRSA and suppression and PGE CoNS2 byof [349]the LPS-activated production of TNF monocytesα, IL-1β, IL-8, [348 IL-10] and PGE2

Antibacterial against(0.6%) MRSA [201] and CoNSby [AntibacterialLow349 LPS-activated ]antinematocidal against monocytes MRSA activity and[348] [281] CoNS [349] Low antinematocidal activity [281] AntibacterialLowAntimycotic antinematocidal (againstC. albicans MRSA activity) [307,350] and [281] CoNS [349] Antimycotic (C. albicans)[307,350] LowAntimycoticInsecticidal antinematocidal (against (C. albicans L. activity serricorne) [307,350] [281]) [351] Z. tenuior (0.08%) [202] Z. tenuior (0.08%) [202] AntimycoticInsecticidalTrypanocidal (against (C. activity albicans L. against serricorne) [307,350] Trypanosoma) [351] evansi [222] Molecules 2016, 21, 826 Insecticidal (againstZ. tenuiorL. (0.08%) serricorne [202] )[351] Trypanocidal activity against Trypanosoma evansi [222] 22 of 53 Trypanocidal activity against TrypanosomaInsecticidal evansi (against[222] L. serricorne) [351] Z. tenuior (0.08%) [202] Trypanocidal activity against Trypanosoma evansi [222] AntifungalMolecules [187 2016,350, 21,352, 826], antimicrobialAntifungal activity [ 306[187,350,352],] antimicrobial activity [306] 22 of 53 Antiviral activity against influenza A⁄PR⁄8Antiviral virus activity subtype against H1N1 influenza [231 A]⁄PR⁄8 virus subtype H1N1 [231] Enhancement of GABA modulation [353Enhancement] of GABA Antifungalmodulation [187,350,352], [353] antimicrobial activity [306] Anticancer (melanoma cells) [343] Anticancer (melanoma cells)Antiviral [343] activity against influenza A⁄PR⁄8 virus subtype H1N1 [231] α-Terpineol (71) Z. clinopodioides (0.3%–5.3%)α-Terpineol [184] (71) Z. clinopodioides (0.3%–5.3%) [184] Insecticidal (against L. serricorneEnhancement) [351] of GABA modulation [353] Anticancer (melanoma cells) [343] Insecticidal (against L. serricorne)[351] Inhibition of the acetic acid-induced writhing and formalin-induced nociception in mice Inhibition of theα-Terpineol acetic acid-induced (71) Z. clinopodioides writhing (0.3%–5.3%) and formalin-induced [184] Insecticidal (against nociception L. serricorne) [351] in mice [354] [354] Inhibition of the acetic acid-induced writhing and formalin-induced nociception in mice OH Analgesic activity reviewed [199] Analgesic activity reviewed[354] [199] OH

Review on metabolism and toxicity [200Review] on metabolism andAnalgesic toxicity activity [200] reviewed [199] Review on metabolism and toxicity [200]

Antimicrobial activity (MDR resistant bacteria)Antimicrobial [355 activity] (MDRAntimicrobial resistant activity bacteria) (MDR resistant[355] bacteria) [355] Hypocholesterolemic (through inhibitionHypocholesterolemic of HMG-CoA reductase(throughHypocholesterolemic inhibition and conversion (throughof HMG-CoA inhibition of reductase of squalene HMG-CoA and reductase toconversion lanosterol and conversion of [319 of ] squalene to lanosterol [319] 1,8-Cineol (72) Z. clinopodioidessqualene (5.4%–21.6%) to lanosterol [185] [319] O 1,8-Cineol (72) Z. clinopodioides (5.4%–21.6%)1,8-Cineol [185] (72) AnalgesicZ. activity clinopodioides reviewed (5.4%–21.6%) [199 ][185] Analgesic activity reviewed [199] O Review on some effects on cardiovascularAnalgesic system activity [221 reviewed] Review [199] on some effects on cardiovascular system [221] Review on metabolism and toxicity [200Review] on some effects Reviewon cardiovascular on metabolism systemand toxicity [221] [200] Review on metabolism and toxicity [200] Antifungal (Penicillium funiculosum and P. ochrochloron, Aspergillus fumigatus, A. niger, A. flavus, A. ochraceus, C. albicans, T. viride) [187,273,277] Antifungal (Penicillium funiculosumAntibacterial ( B.and cereus P., ochrochloronM. flavus, S. aureus, Aspergillus, L. monocytogenes fumigatus, E. coli, ,A. P. nigeraeruginosa, A., P. mirabilis, flavus, A. ochraceus, C. albicansS. typhimurium, T. viride) [273,274];) [187,273,277] against B. cinerea [275]; active against food spoilage Antibacterial (B. cereus, M.microorganisms flavus, S. aureus [356–358], L. monocytogenes, E. coli, P. aeruginosa, P. mirabilis, Low antinematocidal activity [281] S. typhimurium) [273,274];Antileishmanial against B. cinerea (against [275]; L. chagasi active) [279] against food spoilage microorganisms [356–358]Antiviral (HSV-1) [283]; antiviral activity on enteric viruses [359] Z. clinopodioidesLow antinematocidal (8.7%) [184]; Z. activityReview [281]on synergic effect with antibiotics [132] clinopodioides (52.7%) [183] Antileishmanial (againstCytotoxic L. chagasi (HeLa,) [279] B16, MCF-7, 3T3, MRC-5 cells) [284]; against P815 and PBMC [284]; antiproliferative effects on a human metastatic breast cancer cell line, MDA-MB 231 [360]; Antiviral (HSV-1) [283];induction antiviral of activity apoptosis on in HL-60enteric and viruses Jurkat cells [359] by mitochondria-mediated pathway Z. clinopodioides (8.7%) [184]; Z. Review on synergic effect with antibiotics [132] through the involvement of caspase-3 [361] OH clinopodioides (52.7%) [183] Cytotoxic (HeLa, B16, MCF-7,Cytotoxic 3T3, effect MRC-5 on the intestinal cells) [284]; cell line against Caco-2 P815[362]; inhibitionand PBMC of growth [284]; of N-ras oncogene transformed mouse myoblast cells [363] Carvacrol (73) antiproliferative effects on a human metastatic breast cancer cell line, MDA-MB 231 [360]; DNA-protective effects against H2O2-induced DNA lesions in human hepatoma HepG2 cells induction of apoptosis in[295]; HL-60 antioxidant and Jurkat [273,297,299] cells by mitochondria-mediated pathway through the involvementAnti-inflammatory of caspase-3 [361] (inhibition of NO production in LPS-stimulated RAW-264.7 OH macrophages) [223]; anti-inflammatory effect by reducing the production of IL-1β and Cytotoxic effect on the intestinal cell line Caco-2 [362]; inhibition of growth of N-ras oncogene transformed mouseprostanoids, myoblast possibly cells through [363] the induction of IL-10 release [364] Carvacrol (73) Anti-genotoxic [287] DNA-protective effects against H2O2-induced DNA lesions in human hepatoma HepG2 cells Anxiolytic, GABAA receptor modulation [322,365] [295]; antioxidant [273,297,299]Bronchodilatory effect in guinea pigs [366] Anti-inflammatoryZ. tenuior [94] (inhibitionAntinociceptive of NO activity production in mice inin theLPS-stimulated acetic acid-induced RAW-264.7 abdominal constriction, formalin macrophages) [223]; anti-inflammatoryand hot-plate tests [367] effect by reducing the production of IL-1β and Acetyl- and butyrylcholinesterase inhibitory activity [269,368] prostanoids, possibly throughAnalgesic the activity induction reviewed of [199] IL-10 release [364] Anti-genotoxic [287] Review on anti-inflammatory, antioxidant, and immunological effects [292] Anxiolytic, GABAA receptorReview modulation on some effects [322,365] on cardiovascular system [221] Bronchodilatory effect inGeneral guinea reviews pigs on[366] 73 [369,370] Z. tenuior [94] Antinociceptive activity in mice in the acetic acid-induced abdominal constriction, formalin and hot-plate tests [367] Acetyl- and butyrylcholinesterase inhibitory activity [269,368] Analgesic activity reviewed [199] Review on anti-inflammatory, antioxidant, and immunological effects [292] Review on some effects on cardiovascular system [221] General reviews on 73 [369,370]

Molecules 2016, 21, 826 22 of 53

Antifungal [187,350,352], antimicrobial activity [306] Antiviral activity against inﬂuenza A⁄PR⁄8 virus subtype H1N1 [231] Enhancement of GABA modulation [353] Anticancer (melanoma cells) [343] Molecules 2016, 21, 826 α-Terpineol (71) Z. clinopodioides (0.3%–5.3%) [184] Insecticidal (against L. serricorne) [351] 22 of 54 Inhibition of the acetic acid-induced writhing and formalin-induced nociception in mice [354] OH Analgesic activity reviewed [199] Review on metabolism and toxicity [200] Table 3. Cont. Antimicrobial activity (MDR resistant bacteria) [355] Hypocholesterolemic (through inhibition of HMG-CoA reductase and conversion of Monoterpenessqualene to lanosterol [319] 1,8-Cineol (72) Z. clinopodioides (5.4%–21.6%) [185] O Isolation/Detection in Kazakhstan Analgesic activity reviewed [199] Name of Compound and ID spp. of Ziziphora (Percentage Review onBiological some effects on Activity cardiovascular system [221] Chemical Structure Review on metabolism and toxicity [200] Content when Given)

Antifungal (Penicillium funiculosum andAntifungalP. ochrochloron (Penicillium, Aspergillus funiculosum fumigatus and P. ochrochloron, , Aspergillus fumigatus, A. niger, A. A. niger, A. flavus, A. ochraceus, C. albicansflavus, T., virideA. ochraceus)[187, C.,273 albicans,277, ]T. viride) [187,273,277] Antibacterial (B. cereus, M. flavus, S. aureus, L. monocytogenes, E. coli, P. aeruginosa, P. mirabilis, Antibacterial (B. cereus, M. flavus, S. aureus, L. monocytogenes, E. coli, P. aeruginosa, P. mirabilis, S. typhimurium) [273,274]; against B. cinerea [275]; active against food spoilage S. typhimurium)[273,274]; against B. cinereamicroorganisms[275]; active [356–358] against food spoilage microorganisms [356–358] Low antinematocidal activity [281] Low antinematocidal activity [281] Antileishmanial (against L. chagasi)[279Antileishmanial] (against L. chagasi) [279] Z. clinopodioides (8.7%) [184]; Antiviral (HSV-1) [283]; antiviral activityAntiviral on enteric (HSV-1) viruses [283]; antiviral [359] activity on enteric viruses [359] Z. clinopodioides Z. clinopodioides (8.7%) [184]; Z. (52.7%) [183] Review on synergic effect with antibioticsReview [132 on] synergic effect with antibiotics [132] clinopodioides (52.7%) [183] Cytotoxic (HeLa, B16, MCF-7, 3T3, MRC-5Cytotoxic cells) (HeLa, [284 ];B16, against MCF-7, P8153T3, MRC-5 and PBMCcells) [284]; [284 against]; antiproliferative P815 and PBMC [284]; effects on a antiproliferative effects on a human metastatic breast cancer cell line, MDA-MB 231 [360]; human metastatic breast cancer cell line,induction MDA-MB of apoptosis 231 [360 in HL-60]; induction and Jurkat of cells apoptosis by mitochondr in HL-60ia-mediated and Jurkatpathway cells by mitochondria-mediated pathway through the involvement of caspase-3 [361] through the involvement of caspase-3 [361] OH Cytotoxic effect on the intestinal cell lineCytotoxic Caco-2 effect [362 on]; the inhibition intestinal cell of growthline Caco-2 of [362]; inhibition of growth of N-ras oncogene transformed mouse myoblast cells [363] Carvacrol (73) N-ras oncogene transformed mouse myoblast cells [363] Carvacrol (73) DNA-protective effects against H2O2-induced DNA lesions in human hepatoma HepG2 cells DNA-protective effects against H2O2-induced DNA lesions in human hepatoma HepG2 cells [295]; antioxidant [273,297,299] [295]; antioxidant [273,297,299] Anti-inflammatory (inhibition of NO production in LPS-stimulated RAW-264.7 Anti-inflammatory (inhibition of NO productionmacrophages) in [223]; LPS-stimulated anti-inflammatory RAW-264.7 effect by reducing macrophages) the production [223 of]; IL-1β and

anti-inﬂammatory effect by reducing theprostanoids, production possibly of IL-1 throughβ and the prostanoids,induction of IL-10 release [364] possibly through the induction of IL-10Anti-genotoxic release [364 [287]] Anti-genotoxic [287] Anxiolytic, GABAA receptor modulation [322,365] Bronchodilatory effect in guinea pigs [366] Anxiolytic, GABAA receptor modulation [322,365] Z. tenuior [94] Bronchodilatory effectZ. tenuior in [94] guinea pigs [366Antinociceptive] activity in mice in the acetic acid-induced abdominal constriction, formalin and hot-plate tests [367] Antinociceptive activity in mice in the aceticAcetyl- acid-induced and butyrylcholinesterase abdominal inhibitory constriction, activity [269,368] formalin and hot-plate tests [367] Acetyl- and butyrylcholinesterase inhibitoryAnalgesic activity activity [reviewed269,368 ][199] Analgesic activity reviewed [199] Review on anti-inflammatory, antioxidant, and immunological effects [292] Review on anti-inﬂammatory, antioxidant,Review and on immunologicalsome effects on cardiovascular effects [292 system] [221] Review on some effects on cardiovascularGeneral system reviews [221 on] 73 [369,370] Molecules 2016,, 21,, 826826 23 of 53 General reviews on 73 [369,370]

O Anthelmintic Haemonchus contortus [371] O 2-Methyl-5-(1-methyl-Anthelmintic Haemonchus contortus [371] Anthelmintic Haemonchus contortus [371] 2-Methyl-5-(1-methyl-ethyl)phenol 2-Methyl-5-(1-methyl- Anti-inflammatory effect through inhibition of edema induced by carrageenan, histamine, Z. tenuior [94] ethyl)phenolAnti-inﬂammatory acetate (syn. effect throughZ. tenuior inhibition [94] of edemaAnti-inflammatory induced byeffect carrageenan, through inhibition histamine, of edema induced serotonin by carrageenan, or PGE histamine,[372 ] ethyl)phenol acetate (syn. Z. tenuior [94] serotonin or PGE2 [372] 2 O acetate (syn. carvacryl acetate) (74) serotonin or PGE2 [372] O carvacrylcarvacryl acetate)acetate) ((74)) Anxiolytic-like effect probably through acting onAnxiolytic-like the GABAergic effect probably system through [373 acting,374] on the GABAergic system [373,374]

trans-p-Mentha-2,8-di-enol transtrans--p-Mentha-2,8-di-enol-Mentha-2,8-di-enol (syn.(syn. Z. tenuior [94][94] n.f. Z. tenuior [94]transtrans n.f.-Isopiperitenol)-Isopiperitenol) ((75)) (syn. trans-Isopiperitenol) (75) HO

Antibacterial (multi-drug resistant E. coli)) [329][329] OH Insecticidal activity (against Lasioderma serricorne) [351] Z. clinopodioides subsp. rigida (0.1%) Insecticidal activity (against Lasioderma serricorne) [351] cis-Verbenol (76) Z. clinopodioides subsp. rigida (0.1%) GABAA receptor modulation [322] cis-Verbenol (76) GABAA receptor modulation [322] [21][21] Repellent activity against Anopheles gambiae [375][375] Anti-ischemic and anti-inflammatory activity [376]

OH Z. clinopodioides subsp. rigida (0.1%) Antibacterial (multi-drug resistant E. coli) [329] trans-Verbenol (77) Z. clinopodioides subsp. rigida (0.1%) Antibacterial (multi-drug resistant E. coli) [329] trans-Verbenol (77) [21] GABAA receptor modulation [322] [21] GABAA receptor modulation [322]

Z. clinopodioides subsp.subsp. rigidarigida (0.8%)(0.8%) O H [21][21]

Cuminyl aldehyde (syn. Tyrosinase inhibitory activity [377] cumaldehyde)cumaldehyde) ((78)) Suppression of melanin formation in cultured murine B16-F10 melanoma cells [378] Z. clinopodioides (0.12%–0.24%)(0.12%–0.24%) [15][15]

Glc O R Weak inhibitory activity on NO production stimulated by LPS and IFN-γ inin RAWRAW 264.7264.7 cellscells R Ziziphoroside A (79)) Z. clinopodioides [4][4] [4][4] O Glc O R R Weak inhibitory activity on NO production stimulated by LPS and IFN-γ inin RAWRAW 264.7264.7 cellscells R R Ziziphoroside B (80)) Z. clinopodioides [4][4] [4][4] O

MoleculesMolecules 20162016,, 2121,, 826826 2323 ofof 5353 Molecules 20162016,, 2121,, 826826 2323 ofof 5353

OO AnthelminticAnthelmintic Haemonchus Haemonchus contortus contortus [371] [371] O 2-Methyl-5-(1-methyl-2-Methyl-5-(1-methyl- AnthelminticAnthelmintic HaemonchusHaemonchus contortuscontortus [371][371] Molecules 2016, 21, 826 2-Methyl-5-(1-methyl-2-Methyl-5-(1-methyl- Anti-inflammatoryAnti-inflammatory effect effect through through inhibition inhibition of of edema edema induced induced by by carrageenan, carrageenan, histamine, histamine, 23 of 54 ethyl)phenolethyl)phenol acetate acetate (syn. (syn. Z.Z. tenuior tenuior [94] [94] Anti-inflammatoryAnti-inflammatory effecteffect throughthrough inhibitioninhibition ofof edemaedema inducedinduced byby carrageenan,carrageenan, histamine,histamine, ethyl)phenol acetate (syn. Z. tenuior [94] serotonin or PGE22 [372] OO ethyl)phenol acetate (syn. Z. tenuior [94] serotonin or PGE2 [372][372] O carvacrylcarvacryl acetate) acetate) ( (7474)) serotonin or PGE2 [372] O carvacrylcarvacryl acetate)acetate) ((7474)) Anxiolytic-likeAnxiolytic-like effect effect probably probably through through acting acting on on the the GABAergic GABAergic system system [373,374] [373,374] Molecules 2016, 21, 826 Anxiolytic-likeAnxiolytic-like effecteffect probablyprobably throughthrough actingacting onon thethe GABAergicGABAergic systemsystem [373,374][373,374] 23 of 53

Table 3. Cont. O Anthelmintic Haemonchus contortus [371] 2-Methyl-5-(1-methyl- Anti-inflammatory effect through inhibition of edema induced by carrageenan, histamine, ethyl)phenol acetate (syn. Z. tenuior [94] serotonin or PGE2 [372] O carvacryl acetate) (74Monoterpenes) transtrans--pp-Mentha-2,8-di-enol-Mentha-2,8-di-enol (syn. (syn. Anxiolytic-like effect probably through acting on the GABAergic system [373,374] trans-p-Mentha-2,8-di-enol (syn. Z.Z. tenuior tenuior [94] [94][94] n.f.n.f. transtrans-Isopiperitenol)-Isopiperitenol) ( (7575)) Z. tenuior [94] n.f. Isolation/Detection intrans Kazakhstan-Isopiperitenol) (75) HHOO Name of Compound and ID spp. of Ziziphora (Percentage Biological Activity ChemicalHO Structure Content when Given)

trans-p-Mentha-2,8-di-enol (syn. Z. tenuior [94] n.f. Antibacterialtrans (multi-drug-Isopiperitenol) resistant(75) E. coliAntibacterialAntibacterial)[329] (multi-drug (multi-drug resistant resistant E.E. coli coli)) [329] [329] OHOH AntibacterialAntibacterial (multi-drug(multi-drug resistantresistant E.E. colicoli)) [329][329] HO OH Insecticidal activity (against LasiodermaInsecticidal serricorneInsecticidal activity )[activity351] (against (against LasiodermaLasioderma serricorne serricorne)) [351] [351] OH Z. clinopodioides subsp. Z.Z. clinopodioides clinopodioides subsp. subsp. rigida rigida (0.1%) (0.1%) InsecticidalInsecticidal activityactivity (against(against LasiodermaLasioderma serricorneserricorne)) [351][351] cis-cis-VerbenolVerbenol ( (7676)) Z. clinopodioides subsp. rigida (0.1%) GABAGABAAA receptor receptor modulation modulation [322] [322] cis-Verbenol (76) cis-Verbenol (76) GABAA receptorZ. clinopodioides modulation subsp. rigida [322 (0.1%)] GABAA receptor modulation [322] cis-Verbenol (76) [21][21] GABAA receptor modulation [322] rigida (0.1%) [21] [21][21] RepellentRepellent activity activity against against AnophelesAnopheles gambiae gambiae [375] [375] Repellent activity against Anopheles gambiaeRepellentRepellent[375 activityactivity] againstagainst AnophelesAnopheles gambiaegambiae [375][375] Anti-ischemicAnti-ischemic and and anti-inflammatory anti-inflammatoryAntibacterial (multi-drug activity activity resistant [376] [376] E. coli) [329] OH Anti-ischemic and anti-inﬂammatory activityAnti-ischemic [376] and anti-inflammatoryInsecticidal activity activity (against [376]Lasioderma serricorne) [351] Z. clinopodioides subsp. rigida (0.1%) cis-Verbenol (76) GABAA receptor modulation [322] [21] Repellent activity against Anopheles gambiae [375] OHOH Anti-ischemic and anti-inflammatory activity [376] OH Z.Z. clinopodioides clinopodioides subsp. subsp. rigida rigida (0.1%) (0.1%) AntibacterialAntibacterial (multi-drug (multi-drug resistant resistant E.E. coli coli)) [329] [329] Z. clinopodioides subsp.trans-trans-VerbenolVerbenol ( (7777)Antibacterial) Z.Z. clinopodioidesclinopodioides (multi-drug subsp.subsp. resistant rigidarigida (0.1%)(0.1%)E. coliAntibacterialAntibacterial)[329] (multi-drug(multi-drug resistantresistant E.E. colicoli)) [329][329] trans-Verbenol (77) trans-Verbenol (77) [21] GABAAA receptor modulation [322] trans-Verbenol (77) [21] GABAA receptorreceptor modulationmodulation [322][322] OH rigida (0.1%) [21] GABAA receptor modulation[21] [322] GABAA receptor modulation [322] Z. clinopodioides subsp. rigida (0.1%) Antibacterial (multi-drug resistant E. coli) [329] trans-Verbenol (77) [21] GABAA receptor modulation [322] Z.Z. clinopodioides clinopodioides subsp. subsp. rigida rigida (0.8%) (0.8%) OO HH Z.Z. clinopodioidesclinopodioides subsp.subsp. rigidarigida (0.8%)(0.8%) O H [21][21] Z. clinopodioides subsp. [21] Z. clinopodioides subsp. rigida (0.8%) O H [21] rigida (0.8%) [21] Cuminyl aldehyde CuminylCuminyl aldehyde aldehyde (syn. (syn.Tyrosinase inhibitory activity [377] TyrosinaseTyrosinase inhibitory inhibitory activity activity [377] [377] Cuminyl aldehyde (syn. Cuminyl aldehyde (syn. Tyrosinase inhibitory activityTyrosinase [377] inhibitory activity [377] (syn. cumaldehyde) (78) cumaldehyde)cumaldehyde) ( (7878)Suppression) of melanin formation in culturedSuppressionSuppression murine of of melanin melanin B16-F10 formation formation melanoma in in cultur cultureded cells murine murine [378 B16-F10 B16-F10] melanoma melanoma cells cells [378] [378] cumaldehyde) (78) Z.Z. clinopodioides clinopodioidescumaldehyde) (0.12%–0.24%) (0.12%–0.24%) (78) [15] [15] Suppression of melaninSuppression formation of in melanin cultur formationed murine in cultur B16-F10ed murine melanoma B16-F10 melanomacells [378] cells [378] Z.Z. clinopodioidesclinopodioides (0.12%–0.24%)(0.12%–0.24%) [15][15]Z. clinopodioides (0.12%–0.24%) [15] Z. clinopodioides (0.12%–0.24%) [15]

Glc O GlcGlc OO Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O R R Ziziphoroside A (79) Z.WeakWeak clinopodioides inhibitory inhibitory [4] activity activity on on NO NO production production stimulated stimulated by by LPS LPS and and IFN- IFN-γγ in in RAW RAW 264.7 264.7 cells cells R Ziziphoroside A (79) Z. clinopodioidesZiziphoroside[Ziziphoroside4] A A ( (7979 Weak)) inhibitoryZ.Z. activityclinopodioides clinopodioides on [4] NO[4] productionWeak stimulatedinhibitory activity by[4] LPS on NO and production IFN-γ stimulatedin RAW 264.7by LPS cells and IFN- [4]γγ inin RAWRAW 264.7264.7 cellscells R ZiziphorosideZiziphoroside AA ((7979)) Z.Z. clinopodioidesclinopodioides [4][4] [4][4] O [4][4] Glc O OO Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells O R R Ziziphoroside B (80) Z. clinopodioides [4] GlcGlc OO [4] GlcGlc OO RR RR WeakWeak inhibitory inhibitory activity activity on on NO NO production production stimulated stimulated by by LPS LPS and and IFN- IFN-γγ in inin RAW RAWRAW 264.7 264.7264.7 cells cellscells O R R ZiziphorosideZiziphoroside B B ( (8080)) Z.Z. clinopodioides clinopodioides [4] [4] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells R R Ziziphoroside B (80) Z. clinopodioides [Ziziphoroside4] B (80 Weak) inhibitoryZ. activity clinopodioides on NO[4] production[4][4] stimulated by LPS and IFN-γ in RAW 264.7 cells [4] Molecules 2016, 21, 826 [4] OO 24 of 53 Molecules 2016, 21, 826 OO 24 of 53 Molecules 2016, 21, 826 24 of 53 Molecules 2016, 21, 826 24 of 53 Glc O Glc O Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O Ziziphoroside C (81) Z. clinopodioides [Ziziphoroside4] C (81 Weak) inhibitoryZ. activity clinopodioides on NO[4] productionWeak stimulatedinhibitory activity by LPS on NO and production IFN-γ instimulated RAW 264.7by LPS cells and IFN- [4] γ in RAW 264.7 cells Glc O Ziziphoroside C (81) Z. clinopodioides [4] Weak[4] inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Ziziphoroside C (81) Z. clinopodioides [4] [4]Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells O Ziziphoroside C (81) Z. clinopodioides [4] [4] O [4] Glc O O Glc O O Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O R Schizonepetoside C (82) Z. clinopodioides [4] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O R Schizonepetoside C (82) Z. clinopodioidesSchizonepetoside[4] C ( Weak82) inhibitoryZ. activity clinopodioides on NO[4] productionWeak[4] stimulatedinhibitory activity by LPSon NO and production IFN-γ instimulated RAW 264.7by LPS cellsand IFN- [4]γ in RAW 264.7 cells R Schizonepetoside C (82) Z. clinopodioides [4] [4]Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells O R Schizonepetoside C (82) Z. clinopodioides [4] [4] O [4] Glc O O Glc O O Some inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O Schizonepetoside A (83) Z. clinopodioides [4] Some inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O Schizonepetoside A (83) Z. clinopodioides [4] Some[4] inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Schizonepetoside A (83) Z. clinopodioidesSchizonepetoside[4] A ( Some83) inhibitoryZ. activity clinopodioides on NO[4] production[4]Some stimulatedinhibitory activity by LPS on NO and production IFN-γ instimulated RAW 264.7by LPS cells and IFN- [4]γ in RAW 264.7 cells O Schizonepetoside A (83) Z. clinopodioides [4] [4] O [4] Glc O O Glc O O 9-O-Glucopyranosyl-p-menthan- Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O 9-O-Glucopyranosyl-p-menthan- Z. clinopodioides [4] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O 9-O-Glucopyranosyl-3-one (84)p -menthan- Z. clinopodioides [4] Weak[4] inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells 9-O-Glucopyranosyl-p- 9-O-Glucopyranosyl-3-one (84)p -menthan- Z. clinopodioides [4] [4]Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells O Z. clinopodioides [4]3-one (84) Weak inhibitoryZ. activity clinopodioides on NO[4] production[4] stimulated by LPS and IFN-γ in RAW 264.7 cells [4] O menthan-3-one (84) 3-one (84) [4] O HO H H H 4aα,7α,7aα-Nepeta-lactone (85) Z. tenuior (0.5%) [94,179] Some activity against Helicobacter pylori [379] and repellent activity against mosquitoes [380] 4aα,7α,7aα-Nepeta-lactone (85) Z. tenuior (0.5%) [94,179] Some activity against Helicobacter pylori [379] and repellent activity against mosquitoes [380] O 4aα,7α,7aα-Nepeta-lactone (85) Z. tenuior (0.5%) [94,179] Some activity against Helicobacter pylori [379] and repellent activity against mosquitoes [380] O 4aα,7α,7aα-Nepeta-lactone (85) Z. tenuior (0.5%) [94,179] Some activity against Helicobacter pylori [379] and repellent activity against mosquitoes [380] O O H O H O H Sesquiterpenes O H Sesquiterpenes O Isolation/Detection in Kazakhstan Sesquiterpenes Isolation/Detection in Kazakhstan Sesquiterpenes Name of Compound and ID Isolation/Detectionspp. of Ziziphora in (Percentage Kazakhstan Biological Activity Chemical Structure Name of Compound and ID Isolation/Detectionspp. of Ziziphora in(Percentage Kazakhstan Biological Activity Chemical Structure Name of Compound and ID spp.Content of Ziziphora When (Percentage Given) Biological Activity Chemical Structure Name of Compound and ID spp.Content of Ziziphora When (Percentage Given) Biological Activity Chemical Structure Content When Given) Content When Given)

Germacrene B (86) Z. clinopodioides (1.1%) [11] n.f. Germacrene B (86) Z. clinopodioides (1.1%) [11] n.f. Germacrene B (86) Z. clinopodioides (1.1%) [11] n.f. Germacrene B (86) Z. clinopodioides (1.1%) [11] n.f.

Z. clinopodioides (0.24%–4.0 %) Z. clinopodioides (0.24%–4.0 %) Z. clinopodioides[15,184] (0.24%–4.0 %) Z. clinopodioides[15,184] (0.24%–4.0 %) Z. clinopodioides[15,184] subsp. rigida (1.1%) Z. clinopodioides[15,184] subsp. rigida (1.1%) Z. clinopodioides [21]subsp. rigida (1.1%) Germacrene D (87) Z. clinopodioides [21]subsp. rigida (1.1%) Effective aphid repellent [381] Germacrene D (87) Z. tenuior (0.13%)[21] [94,179] Effective aphid repellent [381] Germacrene D (87) Z. tenuior (0.13%)[21] [94,179] Effective aphid repellent [381] Germacrene D (87) Z. tenuior (0.13%) [94,179] Effective aphid repellent [381] Z. clinopodioidesZ. tenuior (0.13%) subsp. [94,179] bungeana Z. clinopodioides subsp. bungeana Z. clinopodioides(0.3%) subsp. [201] bungeana Z. clinopodioides(0.3%) subsp. [201] bungeana (0.3%) [201] Bicyclogermacrene (88) Z. clinopodioides(0.3%) [201] (0.6%) [185] Low antibacterial effect (S. aureus, B. cereus, A. baumanii, E. coli, P. aeruginosa) [382] Bicyclogermacrene (88) Z. clinopodioides (0.6%) [185] Low antibacterial effect (S. aureus, B. cereus, A. baumanii, E. coli, P. aeruginosa) [382] Bicyclogermacrene (88) Z. clinopodioides (0.6%) [185] Low antibacterial effect (S. aureus, B. cereus, A. baumanii, E. coli, P. aeruginosa) [382] Bicyclogermacrene (88) Z. clinopodioides (0.6%) [185] Low antibacterial effect (S. aureus, B. cereus, A. baumanii, E. coli, P. aeruginosa) [382]

Molecules 2016, 21, 826 24 of 53

Molecules 2016, 21, 826 Glc O 24 of 53 Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Ziziphoroside C (81) Z. clinopodioides [4] Molecules 2016, 21, 826 [4] Glc O 24 of 54 Molecules 2016, 21, 826 O 24 of 53 Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Ziziphoroside C (81) Z. clinopodioides [4] Glc O [4] Glc O Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells O R Schizonepetoside C (82) Z. clinopodioides [4] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Ziziphoroside C (81) Z. clinopodioides [4][4] Glc O [4] O Table 3. Cont.Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells O R Schizonepetoside C (82) Z. clinopodioides [4] Glc O [4] Glc O Some inhibitoryWeak activity inhibitory on activity NO production on NO production stimulated stimulated by LPS by and LPS IFN- and γIFN- in γRAW in RAW 264.7 264.7 cells cells O R Schizonepetoside ASchizonepetoside (83) C (82) Z. clinopodioidesZ. [4] clinopodioides [4] Monoterpenes[4] [4] Glc O OO Some inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Schizonepetoside A (83) Z. clinopodioides [4] GlcGlc O Isolation/Detection in Kazakhstan [4] Some inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells 9-O-Glucopyranosyl-p-menthan-Schizonepetoside A (83) Z. clinopodioides [4]Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells O Name of Compound and ID spp. of Ziziphora (Percentage Z. clinopodioides [4] Biological[4] Activity Chemical Structure 3-one (84) [4] Glc O Content when Given) OO 9-O-Glucopyranosyl-p-menthan- Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Glc O Z. clinopodioides [4] 3-one (849-)O -Glucopyranosyl-p-menthan- [4] Weak inhibitory activity on NO production stimulated by LPS and IFN-γ in RAW 264.7 cells Z. clinopodioides [4] H 3-one (84) [4] O O 4aα,7α,7aα-Nepeta-lactone (85) Z. tenuior (0.5%)4a [α94,7α,179,7aα]-Nepeta-lactone Some (85) activityZ. against tenuior (0.5%)Helicobacter [94,179] pylori Some[379] activity and repellent against Helicobacter activity pylori against [379] mosquitoesand repellent activity [380] against mosquitoes [380] H O H

4aα,7α,7aα-Nepeta-lactone (85) Z. tenuior (0.5%) [94,179] Some activity against Helicobacter pylori [379] and repellent activity against mosquitoes [380] H 4aα,7α,7aα-Nepeta-lactone (85) Z. tenuior (0.5%) [94,179] Some activity against Helicobacter pylori [379] and repellent activity against mosquitoes [380] OO O Sesquiterpenes Sesquiterpenes H Isolation/Detection in Kazakhstan O Isolation/Detection inName Kazakhstan of Compound and ID spp. of Ziziphora (Percentage Biological Activity SesquiterpenesSesquiterpenes Chemical Structure Name of Compound and ID spp. of Ziziphora (Percentage BiologicalIsolation/Detection ActivityContent WhenIsolation/Detection in Given) Kazakhstan in Kazakhstan Chemical Structure Content WhenName Given) of CompoundName and of ID Compound spp. and of ID Ziziphora spp. (Percentage of Ziziphora (PercentageBiological ActivityBiological Activity ChemicalChemical Structure Content WhenContent Given) When Given)

Germacrene B (86) Z. clinopodioides (1.1%) [11] n.f. Germacrene B (86) Z. clinopodioides (1.1%) [11] n.f.Germacrene B (86) Z. clinopodioides (1.1%) [11] n.f. Germacrene B (86) Z. clinopodioides (1.1%) [11] n.f.

Z. clinopodioides (0.24%–4.0 %) [15,184]Z. clinopodioides (0.24%–4.0 %) Z. clinopodioides (0.24%–4.0 %) [15,184] Z. Z.clinopodioides clinopodioides subsp. (0.24%–4.0 rigida (1.1%)%) [15,184] Z. clinopodioides subsp. rigida (1.1%) [15,184][21] Germacrene D (87) [21] Effective aphid repellent [381] Germacrene D (87Z.) tenuior (0.13%) [94,179] Effective aphid repellent [381] Z. clinopodioides subsp. Z. clinopodioides subsp.Z. tenuior rigida (0.13%)(1.1%) [94,179] [21] rigida (1.1%) [21Germacrene] D (87) Z. clinopodioides subsp. bungeana Effective aphid repellent [381] Germacrene D (87) Effective aphidZ. tenuior repellent (0.13%)Z. clinopodioides [381 [94,179]] subsp. bungeana Z. tenuior (0.13%) [94,179] (0.3%) [201] (0.3%) [201] Z. clinopodioides subsp. bungeana BicyclogermacreneMoleculesBicyclogermacrene (88 2016) , 21, 826 Z. (88 clinopodioides) Z. (0.6%) clinopodioides [185] (0.6%) Low[185] antibacterialLow antibacterial effect (S. aureuseffect (,S. B. aureus cereus,, B. A. cereus, baumanii A. baumanii, E. coli, ,E. P. coli aeruginosa, P. aeruginosa) [382]) [382] 25 of 53 Z. clinopodioides subsp. Molecules 2016, 21, 826 (0.3%) [201] 25 of 53 bungeana (0.3%) [201] Bicyclogermacrene (88) Z. clinopodioides (0.6%) [185] Low antibacterial effect (S. aureus, B. cereus, A. baumanii, E. coli, P. aeruginosa) [382] Z. clinopodioides (0.6%) [185] Z. clinopodioides subsp. bungeana Z. clinopodioides subsp. bungeana Bicyclogermacrene (88) Low antibacterial effect (S. aureus(0.1%), B.[201] cereus, A. baumanii, E. coli, P. aeruginosa)[382] Z. clinopodioides subsp. (0.1%) [201] bungeana (0.1%) [201] Z. clinopodioides (0.2%) [184] Z. clinopodioides (0.2%) [184] Z. clinopodioides (0.2%) [184]

β-Bisabolene (89) Synergisticβ-Bisabolene (89 antibacterial) activity with ampicillin againstSynergistic strain antibacterial of S. activity aureus with[383 ampicillin] against strain of S. aureus [383] β-Bisabolene (89) Z. tenuior [94] Synergistic antibacterial activity with ampicillin against strain of S. aureus [383] Z. tenuior [94] Z. tenuior [94]

Z. clinopodioides (0.5%) [184] O Z. clinopodioides (0.5%) [184] O Antitermitic [187], antifungal [308,384], antimicrobial [385] Antitermitic [187], antifungal [308,384], antimicrobial [385] Analgesic and anti-inflammatory activity in tested mice [386] Caryophyllene oxide (β- Analgesic and anti-inflammatory activity in tested mice [386] Caryophyllene oxide (β- Z. tenuior (0.11%–0.32%) Modest cytotoxic activity against tested human tumor cell lines [387] caryophyllene oxide) (90) Z. tenuior (0.11%–0.32%) Modest cytotoxic activity against tested human tumor cell lines [387] caryophyllene oxide) (90) [94,179,202] Anti-cancer effects through the modulation of the PI3K/AKT/mTOR/S6K1 and MAPK [94,179,202] Anti-cancer effects through the modulation of the PI3K/AKT/mTOR/S6K1 and MAPK H H signalling [388] H H signalling [388]

Antifungal, antibacterial [187] Antifungal, antibacterial [187] Antiprotozoal (T. cruzi, L. infantum) [389] Antiprotozoal (T. cruzi, L. infantum) [389] Fumigant against Lasioderma serricorne [390] H Fumigant against Lasioderma serricorne [390] H Caryophyllene (syn. Antihyperglycemic effect by decreasing blood glucose and increasing plasma insulin in Caryophyllene (syn. Antihyperglycemic effect by decreasing blood glucose and increasing plasma insulin in β-caryophyllene, diabetic rats [391] β-caryophyllene, Z. tenuior (0.22%) [94,179] diabetic rats [391] trans-caryophyllene, Z. tenuior (0.22%) [94,179] Antioxidant effect and inhibition of 5-lipoxygenase in CCl4-induced fibrosis in rats [392] trans-caryophyllene, Antioxidant effect and inhibition of 5-lipoxygenase in CCl4-induced fibrosis in rats [392] (E)-caryophyllene) (91) Anti-inflammatory effect through the inhibition of TNFα and PGE2 and it is also effective in (E)-caryophyllene) (91) Anti-inflammatory effect through the inhibition of TNFα and PGE2 and it is also effective in reducing PAF-, bradykinin-, ovoalbumin-induced mouse paw edema [393,394] H reducing PAF-, bradykinin-, ovoalbumin-induced mouse paw edema [393,394] H Low inhibition of acetylcholinesterase and butyrylcholinesterase [224] Low inhibition of acetylcholinesterase and butyrylcholinesterase [224] Review on metabolism and toxicity [200] Review on metabolism and toxicity [200] Antibacterial activity against Propionibacterium acnes (MIC of 3.13 µg/mL) [395] Antibacterial activity against Propionibacterium acnes (MIC of 3.13 µg/mL) [395] Antiproliferative activity against several cancer cell lines (MCF-7, PC-3, M4BEU, CT-26, Antiproliferative activity against several cancer cell lines (MCF-7, PC-3, M4BEU, CT-26, human amelanotic melanoma cell line C32, renal cell adenocarcinoma ACHN, hormone- human amelanotic melanoma cell line C32, renal cell adenocarcinoma ACHN, hormone- α-Humulene (syn. α- dependent prostate carcinoma LNCaP, A-549 and human colon adenocarcinoma cell line α-Humulene (syn. α- Z. clinopodioides (2.7%–4.5%) [184] dependent prostate carcinoma LNCaP, A-549 and human colon adenocarcinoma cell line Caryophyllene) (92) Z. clinopodioides (2.7%–4.5%) [184] DLD-1) [396–401] Caryophyllene) (92) DLD-1) [396–401] Anti-inflammatory effect through the inhibition of TNFα, IL-1β and PGE2 and it is also Anti-inflammatory effect through the inhibition of TNFα, IL-1β and PGE2 and it is also effective in reducing PAF-, bradykinin-, ovoalbumin- and histamine-induced mouse paw effective in reducing PAF-, bradykinin-, ovoalbumin- and histamine-induced mouse paw edema [393,394] edema [393,394]

Molecules 2016, 21, 826 25 of 53 Molecules 2016, 21, 826 25 of 53 Molecules 2016, 21, 826 25 of 53 Molecules 2016, 21, 826 25 of 54 Z. clinopodioides subsp. bungeana Z. clinopodioides subsp. bungeana (0.1%) [201] (0.1%)Z. [201] clinopodioides subsp. bungeana (0.1%) [201]

Z. clinopodioides Table(0.2%) [184] 3. Cont. Z. clinopodioides (0.2%) [184] Z. clinopodioides (0.2%) [184] Sesquiterpenes β-Bisabolene (89) Synergistic antibacterial activity with ampicillin against strain of S. aureus [383] Isolation/Detection in Kazakhstanβ-Bisabolene (89) β-Bisabolene (89) Z. tenuior [94] Synergistic antibacterialSynergistic antibacterial activity with activity ampicillin with ampicillin against againststrain ofstrain S. aureus of S. aureus [383] [383] Z. tenuior [94] Z. tenuior [94] Name of Compound and ID spp. of Ziziphora (Percentage Biological Activity Chemical Structure Content When Given) Z. clinopodioides (0.5%) [184] O Z. clinopodioides Z.(0.5%) clinopodioides [184] (0.5%) [184] OO Z. clinopodioides (0.5%) [184] AntitermiticAntitermitic [187], antifungal [187], antifungal[308,384], [308,384], antimicrobial antimicrobial [385] [385] Antitermitic [187], antifungal [308,384],Antitermitic antimicrobial [187], [antifungal385] [308,384], antimicrobial [385] Caryophyllene oxide Analgesic andAnalgesic anti-inflammatory and anti-inflammatory activity in activity tested in mice tested [386] mice [386] Caryophyllene oxideCaryophylleneAnalgesic (β- oxide and (β anti-inflammatory- activityAnalgesic in tested and miceanti-inflammatory [386] activity in tested mice [386] (β-caryophyllene oxide) (90) Caryophyllene oxide (β- Z. tenuior (0.11%–0.32%)Z. tenuior (0.11%–0.32%)Modest cytotoxicModest activity cytotoxic against activity tested against human tested tumor human cell tumor lines cell [387] lines [387] caryophyllene oxide)caryophyllene Modest(90) cytotoxic oxide)Z. (90 tenuior) activity (0.11%–0.32%) against testedModest human cytotoxic tumor activity cell lines against [387 tested] human tumor cell lines [387] caryophyllene oxide) (90) [94,179,202] [94,179,202] Anti-cancer Anti-cancereffects through effects the through modulation the modulation of the PI3K/AKT/mTOR/S6K1 of the PI3K/AKT/mTOR/S6K1 and MAPKand MAPK Z. tenuior (0.11%–0.32%) [94,179,202] [94,179,202] Anti-cancer effects through the modulation of the PI3K/AKT/mTOR/S6K1 and MAPK HH H Anti-cancer effects through the modulationsignalling of the [388]signalling PI3K/AKT/mTOR/S6K1 [388] and MAPK signalling [388] H H signalling [388] Antifungal, antibacterial [187] Antifungal, antibacterial [187] Antifungal, antibacterial [187] Antifungal, antibacterialAntiprotozoal [187](T. cruzi , L. infantum) [389] Antiprotozoal (T. cruzi, L. infantum)[389Antiprotozoal] (T. cruzi, L. infantum) [389] AntiprotozoalFumigant (T. cruzi against, L. infantum Lasioderma) [389] serricorne [390] H Fumigant against Lasioderma serricorne [390] H FumigantCaryophyllene against (syn. Lasioderma serricorne [Fumigant390] againstAntihyperglycemic Lasioderma serricorne effect by decreasing[390] blood glucose and increasing plasma insulin in H Caryophyllene (syn. Caryophyllene (syn. β -caryophyllene, Antihyperglycemicdiabetic ratseffect [391] by decreasing blood glucose and increasing plasma insulin in Caryophyllene (syn.Antihyperglycemic effectZ. by tenuior decreasing (0.22%) [94,179]Antihyperglycemic blood glucose andeffect increasingby decreasing plasma blood glucose insulin and inincreasing diabetic plasma rats insulin [391] in β-caryophyllene, β-caryophyllene, trans -caryophyllene, diabetic rats Antioxidant[391] effect and inhibition of 5-lipoxygenase in CCl4-induced fibrosis in rats [392] Z. tenuior (0.22%) [94,β179-caryophyllene,] Antioxidant effectZ. tenuior and (0.22%) inhibition [94,179] of 5-lipoxygenasediabetic rats [391] in CCl4-induced fibrosis in rats [392] trans-caryophyllene, trans-caryophyllene,(E)-caryophyllene) Z.(91 tenuior) (0.22%) [94,179] Antioxidant Anti-inflammatoryeffect and inhibition effect of through 5-lipoxygenase the inhibition in CCl of TNF4-inducedα and PGEfibrosis2 and in it ratsis also [392] effective in trans-caryophyllene, Antioxidant effect andα inhibition of 5-lipoxygenase in CCl4-induced fibrosis in rats [392] H (E)-caryophyllene) (91Anti-inflammatory) effect through the inhibitionAnti-inflammatory ofreducing TNF effect PAF-,and through bradykinin-, PGE the2 and inhibitionovoalbumin it is also of-induced TNF effectiveα andmouse PGE pa in2w and reducingedema it is [393,394] also PAF-,effective in (E)-caryophyllene) (91) (E)-caryophyllene) (91) Anti-inflammatory effect through the inhibition of TNFα and PGE2 and it is also effective in bradykinin-, ovoalbumin-induced mousereducing paw edemaPAF-,Low bradykinin-, inhibition [393,394 of acetylcholinesteraseovoalbumin] -induced and mousebutyrylcholinesterase paw edema [393,394] [224] H reducing PAF-, bradykinin-, ovoalbumin-induced mouse paw edema [393,394] H Low inhibition of acetylcholinesterase andLow butyrylcholinesteraseinhibitionReview of acetylcholinesterase on metabolism [and224 toxicity ]and butyrylcholinesterase [200] [224] Low inhibition of acetylcholinesterase and butyrylcholinesterase [224] Review on metabolism and toxicity [200Review] on metabolismAntibacterial and activity toxicity against [200] Propionibacterium acnes (MIC of 3.13 µg/mL) [395] Review on metabolismAntiproliferative and toxicityactivity against [200] several cancer cell lines (MCF-7, PC-3, M4BEU, CT-26, Antibacterial activity against Propionibacterium acnes (MIC of 3.13 µg/mL) [395] Antibacterialhuman activity amelanotic against Propionibacteriummelanoma cell line C32,acnes renal (MIC cell of adenocarcinoma 3.13 µg/mL) [395] ACHN, hormone- α-Humulene (syn. α- Antiproliferativedependent activity prostate against carcinoma severalµ LNCaP, cancer A-5cell49 lines and (MCF-7,human colon PC-3, adenocarcinoma M4BEU, CT-26, cell line Antibacterial activity againstZ. clinopodioidesPropionibacterium (2.7%–4.5%)Antiproliferative [184] acnes (MIC activity of against 3.13 severalg/mL) cancer [395 cell] lines (MCF-7, PC-3, M4BEU, CT-26, Caryophyllene) (92) human amelanoticDLD-1) melanoma[396–401] cell line C32, renal cell adenocarcinoma ACHN, hormone- Antiproliferative activity against severalhuman cancer amelanotic cell lines melanoma (MCF-7, cell PC-3,line C32, M4BEU, renal cell CT-26,adenocarcinoma human ACHN, amelanotic hormone- α-Humulene (syn. α- dependent prostateAnti-inflammatory carcinoma effect LNCaP, through A-5 the49 andinhibition human of colonTNFα, adenocarcinomaIL-1β and PGE2 and cell it is line also α-Humulene (syn. α-Humulene (syn. αmelanoma- Z. cellclinopodioides line C32, (2.7%–4.5%) renal cell [184] adenocarcinoma dependent prostate ACHN, carcinoma hormone-dependent LNCaP, A-549 and human prostate colon carcinomaadenocarcinoma LNCaP, cell line Caryophyllene) (92) Z. clinopodioides (2.7%–4.5%) [184] DLD-1) [396–401]effective in reducing PAF-, bradykinin-, ovoalbumin- and histamine-induced mouse paw Z. clinopodioides (2.7%–4.5%)Caryophyllene) [184] (92) DLD-1) [396–401] α-Caryophyllene) (92) A-549 and human colon adenocarcinomaAnti-inflammatory cell lineedema DLD-1) [393,394] effect [396 through –401 the] inhibition of TNFα, IL-1β and PGE2 and it is also Anti-inflammatory effect through the inhibition of TNFα, IL-1β and PGE2 and it is also Molecules 2016, 21, 826 Anti-inflammatory effect through the inhibitioneffective in ofreducing TNFα PAF-,, IL-1 bradykinin-,β and PGE ovoalbumin-2 and it is and also histamine-induced effective in reducing mouse paw PAF-, 26 of 53 Molecules 2016, 21, 826 effective in reducing PAF-, bradykinin-, ovoalbumin- and histamine-induced mouse paw 26 of 53 Moleculesbradykinin-, 2016, 21, 826 ovoalbumin- and histamine-inducededema [393,394] mouse paw edema [393,394] 26 of 53 edema [393,394]

H Antimicrobial activity against StreptococcusAntimicrobial pneumoniaeAntimicrobial activitystrains against activity resistant StreptococcusStreptococcus against Streptococcus to pneumoniaepneumoniaeβ-lactamic pneumoniae strainsstrains antimicrobials strains resistantresistant resistant toto ββ-lactamic-lactamic to β-lactamic (MIC of 31.25 µg/mL) [402] antimicrobialsantimicrobialsantimicrobials (MIC(MIC ofof 31.2531.25 (MIC µg/mL)µg/mL) of 31.25 [402][402] µg/mL) [402] δ-Cadinene (93) Z. tenuior [94] δδ-Cadinene-Cadinene ((9393)) δ-Cadinene (93) Z. tenuior [94][94] Z. tenuior [94] Antibacterial activity against PropionibacteriumAntibacterial acnesAntibacterial activity(MIC against ofactivity 3.13 PropionibacteriumPropionibacterium againstµg/mL) Propionibacterium [395 acnesacnes] (MIC(MIC acnes of of(MIC 3.133.13 of µg/mL)µg/mL) 3.13 µg/mL) [395][395] [395] Antileishmanial effect against L. donovani [403] Antileishmanial effect against L. donovaniAntileishmanial[403] effect against L.L. donovanidonovani [403][403]

Weak antimite activity against Dermatophagoides pteronyssinus [404] H Weak antimite activity against DermatophagoidesWeak antimite pteronyssinus activity against[404 Dermatophagoides] pteronyssinus [404] H Weak antimiteGood activity antifungal against activity Dermatophagoides against brown rot pteronyssinus fungi Laetiporus [404] sulphureus and weak antifungal H τ-Cadinol (94) Z. tenuior [94] Good antifungal activity against brownGood rot fungi antifungalactivityLaetiporus activity against against sulphureuswhite rot brown fungiand rotCoriolus fungi versicolor LaetiporusLaetiporus [405] sulphureussulphureus andand weakweak antifungalantifungal H τ-Cadinol (94) Z. tenuior [94] ττ--Cadinol (9494)) Z. tenuior [94][94] weak antifungal activity against white rotactivityactivity fungi againstagainstCoriolusAnti-wood-decay whitewhite versicolorrotrot fungifungi fungal Coriolus[ activity405] versicolor [274,406] [405][405] H Anti-wood-decay fungal activity [274,406] Anti-wood-decay fungal activity [274,406Anti-wood-decay] fungal activity [274,406] OH OH Anti-inflammatory activity through inhibition of over-expression of iNOS and IL-6 in LPS- OH Anti-inflammatorystimulated activity RAW264.7 through and TNF-inhibitionα HT-29 of cellsover-expression [407,408]; anti-inflammatory of iNOS and IL-6 effect in in LPS- vivo in Patchouli alcohol (95) Z. clinopodioides (0.1%–1.04Anti-inflammatory %) [15] rats [409] activity through inhibition of over-expression of iNOS and IL-6 in LPS- Anti-inﬂammatory activity through inhibitionstimulated of RAW264.7 over-expression and TNF-α ofHT-29 iNOS cells and [407,408]; IL-6 anti-inflammatory in LPS-stimulated effect RAW264.7 in vivo in stimulated RAW264.7Gastroprotective and TNF-[410] α HT-29 cells [407,408]; anti-inflammatory effect in vivo in Patchouli alcohol (95and) TNF-Z.α clinopodioidesHT-29 cells (0.1%–1.04 [407,408 %)]; [15] anti-inﬂammatory rats [409] effect in vivo in rats [409] H Patchouli alcohol (95) Z. clinopodioides (0.1%–1.04Patchouli %) [ 15alcohol] (95) Z. clinopodioides (0.1%–1.04 %) [15] rats [409] Review on metabolism and toxicity [200] OH Gastroprotective [410] Gastroprotective [410] H (Z)-6,10-dimethyl-5,9- H OH Review on metabolism and toxicity [200Review] on metabolism and toxicity [200] O OH undecadien-2-one (syn. Z- Z. tenuior [94] n.f. Z ((Z)-6,10-dimethyl-5,9-)-6,10-dimethyl-5,9-geranylacetone, nerylacetone) O undecadien-2-one (syn. Z- (96) O undecadien-2-one (syn. Z- Z Z. tenuior [94][94] n.f.n.f. Z geranylacetone,geranylacetone, nerylacetone)nerylacetone)

((9696)) Cyclohexane, 1-ethenyl-1- methyl-2-(1-methylethenyl)-4-(1- Z. tenuior [94] n.f. methylethylidene) (97) Cyclohexane, 1-ethenyl-1- methyl-2-(1-methylethenyl)-4-(1- Z. tenuior [94][94] n.f.n.f. methylethylidene) (9797))

HO H

Spathulenol (98) Z. tenuior [94] Antimicrobial activity against S. aureus and P. mirabilis [385] HO H H SpathulenolSpathulenol ((9898)) Z. tenuior [94][94] Antimicrobial activity against S.S. aureusaureus andand P.P. mirabilismirabilis [385][385]

MoleculesMolecules 2016 2016,, ,21 21,, ,826826 826 2626 of of 53 53

HH AntimicrobialAntimicrobial activity activity against against Streptococcus Streptococcus pneumoniae pneumoniae strainsstrains strains resistantresistant resistant toto to β β-lactamic-lactamic-lactamic antimicrobialsantimicrobials (MIC (MIC of of 31.25 31.25 µg/mL) µg/mL) [402] [402] δδ-Cadinene-Cadinene-Cadinene (( 93(93)) ) Z.Z. tenuior tenuior [94][94] [94] AntibacterialAntibacterial activity activity against against Propionibacterium Propionibacterium acnes acnes (MIC(MIC (MIC ofof of 3.133.13 3.13 µg/mL)µg/mL) µg/mL) [395][395] [395] AntileishmanialAntileishmanial effect effect against against L. L. donovani donovani [403][403] [403]

Molecules 2016, 21, 826 26 of 54 HH WeakWeak antimite antimite activity activity against against Dermatophagoides Dermatophagoides pteronyssinus pteronyssinus [404][404] [404] H GoodGood antifungal antifungal activity activity against against brown brown rot rot fungi fungi Laetiporus Laetiporus sulphureus sulphureus andand and weakweak weak antifungalantifungal antifungal ττ--Cadinol-Cadinol ( 94(94)) ) Z.Z. tenuior tenuior [94][94] [94] activityactivity against against white white rot rot fungi fungi Coriolus Coriolus versicolor versicolor [405][405] [405] HH Table 3. Cont.Anti-wood-decayAnti-wood-decay fungal fungal activity activity [274,406] [274,406] OHOH

SesquiterpenesAnti-inflammatoryAnti-inflammatory activity activity through through inhibition inhibition of of over-expression over-expression of of iNOS iNOS and and IL-6 IL-6 in in LPS- LPS- stimulatedstimulatedstimulated RAW264.7RAW264.7 RAW264.7 andand and TNF-TNF- TNF-αα HT-29HT-29 HT-29 cellscells cells [407,408];[407,408]; [407,408]; anti-inflammatoryanti-inflammatory anti-inflammatory effecteffect effect inin in vivovivo vivo inin in Isolation/Detection in KazakhstanPatchouliPatchouli alcohol alcohol ( 95(95)) ) Z.Z. clinopodioides clinopodioides (0.1%–1.04(0.1%–1.04 (0.1%–1.04 %)%) %) [15][15] [15] ratsratsrats [409][409] [409] Name of Compound and ID spp. of Ziziphora (Percentage Biological Activity GastroprotectiveGastroprotective [410] [410] HChemicalH Structure H OHOH Content When Given) ReviewReview on on metabolism metabolism and and toxicity toxicity [200] [200] OH (Z(Z)-6,10-dimethyl-5,9-)-6,10-dimethyl-5,9- (Z)-6,10-dimethyl-5,9-undecadien-2-one (Z)-6,10-dimethyl-5,9- OO undecadien-2-oneundecadien-2-one (syn. (syn. Z Z--- (syn. Z-geranylacetone, nerylacetone) Z. tenuior [94] n.f. Z.Z. tenuior tenuior [94][94] [94] n.f.n.f. ZZ geranylacetone,geranylacetone, nerylacetone) nerylacetone) (96) ((96(96)) )

Cyclohexane, 1-ethenyl-1- Cyclohexane,Cyclohexane, 1-ethenyl-1- 1-ethenyl-1- methyl-2-(1-methylethenyl)- Z. tenuiormethyl-2-(1-methylethenyl)-4-(1-methyl-2-(1-methylethenyl)-4-(1-[94] n.f. Z.Z. tenuior tenuior [94][94] [94] n.f.n.f. 4-(1-methylethylidene) (97) methylethylidene)methylethylidene) ( 97(97)) )

HHOO HH

Spathulenol (98) Z. tenuior [94]SpathulenolSpathulenol ( 98(98)) Antimicrobial) activityZ.Z. tenuior tenuior against [94][94] [94] S. aureus andAntimicrobialAntimicrobialP. mirabilis activity activity[385 against against] S. S. aureus aureus andand and P. P. mirabilis mirabilis [385][385] [385]

HH Molecules 2016,, 21,, 826826 27 of 53 Molecules 2016, 21, 826 27 of 53

Bicyclo[5.2.0]no-nane, Bicyclo[5.2.0]no-nane, Bicyclo[5.2.0]no-nane,Antimicrobial, anti-inﬂammatory, antihyperlipidemic,Antimicrobial, anti-inflammatory, antioxidant antihype activitiesrlipidemic,rlipidemic, [411] antioxidantantioxidant activitiesactivities [411][411] 2-methylene-4,8,8-tri-methyl-4-vinyl Z. tenuior2-methylene-4,8,8-tri-methyl-4-[94] Z. tenuior [94][94] Antimicrobial, anti-inflammatory, antihyperlipidemic, antioxidant activities [411] 2-methylene-4,8,8-tri-methyl-4-Repellent activityZ. against tenuior [94]Tribolium castaneumRepellentand activityMyzus against persicae Tribolium[412 castaneum] andand Myzus persicae [412][412] (99) vinyl (99)) Repellent activity against Tribolium castaneum and Myzus persicae [412] vinyl (99)

2-Methylene-6,8,8-trimethyl- 2-Methylene-6,8,8-trimethyl-tricyclo- 2-Methylene-6,8,8-trimethyl- Z. tenuiortricyclo-[5.2.2.0(1,6)]undecan-3-tricyclo-[5.2.2.0(1,6)]undecan-3-[94] n.f. Z. tenuior [94][94] n.f. 100 tricyclo-[5.2.2.0(1,6)]undecan-3-ol (100) Z. tenuior [94] n.f. [5.2.2.0(1,6)]undecan-3-ol ( ) ol (100) HO ol (100) HO

Significant repellent action against Sitophilus zeamais andand toxictoxic effecteffect againstagainst Spodoptera Signiﬁcant repellent action against SitophilusSignificantfrugiperda zeamais [413]; repellent insecticidaland action toxic against activities effect Sitophilus againstagainst zeamaisNilaparvataSpodoptera and lugenstoxic frugiperda effect and Plutella against[413 xylostella Spodoptera]; [414] O frugiperda [413]; insecticidal activities against Nilaparvata lugens and Plutella xylostella [414] O frugiperdaInhibition [413];of platelet insecticidal aggregation activities induced against by Nilaparvatacollagen (IC lugens50, 14.4. and µM) Plutella and arachidonic xylostella [414] acid insecticidal activities against NilaparvataInhibition lugens and of plateletPlutella aggregation xylostella induced[414 by] collagen (IC50, 14.4. µM) and arachidonic acid Ar-turmerone (101) Z. tenuior [94] Inhibition(IC50, 43.6. ofµM) platelet and no aggregation effect on PAF induced and thrombin-induced by collagen (IC50, 14.4. platelet µM) aggregation and arachidonic on washed acid Ar-turmerone (101Inhibition) of plateletZ. tenuior aggregation [94] induced(IC by50, 43.6. collagen µM) and (IC no50 effect, 14.4. on µPAFM) and and thrombin-induced arachidonic acid platelet (IC aggregation50, 43.6. µ onM) washed and no Ar-turmerone (101) Z. tenuior [94]Ar-turmerone (101) Z. tenuior [94] (IC50, 43.6. µM) and no effect on PAF and thrombin-induced platelet aggregation on washed effect on PAF and thrombin-induced plateletrabbitrabbitaggregation plateletsplatelets [415];[415]; anti-inflammatory onanti-inflammatory washed rabbit effectseffects platelets throughthrough [ blocking415blocking]; anti-inﬂammatory ofof NF-NF-κB, JNK and p38 effects rabbitMAPK platelets signalling [415]; pathways anti-inflammatory in amyloid β effects-stimulated through microglia blocking [416] of NF- κB, JNK and p38 κ MAPK signalling pathways in amyloid β-stimulated microgliaβ [416] through blocking of NF- B, JNK and p38MAPKReview MAPK signalling on activity signalling pathways [417] pathways in amyloid inβ-stimulated amyloid microglia-stimulated [416] microglia [416] Review on activity [417] Review on activity [417] Review on activity [417]

Molecules 2016, 21, 826 27 of 54

Essential oils are almost always complex mixtures of numerous substances, and therefore their biological effects are often described as the result of a synergism of all molecules or they mirror major activities of molecules present at the highest concentrations [418]. Moreover, the synergistic action is beneficial because the bacteria can undergo adaptation to maintain their membrane functionality in the presence of sub-inhibitory concentrations of antibacterial compounds and the resistance can occur, but the complex action of essential oil can help suppress this resistance [419]. Therefore, only the biological activities of essential oils in their entirety or of their main compounds have usually been evaluated. There are some reports about bioactivities of Ziziphora essential oils, mainly connected with evaluation of antibacterial activity. Moreover, antioxidant properties and anti-inflammatory effect was evaluated using different methods. 5-LOX was inhibited by Z. clinopodioides esstential oil (could be due to the presence of compounds structurally related to fatty acids serving as substrate of LOX) [420]. Generally, the major compounds reflect the biophysical and biological characteristics of the parent essential oils quite well (as visible for example for Origanum oil and carvacrol (73)[421]), and the exhibition of their effects depends on their concentration [422,423]. The very complex mixture of compounds present in essential oil also strongly affects the smell, thickness, texture, colour and cell penetration [424], lipophilic or hydrophilic attraction and fixation on cell walls and membranes, and cellular distribution [418]. Therefore, it is sometimes better to analyse the activity of the entire essential oil and compare it with the activity of pure main components. However, some reports highlight the antagonism of single components of essential oil [281,425], so the information about the activity of pure compounds could be useful. As visible from Table3, we tried to summarize all information about biological effects of compounds present in Ziziphora essential oils available in recent literature, but for some compounds the information is missing or it is scarce. Reports on the essential oils of different Ziziphora species often discuss their antibacterial activity. The essential oils obtained from different Kazakh Ziziphora species are generally rich in oxygenated monoterpenes (see Table3); their antibacterial effect can be attributed to the presence of these compounds; however, this effect is not the consequence of the presence of oxygenated monoterpenes only. Z. clinopodioides essential oils were found to be effective against both Gram-negative and Gram-positive bacterial species [184,426]. The presence of thymol (62) could be responsible for the antibacterial activity. The activity of Z. tenuior essential oil was lower [426]. Similar results have been presented by Salehi et al. [21], showing good activity of Z clinopodioides subsp. rigida essential oil against several bacterial strains (with the exception of insensitive P. aeruginosa). Thymol (62) and pulegone (53) showed at least partial responsibility for the antibacterial effects of these materials. Also, the assays carried out on Z. clinopodioides subsp. bungeana essential oils showed activity against both Gram-positive and negative bacterial species, and pulegone (53) and 1,8-cineol (72) were assigned as compounds responsible for the effect [201]. The high concentration of pulegone (53) is mentioned when the antimicrobial activity of essential oils is analysed: it showed activity especially against C. albicans and S. typhimurium. C. albicans was found to be susceptible to pulegone (53), which was found to be twice as effective as nystatin [427,428]. In other test, the antibacterial activity of essential oil and methanolic extract from Z. clinopodioides was compared using 52 Gram-positive and Gram-negative bacterial species, with disc diffusion method [11]. Both tested materials varied in level of activity, with much higher activity of essential oil. Pulegone (53), limonene (38), and piperitone (45) appeared to be the most active substances; however, further information about antibacterial activity of these compounds is not abundant. We attempted to summarise compounds found in the literature with the antibacterial effect of Ziziphora essential oils and, if possible, their underlying mechanisms (Table3). Carvacrol ( 73) and thymol (62) are placed in the first place, as their antibacterial and antiseptic effect is well known [429]. Their synergic action has been described previously and is well reviewed [369]. Carvacrol (73) acts on B. cereus via depletion of intracellular ATP pool, changes the membrane potential and increase the permeability of membrane for protons and potassium. Carvacrol (73) integrates into the lipidic Molecules 2016, 21, 826 28 of 54 monolayer of the cell membrane, changes its fluidity and damaging its functions [430]. There are evidences of other mechanisms of antibacterial effect, such as interaction with DNA. Moreover, application of carvacrol (73) has been found to inhibit the formation of bacterial biofilm, which is one of the mechanisms of bacterial resistance [369]. Thymol (62), an aromatic p-menthane type monoterpene phenol, isomeric to carvacrol (73), is established as a good antimicrobial agent, interacting both with outer and inner cytoplasmic cell membranes via incorporation of the polar head group region into the lipid bilayer. This interaction changes the properties of the cell membrane and leads to its increased permeability/ disintegration [431–433]. Moreover, thymol (62) can also up- or down-regulate the genes encoding the outer membrane protein synthesis. Beside this, it is able to inhibit the enzymes involved in protection against thermal stress, to affect the synthesis of ATP or to alter citric acid metabolic pathways [434,435]. As mentioned above, carvacrol (73) and thymol (62) exert a synergic effect, similar to many other combinations of components of essential oils against different common human pathogens (carvacrol/thymol (73/62), terpinene-4-ol/myrcene (70/31), carvacrol/p-cymene (73), eugenol/thymol (25/62), eugenol/carvacrol (25/73), cinnamaldehyde/eugenol (106/25), citronellol/geraniol and others) [436–438]. The synergic action of p-cymene and carvacrol (73) combination is based on the high affinity of p-cymene to the cytoplasmic membrane and its bonding to the membrane causes its expansion, altering its potential and resulting in its higher sensitivity to the action of carvacrol (73)[358]. Some of these combinations of compounds with synergic activities are also present in Ziziphora essential oils. The mechanism of thymol (62) and carvacrol (73) synergism was also elucidated and reviewed [132,439]; however, the mechanistic studies describing the mechanisms of synergy are relatively scarce. Owing to their hydrophobic nature, 73 and 62 interact with the lipid bilayer of cytoplasmic membranes, causing loss of integrity and leakage of cellular material. This effect can, in general, increase the permeability of the membrane to other antimicrobial compounds by general disintegration of the membrane or by formation of a large number of pores. The synergic activity of some terpenoids can be also observed for other organisms than bacteria, e.g., Meloidogyne incognita [440]. Synergic activity was observed also during development of insecticides (pulegone (53)/perillaldehyde) [260]. Of note, essential oil components of the thymol (61) and carvacrol (72) type can act as antagonists, as several essential oils showed lower activity than their single monoterpenic components [281]. The review of Bassolé and Juliani [439] showed some examples of synergic, additive or even antagonistic activity of well-known components of essential oils in different bacterial species. Carvacrol (72) and thymol (61) are often mentioned as inhibitors of growth of food-borne pathogens. These pathogens are represented for example by different strains of Salmonella, Shigella, E. coli or Clostridium. The activity of the essential oils of Z. tenuior and Z. clinopodioides against food-borne bacteria has been proven by Aliakbarlu and Shameli [426]. Together with the results of experiments on the antiradical activity of Z. clinopodioides essential oil, which showed better activity than Z. tenuior [426], Z. clinopodioides essential oils can be seen as promising food preservatives. This observation is supported by some other reports that examined the single components identified in Ziziphora essential oils (Table3). The hypolipidemic activity of aromatic water obtained by mixing the Z. tenuior essential oil in water was proven in tests on cholesterol-fed rabbits. However, the levels of measured parameters of hypercholesterolemia were not restored to basal levels [202]. Several patent applications cover the usage of Ziziphora in the treatment of some cardiovascular diseases. It is clear that the components of essential oils obtained from Ziziphora species can affect the cardiovascular system, as visible from data reviewed in Table3. The cardiovascular activities of thymol ( 61), carvacrol (72), limonene (38), α-terpineol (71), terpinen4-ol (70), linalool (66) and menthol (56) were reviewed by Santos et al. [221]; however, this review examined a limited number of literature sources. The effects of linalool (66) were tested in a human study, and the activity of several compounds (72, 38, 56, 61, 70 and 71) was examined in animal studies. Molecules 2016, 21, 826 29 of 54

Molecules 20162016,, 2121,, 826826 3030 ofof 5353 Molecules 2016, 21, 826 30 of 53 TableMolecules 4. Miscellaneous 2016, 21, 826 substances isolated from Kazakhstan Ziziphora species (N.f.—not found). 30 of 53 Molecules 2016, 21, 826 30 of 53 TableTable 4.4. MiscellaneousMiscellaneous substancessubstances isolatedisolated fromfrom KazakhstanKazakhstan ZiziphoraZiziphora speciesspecies (N.f.—not(N.f.—not found).found). Molecules 2016, 21, 826 Table 4. Miscellaneous substances isolated from Kazakhstan Ziziphora species (N.f.—not found). 30 of 53 Table 4. Miscellaneous substances isolated from Kazakhstan Ziziphora species (N.f.—not found). Isolation/Detection in KazakhstanIsolation/DetectionIsolation/DetectionTable spp. in4.in of MiscellaneousKazakhstanKazakhstan spp.spp. substances ofof isolated from Kazakhstan Ziziphora species (N.f.—not found). Name of Compound and IDNameName ofof CompoundCompound andand IDID Isolation/Detection in Kazakhstan spp. of BiologicalBiologicalBiological Activity ActivityActivity Chemical Chemical Chemical StructureStructure ZiziphoraName of Compound andZiziphora ZiziphoraID (Percentage(PercentageTableIsolation/Detection 4. ContentContent Miscellaneous WhenWhen in Kazakhstan Given)Given) substances spp. of isolated from KazakhstanBiological Ziziphora Activity species (N.f.—not found). Chemical Structure Name of(Percentage Compound and Content ID WhenZiziphoraIsolation/Detection Given) (Percentage in Content Kazakhstan When spp. Given) of Biological Activity Chemical Structure Name of Compound and ID Ziziphora (Percentage Content When Given) Biological Activity Chemical Structure ZiziphoraIsolation/Detection (Percentage in Content Kazakhstan When spp. Given) of Name of Compound and ID Biological Activity Chemical Structure Ziziphora (Percentage Content When Given) StyreneStyrene ((102102)) Styrene (102) Z.Z. tenuiortenuior [94][94]Z. tenuior [94] n.f.n.f. n.f. Styrene (102) StyreneZ. (102 tenuior) [94]Z. tenuior n.f. [94] n.f. Styrene (102) Z. tenuior [94] n.f. Styrene (102) Z. tenuior [94] n.f. HH OO H O Weak antifungal activity against wood decay fungi [441] Weak antifungalWeak activity antifungalWeak againstantifungal activity activity woodagainst against decaywood wood decay fungi decay fungi [441 fungi [441]] [441] Benzaldehyde (103) Z. tenuior [94] AntimicrobialWeak antifungal activity activity against against Listeria wood monocytogenes decay fungi [441]and H O Benzaldehyde (103) BenzaldehydeBenzaldehyde ((103103Benzaldehyde)) Z. tenuior (103) [94] Z.Z. tenuiortenuior [94][94]Z. tenuiorAntimicrobial [94] AntimicrobialAntimicrobial activityAntimicrobial against activityactivityListeria activity againstagainst against ListeriaListeria monocytogenes Listeria monocytogenesmonocytogenes monocytogenesand andand and Benzaldehyde (103) Z. tenuior [94] SalmonellaAntimicrobialWeak antifungal typhimurium activity activity against [442] against Listeria wood monocytogenes decay fungi [441]and Salmonella typhimuriumSalmonellaSalmonellaSalmonella typhimuriumtyphimurium[442] typhimurium [442][442] [442] Benzaldehyde (103) Z. tenuior [94] SalmonellaAntimicrobial typhimurium activity against [442] Listeria monocytogenes and Salmonella typhimurium [442] O OO 2-Methyl-3-methylbutyl-butanoic acid O 2-Methyl-3-methylbutyl-butanoic acid Z. tenuior [94] n.f. 2-Methyl-3-methylbutyl-butanoic2-Methyl-3-methylbutyl-butanoic2-Methyl-3-methylbutyl-butanoic2-Methyl-3-methylbutyl-butanoicester acidacid (104 ) acid Z. tenuior [94] n.f. O O ester Z.(104 tenuior) [94]Z.Z. tenuiortenuior [94][94]Z. tenuior n.f. [94] n.f.n.f. n.f. O acid ester (104) esterester 2-Methyl-3-methylbutyl-butanoic ((104104)) ester (104) acid OO Z. tenuior [94] n.f. ester (104) OO O n-Amyl isovalerate (105) Z. tenuior [94] n.f. O n-Amyl isovalerate (105) Z. tenuior [94] n.f. n-amyl O n-Amyl isovalerate (105) Z. tenuior [94] n.f. n-amyl O n-Amyl isovalerate (105) Z. tenuior [94] n.f. n-amyl O n-Amyl isovalerate (105) n-Amyl isovalerate (105) Z. tenuior [94]Z. tenuior [94] n.f. n.f. n-amyln-amyl O n-Amyl isovalerate (105) Z. tenuior [94] n.f. n-amyl O O

Antibacterial, antifungal, antidiabetic, anti-inflammatory, 3-Phenyl-2-propenal (syn. Antibacterial, antifungal, antidiabetic, anti-inflammatory, 3-Phenyl-2-propenal (syn. Z. tenuior [94] antiproliferativeAntibacterial, antifungal, activities antidiabetic, ([132,443] anti-inflammatory, 3-Phenyl-2-propenalcinnamaldehyd) (106 (syn.) Z. tenuior [94] antiproliferative activities ([132,443] cinnamaldehyd) (106) Z. tenuior [94] Inhibitionantiproliferative of tyrosin activities kinase ([132,443] [129] cinnamaldehyd) (106) Antibacterial,Antibacterial,Antibacterial, antifungal,InhibitionAntibacterial, antifungal,antifungal, antidiabetic, of tyrosin antifungal, antidiabetic,antidiabetic, kinase antidiabetic, [129] anti-inflammatory,anti-inflammatory, anti-inflammatory, 3-Phenyl-2-propenal (syn. 3-Phenyl-2-propenal3-Phenyl-2-propenal3-Phenyl-2-propenal (syn.(syn. (syn. Inhibition of tyrosin kinase [129] Z. tenuior [94] Z.Z. tenuiortenuior [94][94]Z. tenuioranti-inﬂammatory, [94] antiproliferativeantiproliferative antiproliferativeantiproliferative activitiesactivities activities ([132,443]([132,443] activities ([132,443] ([ 132,443] cinnamaldehyd) (106) cinnamaldehyd)cinnamaldehyd) ((106cinnamaldehyd)106)) (106) Inhibition of tyrosinInhibitionInhibition kinaseInhibition ofof tyrosintyrosin[ of129 kinasetyrosinkinase] [129]kinase[129] [129] O H O H O H O HH

2,4,4,6-Tetramethyl-6-phenyl-1-heptene 2,4,4,6-Tetramethyl-6-phenyl-1-heptene Z. tenuior [94] n.f. 2,4,4,6-Tetramethyl-6-phenyl-1-heptene(107) Z. tenuior [94] n.f. (107) Z. tenuior [94] n.f. 2,4,4,6-Tetramethyl-6-phenyl-1-heptene(107) Z. tenuior [94] n.f. 2,4,4,6-Tetramethyl-6-2,4,4,6-Tetramethyl-6-phenyl-1-heptene2,4,4,6-Tetramethyl-6-phenyl-1-heptene(107) Z. tenuior [94]Z.Z. tenuiortenuior [94][94] n.f. n.f.n.f. phenyl-1-heptene (107) ((107107))

Molecules 2016, 21, 826 31 of 53

PhotosensitizationPhotosensitization of lipid peroxidation of lipid peroxidation due todue to H- Benzophenone (108) Benzophenone (108) Z. tenuior [94] Z. tenuior [94] H-abstractionabstraction by its long by its lived long tripletlived triplet state state [444 [444]]

O Could be effective repellent against Anopheles species 6,10,14-Trimethyl-2-pentadecanone (109) Z. tenuior [94] [445] (CH ) (CH ) (CH ) 2 3 2 3 2 3

2,6,10,14-Tetramethyl-heptadecane (110) Z. tenuior [94] n.f. (CH ) (CH ) (CH ) n-Pr 2 3 2 3 2 3 OH 1-octen-3-ol (111) Z. clinopodioides [238] n.f.

OAc Z. clinopodioides subsp. bungeana (Juz.) Rech.f. 1-octen-3-yl acetate (112) n.f. [201]

Nonadecane (113) Z. tenuior [94] n.f. CH3(CH2)17CH3

Heneicosane (114) Z. tenuior [94] n.f. CH3 (CH2 )19CH3

Z. clinopodioides (0.9%) [184] 3-octanol (115) n.f. Z. tenuior [94] OH Significant inhibitory effect on mice with diarrhoea O induced with castor oil, MgSO4 and arachidonic acid [446] Nonanal (116) Z. tenuior [94] (CH ) CH Low antifungal activity against fungi of the genus 2 7 3 Colletotrichum [447] H (CH ) COOH n-Decanoic acid (syn. capric acid) (117) Z. tenuior [94] Increasing of total cholesterol level [448] H3C 2 8

Dodecanoic acid (syn. lauric acid) (118) Z. tenuior [94] Increase in total cholesterol level [448] HOOC (CH2)10CH3 Hexadecanoic acid (syn. palmitic acid) Z. tenuior (0.13%–0.31%) [179,202] Increase in total cholesterol level [448] H C (CH2)14COOH (119) Z. tenuior [94] 3 Reduction of LDL cholesterol [448] 9,12-Octadecadienoic acid (syn. linoleic Antibacterial activity against five Gram-positive bacteria (CH ) (CH ) COOH Z. tenuior (0.71%) [187] 2 4 2 7 acid) (120) [449] and significant activity against rapidly-growing H3C

mycobacteria [450] High concentration may reduce LDL cholesterol [448] (CH ) (CH ) COOH 9-Octadecenoic acid (syn. oleic acid) (121) Z. tenuior (0.89%) [202] Antibacterial activity against three of the five tested 2 4 2 7 H3C Gram-positive bacteria [449] Weak inhibitory activity on NO production stimulated by Glc Erigeside B (122) Z. clinopodioides [4] LPS and IFN-γ in RAW 264.7 cells [4] O

Molecules 2016, 21, 826 30 of 54

Molecules 2016, 21Molecules, 826 2016, 21, 826 3131 of of53 53 Molecules 2016, 21Molecules, 826 2016, 21, 826 31 31of 53of 53 Molecules 20162016,, 2121Molecules,, 826826 2016, 21, 826 Table 4. Cont. 3131 31of of53of 5353 O Molecules 2016, 21, 826 O 31 of 53 Molecules 2016, 21Molecules, 826 2016, 21, 826 O 3131 of of53 53 Photosensitization of lipid peroxidation due to H- O Molecules 2016, 21, 826 Benzophenone (108) Z. tenuior [94] PhotosensitizationPhotosensitization of lipid of peroxidation lipid peroxidation due todue H- to H- 31 of 53 BenzophenoneIsolation/Detection (108Benzophenone) (108 in) KazakhstanZ. spp. tenuior of [94]Z. tenuior [94] PhotosensitizationPhotosensitizationabstraction of by lipid its long of peroxidation lipid lived peroxidation triplet duestate to [444]due H- to H- O Molecules 2016Benzophenone, 21, 826 (108) Z. tenuior [94] Photosensitizationabstractionabstraction by its long ofby lipid its lived long peroxidation triplet lived triplet state due[444]state to[444] H- 31 of 53 Name of Compound and ID Benzophenone (108Benzophenone) (108) Z. tenuior [94]Z. tenuior [94] abstractionPhotosensitizationBiological by its long of lipid Activitylived peroxidation triplet state [444]due to H- ChemicalO Structure Molecules 2016Benzophenone, 21Ziziphora, 826 (108)(Percentage Content WhenZ. tenuior Given) [94] abstractionabstraction by its long by itslived long triplet lived tripletstate [444] state [444] O 31 of 53 Photosensitizationabstraction by its long of lipid lived peroxidation triplet state due[444] to H- Molecules 2016Benzophenone, 21, 826 (108) Z. tenuior [94] O 31 of 53 abstractionPhotosensitization by its long lived of tripletlipid peroxidation state [444] due to H- O 6,10,14-Trimethyl-2-pentadecanone Benzophenone (108) Z. tenuior [94] PhotosensitizationCould be effective of lipid repellent peroxidation against due Anopheles to H- species OO O Benzophenone6,10,14-Trimethyl-2-pentadecanone (108) Z. tenuior (109) Z. tenuior [94]Z. tenuior [94] Couldabstraction be effective by its long repellentAnopheles lived againsttriplet stateAnopheles [444] species OO 6,10,14-Trimethyl-2-pentadecanone[ (94109]) Z. tenuior Could [94] be effectiveabstractionCouldPhotosensitization repellentbe [445]effective by its long repellent againstof lipid lived peroxidation againsttriplet state Anopheles [444]duespecies to species H- [445 ] O (109) 6,10,14-Trimethyl-2-pentadecanone (109) Z. tenuior [94] Could be Couldeffective be effective repellent repellent against against Anopheles Anopheles species species O (CH2)3 (CH2)3 (CH ) Benzophenone6,10,14-Trimethyl-2-pentadecanone (108) (109) Z. tenuior [94]Z. tenuior [94] Photosensitization[445] of lipid peroxidation due to H- O (CH ) (CHO) 2 3 6,10,14-Trimethyl-2-pentadecanone (109) Z. tenuior [94] Could[445]abstraction be effective by its long repellent lived againsttriplet state Anopheles [444] species 2 3 2 3 (CH2)3 Benzophenone (108) Z. tenuior [94] Could be[445] effective repellent against Anopheles species (CH(CH2)3) (CH(CH2))3 (CH ) 6,10,14-Trimethyl-2-pentadecanone (109) Z. tenuior [94] [445] (CH )2 3 (CH2)3 (CH(CH2)23)3 6,10,14-Trimethyl-2-pentadecanone (109) Z. tenuior [94] [445]abstractionPhotosensitization by its long of lipid lived peroxidation triplet state [444]due to H- OO 2 3 2 3 2 3 Benzophenone (108) Z. tenuior [94] Could[445] be effective repellent against Anopheles species (CH2)3 (CH2)3 (CH2)3 2,6,10,14-Tetramethyl-heptadecane (110) Z. tenuior [94] PhotosensitizationCouldn.f. be effective of lipid repellent peroxidation against due Anopheles to H- species (CH ) (CH2)3 (CH ) 2,6,10,14-Tetramethyl-heptadecane6,10,14-Trimethyl-2-pentadecanone2,6,10,14-Tetramethyl-heptadecane (109) (110) Z. tenuior [94]Z. tenuior [94] abstractionn.f. by its long lived triplet state [444] O 2 3 2 3 Benzophenone6,10,14-Trimethyl-2-pentadecanone (108) Z. tenuior [ 94(109]) Z. tenuior [94]Z. tenuior n.f. [94] (CH2)3 (CH2)3 (CH ) n-Pr 2,6,10,14-Tetramethyl-heptadecane2,6,10,14-Tetramethyl-heptadecane (110) (110) Z. tenuior [94]Z. tenuior [94] Could[445]n.f.abstraction be [445]n.f.effective by its long repellent lived againsttriplet state Anopheles [444] species (CH(CH ) (CH(CH) ) 2 3 n-Pr (110) O (CH22 3) (CH2 32) 3 (CH(CH(CH2)3 )2)3 6,10,14-Trimethyl-2-pentadecanone2,6,10,14-Tetramethyl-heptadecane ((110109)) Z. tenuior [94] n.f. (CH(CH) 2) 3 (CH(CH )2 3 (CH(CH) )2 3 n-Prn-Pr 2,6,10,14-Tetramethyl-heptadecane (110) Z. tenuior [94] n.f.[445]Could be effective repellent against Anopheles species O (CH(CH2)2)3 3 OH(CH(CH2)3) (CH(CH2 23)3 ) n-Pr 6,10,14-Trimethyl-2-pentadecanone2,6,10,14-Tetramethyl-heptadecane (110109) Z. tenuior [94] n.f. 2233 OH 2 23 3 2 32 3 1-octen-3-ol (111) Z. clinopodioides [238] Could be n.f.effective repellent against Anopheles species (CH2)3 OH(CH2)3 (CH2)3 n-Pr 6,10,14-Trimethyl-2-pentadecanone (109) Z. tenuior [94] [445] O (CH(CH2))3 OH(CH(CH2)3) (CH ) n-Pr 2,6,10,14-Tetramethyl-heptadecane2,6,10,14-Tetramethyl-heptadecane1-octen-3-ol (110 )( 111) (110) Z. tenuiorZ. [94] clinopodioidesZ. tenuior [94] [238] n.f. n.f.n.f. 2 3 2 3 (CH2 32)3 1-octen-3-ol (111) Z. clinopodioides [238] [445]Could be n.f.effective repellent against Anopheles species O (CH ) OH(CH ) (CH ) 1-octen-3-ol (111) Z. clinopodioides [238] n.f. (CH(CH2)2)33 OH(CH(CH2)23 3 (CH(CH) ) 2 3 n-Prn-Pr 6,10,14-Trimethyl-2-pentadecanone1-octen-3-ol (111) (109) Z. clinopodioidesZ. tenuior [94] [238] n.f.Could be effective repellent against Anopheles species 2 3 OH 2 3 2 23 3 2,6,10,14-Tetramethyl-heptadecane1-octen-3-ol (111) (110) Z. clinopodioidesZ. tenuior [94] [238] n.f.[445] (CH ) OAc(CH ) 6,10,14-Trimethyl-2-pentadecanone1-octen-3-ol (111) (109) Z. Z.clinopodioidesZ. clinopodioides tenuior [94] [238] subsp. bungeana (Juz.) Rech.f.n.f. (CH 2) 3 OAc(CH )2 3 (CH(CH) 2)3 n-Pr 1-octen-3-ol (111) Z. clinopodioides [238] n.f.[445] 2 3 OHOH 2 3 2 3 2,6,10,14-Tetramethyl-heptadecane1-octen-3-yl (110 acetate) (112) Z. Z.clinopodioides tenuior [94] subsp. bungeana (Juz.) Rech.f.n.f. n.f. (CH2)3 OAc(CH2)3 (CH ) 2,6,10,14-Tetramethyl-heptadecane1-octen-3-yl1-octen-3-ol (110 acetate) (111 (112) ) Z.Z. clinopodioides tenuior Z.[94] clinopodioides subsp. [201] bungeana [238] (Juz.) Rech.f.n.f. n.f.n.f. (CH ) (CH ) 2 3 n-Pr [201] 2 3 OHOAc 2 3 (CH2)3 1-octen-3-ol (111Z.1-octen-3-yl) clinopodioides acetate (112subsp.Z.) clinopodioidesbungeanaZ. clinopodioides subsp. bungeana [238] (Juz.) Rech.f. n.f. n.f. (CH ) OAc(CH ) (CH ) n-Pr 1-octen-3-yl acetate (1122,6,10,14-Tetramethyl-heptadecane) 1-octen-3-yl acetate (112) (110) Z. clinopodioides Z.subsp. tenuior bungeana [94] [201](Juz.)n.f. Rech.f. n.f. 2 3 OAc 2 3 2 3 1-octen-3-yl1-octen-3-ol acetate (111 ()112 Nonadecane) (113) Z. clinopodioides[201] [238]Z. tenuior [94] n.f. n.f. CHOHOAc3(CH2)17CH3 2,6,10,14-Tetramethyl-heptadecane(Juz.) (110) Rech.f.Z. clinopodioides [201] subsp.Z. tenuior bungeana [94] (Juz.) Rech.f. n.f. (CH ) CHOAc(CH(CH2)3) CH(CH ) n-Pr 1-octen-3-yl acetate (112Nonadecane) (113) Z. clinopodioides subsp.[201] bungeana Z. tenuior (Juz.) [94] Rech.f. n.f. n.f. 2 3 OH3 2 17 3 2 3 1-octen-3-yl1-octen-3-ol acetate (111 ()112 Nonadecane) (113) Z.Z. clinopodioides clinopodioides [238]Z.subsp. tenuior bungeana [94] (Juz.) Rech.f.n.f. n.f. (CH ) CHOAc3(CH(CH )2)17CH(CH3 ) n-Pr 1-octen-3-ylHeneicosane acetate (114 (112) ) [201][201] Z. tenuior [94] n.f. 2 3CH3 (CH2 23)19CH3 2 3 1-octen-3-ol (111) Z. clinopodioidesZ. clinopodioides subsp. bungeana [238] [201](Juz.) Rech.f. n.f. CHOH(CH )) CHCH 1-octen-3-ylNonadecane acetate (113 (112Heneicosane) ) (114) Z. tenuior [94]Z. tenuior [94] n.f. n.f. CHCHOAc3(CH(CH22)1917CH33 Nonadecane (113) Nonadecane1-octen-3-ol ((111113)) Heneicosane Z. tenuior(114) Z. clinopodioides[94]Z. clinopodioides Z.subsp. tenuior[201] bungeana [94] [238]Z. tenuior (Juz.) n.f. [94] Rech.f. n.f. n.f. CHOH33(CH2)1917CH33 1-octen-3-ylNonadecane acetate (113 ()112 ) Z. tenuiorZ. clinopodioides [94] (0.9%) [184] n.f. CHOAc3 (CH2 )17 CH3 HeneicosaneNonadecane1-octen-3-ol (111114113))Nonadecane (113) Z. clinopodioidesZ. tenuiorZ. clinopodioides [94][94] Z.[238] tenuior (0.9%) [94] [184] n.f. n.f. CHCH33(CH(CH22))1717CHCH3 3 3-octanol (115) Z. clinopodioides subsp.[201] bungeana (Juz.) Rech.f. n.f. CHOAc3(CH2) 19CH3 1-octen-3-ylHeneicosane acetate (114 (112) ) Z. tenuiorZ. clinopodioides [94] (0.9%) [184] n.f. CH3 (CH2) 19CH 3 HeneicosaneNonadecane (114113) 3-octanol (115) Z. clinopodioides Z.subsp. tenuior bungeana [94][94] (Juz.) Rech.f. n.f. n.f. CH33(CH2 )1917 CH33 Heneicosane (114) 1-octen-3-ylHeneicosane acetate (114 (112)Heneicosane 3-octanol) Z. (115 tenuior(114) ) [94]Z. tenuior[201] [94]Z. tenuior n.f. [94] n.f. n.f. CHCHOAc33(CH(CH22))1919CHCH3 3 Z. clinopodioides (0.9%)Z. tenuior [184] [94] n.f. CHOH(CH ) CH Nonadecane (113) Z. clinopodioidesZ. clinopodioides Z.subsp. tenuior[201] bungeana (0.9%) [94] [184] (Juz.) Rech.f. n.f. OHOAc3 2 17 3 1-octen-3-ylHeneicosane acetate (114 (112) ) Z. tenuior [94]Z. tenuior [94] n.f. CH3 (CH2 )19CH3 3-octanol (115) Z. clinopodioidesZ. clinopodioides subsp.Z. bungeana clinopodioides(0.9%) [184] (Juz.) (0.9%) Rech.f. [184] n.f. Significant inhibitory effect on mice with diarrhoea O OH 1-octen-3-ylNonadecane3-octanol acetate (115 (113) Z.()112 clinopodioides) Z. clinopodioidesZ. tenuior[201] (0.9%) [94] [184] n.f.n.f. Significant inhibitory effect on mice with diarrhoea CHO 3(CH2)17CH3 Heneicosane (114) (0.9%) [184]Z. tenuior [94] n.f. induced with castor oil, MgSO4 and arachidonic acid [446] CH (CH ) CH Nonadecane3-octanol (115 (113) ) 3-octanol (115) Z. tenuior[201] [94] n.f. n.f.Significant inhibitory effect on mice with diarrhoea CHO 33(CH2)1719CH33 3-octanol (115) 3-octanol (115) Nonanal (116) Z. clinopodioidesZ. tenuior (0.9%) [94]Z. tenuior [184]n.f. [94] n.f. induced with castor oil, MgSO4 and arachidonic acid [446] OH (CH2)7CH3 Heneicosane (114) Nonanal (116) Z. tenuior [94]Z.Z. tenuiortenuior [94][94] n.f. inducedLow antifungal with castor activity oil, againstMgSO4 andfungi arachidonic of the genus acid [446] CHOH3 (CH(CH2)2))197CHCHCH3 3 Nonadecane (113) NonanalZ. (116 tenuior) [94] Z.Z. tenuiortenuior [94][94]Z. tenuior [94] n.f. Low antifungal activity against fungi of the genus H OHOH3 (CH2 17) CH 3 Heneicosane3-octanol (115 (114) ) Z. clinopodioidesZ. tenuior (0.9%) [94] [184] n.f.Significant Colletotrichum inhibitory effect[447] on mice with diarrhoea CHCHOH3 (CH(CH2 ))2197 CH3 3 Nonadecane (113) Z. tenuior [94] Significantn.f. Low inhibitory antifungal effect activity on againstmice with fungi diarrhoea of the genus OH 3 2 17 3 ColletotrichumSignificant inhibitory [447] effect on mice with diarrhoea CHOH (CH ) CH Heneicosane3-octanol (115 (114) ) Z. clinopodioidesZ. tenuior (0.9%) [94] [184] Significantn.f.induced withColletotrichum inhibitory castor oil, effect[447] MgSO on 4mice and witharachidonic diarrhoea acid [446] OO OH3 (CH2) COOH19 3 Nonanaln-Decanoic (116) acid (syn. capric acid) (117) Z. tenuior [94]Z. tenuiorSignificant [94] inhibitoryinducedSignificant withIncreasing effect inhibitory castor on of oil, total miceeffect MgSO cholesterol on with4 mice and diarrhoea arachidoniclevelwith [448]diarrhoea induced acid [446] OH C (CH2 8 ) CH Heneicosane (114) Z. clinopodioidesZ. tenuior (0.9%) [94] [184] n.f. induced with castor oil, MgSO4 and arachidonic acid [446] CHH3C (CH(CH ))COOH2 7 CH3 3-octanolNonanaln-Decanoic ((116115)) acid (syn. capric acid) (117) Z. tenuior [94]Z. tenuior [94] inducedLown.f. antifungal withIncreasing castor activity of oil, total MgSOagainst cholesterol4 andfungi levelarachidonic of the[448] genus acid [446] 3 3 (CH(CH2282)19)7CHCH33 n-Decanoic acidNonanal (syn. (capric116) acid) (117) Z. tenuior [94] Lowinduced antifungal with castor activity oil, againstMgSO4 fungiand arachidonic of the genus acid [446] H COH(CH )2COOH7 3 3-octanolNonanal ((116115)) Z. clinopodioidesZ. tenuior (0.9%) [94]Z. tenuior [184]with [94] castor oil,n.f.Significant MgSO LowIncreasing4 inhibitoryand antifungal arachidonic of totaleffect activity cholesterol on againstmice acid levelwith fungi [ [448]446diarrhoea of the ] genus HOOCOH 3 (CH(CH(CH2 82))7)CHCH3 Nonanal (116) NonanalDodecanoic (116) acid (syn.Z. lauric tenuior acid) [(94118]) Z. tenuior [94]Z. tenuior [94] LowColletotrichum antifungalIncrease [447] activity in total againstcholesterol fungi level of [448] the genus HH 2 27 10 3 3 Dodecanoic acid (syn. lauric acid) (118) Z. clinopodioides (0.9%)Z. tenuior [184] [94] SignificantColletotrichuminducedLow antifungal IncreasewithColletotrichum inhibitory castor[447] activity in total oil, effect[447] cholesterol MgSOagainst on 4mice andfungi level arachidonicwith of [448] the diarrhoea genus acid [446] HOOCOH (CH ) CH 3-octanolNonanal (116115)) Z. tenuior [94] Low antifungaln.f. activity against fungi of the genus HOOCHO (CH(CH)2 )CH10 CH3 DodecanoicHexadecanoic acid acid (syn. (syn. lauric palmitic acid) acid)(118) Z. tenuior (0.13%–0.31%)Z. tenuior [94] [179,202] ColletotrichumColletotrichumIncrease [447][447] in total cholesterol level [448] H OH(CH )2COOH27 10 3 3 n-Decanoic acid3-octanol (syn. capric(115) acid) (117) Z. tenuior [94] inducedLowIncreasingSignificantn.f. antifungal withIncrease ofinhibitory totalcastor activity in cholesterol total oil, effect cholesterolagainstMgSO on level 4mice andfungi level [448] arachidonicwith of [448] the diarrhoea genus acid [446] H3C (CH(CH2))8COOHCOOH n-Decanoic acidNonanal (syn.Hexadecanoicn-Decanoic (capric116) acid) acid acid (syn.(117 (syn. )capric palmitic acid) acid) (117) Z. tenuiorZ. tenuior [94] (0.13%–0.31%)Z. tenuiorColletotrichum [94] [179,202] Increasing[447] Increasing of total cholesterolof total cholesterol level [448] level [448] HOH3C3C (CH(CH(CH22))148COOH) CH Hexadecanoic acid(119 (s)yn. palmitic acid) Z. tenuior (0.13%–0.31%)Z. tenuior [94] [179,202] SignificantIncrease inhibitory in total effect cholesterol on mice level with [448] diarrhoea HH33COH(CH2 )142COOH7 3 n-Decanoic acid (syn. capric acid) (119117)) Z.Z. tenuiortenuior [94][94]Z. tenuior [94] IncreasingLowColletotrichuminduced antifungal with of total castor[447] activity cholesterol oil, againstMgSO level4 fungiand [448] arachidonic of the genus acid [446] HOC (CH(CH2))8COOH n-Decanoic acid (syn. capric acid) (117) Z. tenuior [94] IncreasingIncrease of total in cholesterol total cholesterol level level [448] [448] H3COH(CH22148) CH Dodecanoic acidNonanal (syn. ( lauric116) acid) (119118)) Z. tenuior [94]Z. tenuior [94] SignificantinducedIncrease withinReduction inhibitorytotal castor cholesterol of oil, LDLeffect MgSO cholesterol onlevel 4mice and [448] arachidonic[448]with diarrhoea acid [446] HOOCHOOCH (CH2 7)) CHCH3 n-Decanoic acid (syn. capricDodecanoic acid) acid (syn.Dodecanoic lauric acid) acid (syn.(118) lauric acid) (118) Z. tenuior [94]Z. tenuior [94] IncreaseColletotrichumLow antifungal ReductioninIncrease total [447] activitycholesterol in of total LDL cholesterolagainst cholesterol level fungi [448] level [448] of [448] the genus HOOCO (CH(CH(CH) COOH)22CH)1010CH3 3 n-Decanoic acidNonanal (syn.9,12-Octadecadienoic (capric116) acid) (117Z. )acid tenuior (syn. linoleic[94] Z. tenuior [94] Increasing ofIncreasing totalSignificant cholesterolAntibacterial of inhibitory total cholesterol levelactivity effect [onagainst448 level mice] [448]five with Gram-positive diarrhoea bacteria (CHHOOC) H3C (CH2 82 72) 10CH3(CH3) COOH Dodecanoic acid (syn.9,12-Octadecadienoic lauric acid) (118118 acid)) (syn. linoleic Z.Z. tenuiortenuiorZ. [94][94] tenuior (0.71%) [187] IncreaseinducedLowIncrease antifungal inwithAntibacterialinReduction totaltotal castor activity cholesterolcholesterol of oil, activityLDL againstMgSO cholesterol levellevelagainst4 andfungi [448][448] five arachidonic[448] of Gram-positive the genus acid bacteria[446] (CHHOOC2) 4 HO (CH2 )10 CH(CH32) 7COOH (117) HexadecanoicNonanal acidHexadecanoic (s yn.(116 palmitic) acid)acid acid) (s(120yn. ) palmitic acid)Z. tenuior (0.13%–0.31%)Z. tenuiorZ. tenuior [94] (0.13%–0.31%) [179,202] [179,202] Colletotrichum[449] and[447] significant activity against rapidly-growing H C 2 4H C (CH(CH)) COOH) 2CH10 23 7 nHexadecanoic-Decanoic acid acid (syn.9,12-Octadecadienoic (syn. capric palmitic acid) acid)(117 )acid (syn. linoleicZ. tenuior (0.13%–0.31%)Z. tenuiorZ. [94] tenuior [179,202] (0.71%) [187] IncreasingIncreaseinduced inwithIncreaseAntibacterial oftotal total castor cholesterol in cholesterol total oil, activity cholesterolMgSO level against level4 and [448] level [448]five arachidonic [448] Gram-positive acid bacteria[446] H 3C (CH2)H4HC3C (CH22)1482 COOH7 3(CH ) COOH Nonanal(119) ( 116) acid)(119 (120) ) Z. tenuior (0.13%–0.31%)Z. tenuiorZ. [94] tenuiorZ. [179,202]tenuior (0.71%) [94] [187] IncreaseLowColletotrichum antifungal [449]in total and [447] activitycholesterol significant against activitylevel fungi [448] against of the rapidly-growing genus 3 HOOCH3C3 (CH(CH(CH) COOH) CH) CH2 7 DodecanoicHexadecanoic acid acid (syn. (syn.yn. lauric palmiticpalmitic acid)acid) acid)acid)(118 (120) ) Z. tenuior Z.(0.13%–0.31%) tenuior [94] [179,202] Increase inmycobacteria total cholesterol [450] level [448] H C H3 (CH(CH2))142COOHCOOH27 10 3 3 Dodecanoic acid (syn. lauricn-Decanoic acid) acid (syn.(119) capric acid) (117) Z. tenuior [94] IncreaseColletotrichumIncreasingLow antifungal inmycobacteria[449] oftotal total and[447] activitycholesterol significant cholesterol [450] against levelactivity level fungi [448] against[448] of the rapidly-growing genus 3 HHC3C (CH22)148 COOH (119) Z. tenuior [94] Increase inReduction total cholesterol of LDL cholesterol level [448] [448] HOOCHHH33CC (CH(CH2)14COOH) CH DodecanoicnHexadecanoic-Decanoic acidacid acid (syn.(syn.(119 (s yn.)capric lauric palmitic acid) acid)(117118Z.) tenuior [94Z.] tenuior (0.13%–0.31%)Z. tenuior [94][94] [179,202] Increase in totalIncreaseIncreasingReductionColletotrichum cholesterol inmycobacteriaHigh oftotal LDLtotal concentration[447] cholesterol levelcholesterol [450] [ 448 may level level[448]] reduce [448] [448] LDL cholesterol [448] (CH ) 3 2 8 2 10 3 (118) 9,12-Octadecadienoic acid (syn. linoleic ReductionHighAntibacterial of LDLconcentration cholesterol activity may against [448] reduce five LDL Gram-positive cholesterol [448]bacteria (CH2)4 (CH ) COOH(CH2)7COOH 9,12-Octadecadienoicn-Decanoic acid (syn.9-Octadecenoic acidcapric (syn. acid) linoleicacid (117 (syn.) oleic acid) (121) Z. tenuiorZ. [94] tenuior (0.89%) [202] ReductionIncreasingIncreaseAntibacterial inHighAntibacterial oftotal LDLtotalactivity concentration cholesterol cholesterol activityagainst may level against five[448]level reduce [448] Gram-positive [448]three LDL of cholesterolthe five bacteria tested [448] (CH(CHHOOC)2)H4H3CC (CH(CH2)14COOH) CH(CH(CH2) 7COOH) COOH DodecanoicHexadecanoic acid acid ((syn.119 (s)yn. lauric palmitic acid) acid)(118) Z. tenuior (0.13%–0.31%)Z. tenuiorZ. [94] tenuior [179,202] (0.71%) [187] IncreaseReduction in oftotal LDL cholesterol cholesterol level [448] [448] H3C(CH2)244 3 2 8 2 10 23 72 7 9,12-Octadecadienoic9-Octadecenoic acid (syn. acidacid)linoleic (syn. (120 )oleic acid) (121) Z. tenuior (0.71%)Z. tenuior [187] (0.89%) [202] AntibacterialAntibacterial[449] activityand significant activity against activityagainst five Gram-positive againstthree of rapidly-growing the five bacteria tested H3C (CHHOOC2 24)4H C (CH(CH(CH)) COOH) CH(CH(CH) )COOHCOOH 9,12-OctadecadienoicDodecanoicn-Decanoic acidacid) (syn.9-Octadecenoic (120 acid capriclauric) (syn. acid) linoleicacid (118117 (syn.)) oleic acid) (121) Z. tenuiorZ.Z. tenuiortenuior (0.71%)Z. [94][94] tenuior [187] (0.89%) [202] AntibacterialIncrease[449]Increasing and inAntibacterialGram-positive significant oftotal activitytotal cholesterol cholesterol activityactivityagainst bacteria level againstagainstfive level[449] [448]Gram-positive three[448] rapidly-growing of the five bacteria tested H3C3 (CH ) H3C3 22148 2 10 (CH32 27)7COOH Hexadecanoic acid 9,12-OctadecadienoicHexadecanoicacid) acid(119 (s(120) yn.acid Z.) palmitic (syn. tenuior linoleic acid)(0.13%–0.31%) Z. tenuior [179Z. tenuior, 202(0.13%–0.31%)Z. tenuior] (0.71%) [94] [187] [179,202] [449]ReductionAntibacterial andGram-positivemycobacteria significant of LDLactivity cholesterol activity [450] againstbacteria against five[449][448] Gram-positive rapidly-growing bacteria H3HC3C(CH22)44 (CH2)7COOH Dodecanoic acid (syn. lauric acid) (118) Z. tenuiorZ. tenuior (0.71%) [94] [187] Increase in totalIncrease cholesterol inGram-positiveWeak total inhibitory cholesterol level bacteria activity [448 level [449]] on [448] NO production stimulated by H C HOOCGlcH C (CH(CH) COOH2)10CH3 2 7 Hexadecanoicacid) acid)acid (s((120120yn.)) palmiticErigeside acid) B (122) Z. tenuior (0.13%–0.31%)Z. clinopodioides [179,202] [4] [449]mycobacteriaIncrease and Weakin significant total [450]inhibitory cholesterol activity activity level against on [448] NO rapidly-growing production stimulated by H3C 3 2 14 (syn. palmitic acid) (1199,12-OctadecadienoicDodecanoic) acid ((syn.119 )acid lauric (syn. acid) linoleic (118Z.) tenuior [94] Z. tenuior [94][94] ReductionmycobacteriaAntibacterial[449]Increase and inHighLPS significant of total andLDLactivity [450]concentration cholesterol IFN- cholesterol activity γagainst in RAW may level against five[448] 264.7 reduce [448]Gram-positive cells rapidly-growing LDL [4] cholesterol bacteria [448] 3 (CHGlcHOOC2)4H CO (CH(CH) COOH) CH(CH ) COOH Erigeside B (122) Z. tenuior (0.71%)Z. clinopodioides [187] [4] mycobacteriaIncreaseHigh concentration inWeak total [450] inhibitory cholesterol may activity reduce level on LDL [448] NO cholesterol production stimulated[448] by (CHGlc) 3O 2 14 2 10 (CH3)2COOH7 Hexadecanoic acid)acid(9-Octadecenoic119 (s(120)yn. ) palmiticErigeside acid acid) (syn. B (122 oleic) acid) (121Z. )tenuior (0.13%–0.31%)Z. tenuiorZ. [94]Z. tenuior clinopodioides [179,202] (0.89%) [202][4] [449]mycobacteria andLPSAntibacterial significant and [450] IFN- activity γactivity in RAW againstagainst 264.7 cellsthree rapidly-growing [4] of the five tested H C (CH )2 4 2 7 9,12-Octadecadienoic acid (syn. linoleic AntibacterialHighIncreaseReduction concentration inLPS oftotal andLDLactivity cholesterol IFN- cholesterol may γagainst in reduce RAW level five [448] 264.7 LDL [448] Gram-positive cells cholesterol [4] bacteria[448] 3H C 2 4H CO (CH2)14COOH(CH2)7COOH 9-OctadecenoicHexadecanoic acidacid (119 (syn. (s)yn. oleic palmitic acid) acid) (121 ) Z. tenuiorZ. tenuior (0.13%–0.31%) (0.71%)(0.89%) [187][202] [179,202]Reduction ofHigh LDLAntibacterial concentration cholesterol activity may [against448 reduce] three LDL of cholesterolthe five tested [448] 3 (CH2)4 3 (CH2)7COOH 9-Octadecenoic acid)acid (syn.(120) oleic acid) (121) Z. tenuiorZ. tenuior (0.89%) [94] [202] [449]AntibacterialReductionmycobacteriaHighIncrease andconcentration inGram-positive significant of total LDL activity[450] cholesterol cholesterol may activity against bacteria reduce level against three [448][449] LDL [448] of rapidly-growing cholesterolthe five tested [448] H3C (CH ) H C (CH2)14COOH 2 7 9,12-Octadecadienoic(119 )acid (syn. linoleic Antibacterial activity against five Gram-positive bacteria H3C (CH2)4 3 (CH2)7COOH 9,12-Octadecadienoic9-Octadecenoic acid9-Octadecenoic9,12-Octadecadienoic acidacid (syn.(syn. acid oleicoleic (syn. acid)acid) linoleic ((121121 )) Z.Z. tenuiortenuiorZ. tenuior (0.89%)(0.71%)(0.89%) [94] [202][187][202] Antibacterial AntibacterialReductionGram-positive activityWeak againstof LDLactivity inhibitorybacteria cholesterol five against [449] activity Gram-positive three five[448] on Gram-positive NO of the production five tested stimulatedbacteria by H3C (CH2Glc)4 (CH2)7COOH acid) (120) Erigeside B (122) Z. tenuior (0.71%)Z. clinopodioides[187] [4] mycobacteriaGram-positiveHigh[449] andconcentration significant [450] bacteria may activity [449] reduce against LDL rapidly-growing cholesterol [448] H3C 2 4 2 7 Z. tenuior (0.71%) [187] Gram-positiveWeakReduction inhibitoryLPS of andLDL bacteria activityIFN- cholesterolγ in[449] onRAW NO [448] 264.7 production cells [4] stimulated by H3C (CHGlc2)4 O (CH ) COOH (syn. linoleic acid) (1209-Octadecenoic9,12-Octadecadienoic) Erigeside acid)acid (syn.( 120B acid (122) oleic (syn.) acid) linoleic (121 ) Z.Z. tenuior clinopodioides (0.89%) [202][4] bacteria [449]WeakHighAntibacterial[449]mycobacteriaGram-positive and andconcentration inhibitory significant significant activity[450] bacteria activity may activityactivity against [449] onreduce NO againstfivethree against productionLDL Gram-positive of rapidly-growing cholesterolthe five stimulated tested bacteria[448] by 3 Glc2 4 (CH2)7COOH 9,12-OctadecadienoicErigeside B acid (122 (syn.) linoleic Z.Z. tenuior clinopodioides (0.71%) [187][4] Antibacterial activity against five Gram-positive bacteria H3C (CH(CH )) O (CH ) COOH acid) (120) Weak[449]mycobacteriaLPS and and inhibitory IFN- significant γ[450] in activity RAW activity 264.7 on NO against cells production [4] rapidly-growing stimulated by 3 Glc22 44 O (CH22)77COOH 9-OctadecenoicErigeside acid (syn. B (122 oleic) acid) (121) Z.Z.Z. tenuiortenuior clinopodioides (0.89%)(0.71%) [202][4][187] rapidly-growing LPSAntibacterialGram-positiveHigh and mycobacteria concentration IFN- γactivity bacteriain RAW may against [ [449]450264.7 reduce] threecells LDL [4]of cholesterolthe five tested [448] H C Glc Erigesideacid) ( 120B (122) ) Z. clinopodioides [4] LPSmycobacteria[449] and and IFN- significant γ[450] in RAW activity 264.7 againstcells [4] rapidly-growing 33 (CH ) O (CH ) COOH 9-Octadecenoic acid (syn. oleic acid) (121) Z. tenuior (0.89%) [202] Gram-positiveHighWeakAntibacterialLPS and concentration inhibitory IFN- activityγ bacteria in activity RAW may against [449] 264.7reduceon NO threecells LDLproduction [4]of cholesterol the five stimulated tested [448] by (CHGlc2)4 (CH2)7COOH Erigeside B (122) Z. clinopodioides [4] High concentrationmycobacteria may [450] reduce LDL cholesterol [448] H3C 2 4 2 7 9-Octadecenoic acid (syn. oleic acid) (121) Z. tenuior (0.89%) [202] WeakHighAntibacterialLPSGram-positive and concentration inhibitory IFN- activityγ bacteriain activity RAW may against [449]264.7 onreduce NO threecells productionLDL [4]of cholesterol the five stimulated tested [448] by H C (CHGlc) O 9-Octadecenoic acid (syn. oleic acid) Erigeside B (122) Z. clinopodioides [4] High concentration may reduce LDL cholesterol [448] 3 2 4 (CH2)7COOH 9-Octadecenoic acid (syn. oleic acid)Z. tenuior (121) (0.89%) [202Z.] tenuior (0.89%) [202]Antibacterial LPSAntibacterialGram-positive activity and IFN- against γactivity bacteriain RAW three against [449] 264.7 of threecells the [4]of five the testedfive tested H C (CH ) O (121) Weak inhibitory activity on NO production stimulated by 3 Glc2 4 (CH2)7COOH 9-OctadecenoicErigeside acid (syn. B (122 oleic) acid) (121) Z.Z. tenuior clinopodioides (0.89%) [202][4] WeakGram-positiveAntibacterial inhibitory activity bacteria activity against [449] on NO three production of the five stimulated tested by H C Glc O Erigeside B (122) Z. clinopodioides [4] Gram-positiveLPS bacteria and IFN- [γ449 in RAW] 264.7 cells [4] 3 LPSWeakGram-positive and inhibitory IFN-γ bacteriain activity RAW [449]264.7 on NO cells production [4] stimulated by Glc O Erigeside B (122) Z. clinopodioides [4] Weak inhibitoryWeak activity inhibitory on activity NO production on NO production stimulated stimulated by by Glc O Erigeside B (122 ) Erigeside B (122) Z. clinopodioides [4] Z. clinopodioides [4] LPS and IFN-γ in RAW 264.7 cells [4] γLPS and IFN-γ in RAW 264.7 cells [4] O LPS and IFN- in RAW 264.7 cells [4]

Molecules 2016, 21, 826 31 of 54

Further, linalool (66) and 1,8-cineol (72) showed hypocholesterolemic activity via inhibition of HMG-CoA reductase and inhibition of cholesterol synthesis [318,319]. Endo-borneol (68) exerts a vasorelaxant effect on rat thoracic aorta artery rings [330] and terpinen-4-ol (70) has a relaxant effect on vascular smooth muscle [332]. Several components of Ziziphora essential oils were tested and found to possess antioxidant activity, proven in both in vitro and in vivo assays. For example, monoterpenic α-terpinene (36), terpinolene (37)[217,218], thymol (62)[293], borneol (67)[324], carvacrol (73)[273,294,297,299], and sesquiterpenic caryophylene (91)[392] were found to possess antioxidant activity. The antioxidant activity of Lamiaceae essential oils is known, so they can be used in their entirety or their single compounds can be used as food preservatives; moreover, their antibacterial activity and relative non-toxicity makes them more beneﬁcial than some synthetic antioxidants.

Potential Toxicity Monoterpenic pulegone (53) is present in many Lamiaceae plants. It is commonly connected with potential toxic effect of so called pennyroyal oil. In high doses, it can cause hepatic failure, central nervous system toxicity, gastritis, renal and pulmonary toxicity, and, in very serious cases, death [451,452]. Assays carried out on mice showed its hepatotoxicity and pulmonary toxicity [451,453]. The toxic potential of pulegone (53) is connected to its extensive metabolism in liver, which includes its oxidation to menthofuran, p-cresol and other compounds. These compounds can be further metabolized and cause depletion of glutathione; then, they can covalently bind to proteins and modify their function, causing cell injury [454].

3. Conclusions The traditional medicine of Kazakhstan uses Ziziphora species (Lamiaceae) to combat several diseases. Especially, Z. bungeana Lam. and Z. clinopodioides Lam. are used for the treatment of illnesses connected with cardiovascular system or to combat different infections. We gathered information about four Kazakh Ziziphora species, their traditional utilization and the compounds identified in extracts obtained from these plants. This review presented information about each compound and their bioactivities. We can conclude that as a typical example of the Lamiaceae family, phytochemicals present in Ziziphora are represented especially by monoterpenic essential oil, phenolic substances belonging to the flavonoids and phenolic acids, and triterpenes. The presence of these particular compounds with confirmed activity can be seen as proof of the traditional use and validation of numerous patent applications. We hope that the review on the compounds isolated from Ziziphora, their medicinal uses and published patents will draw the attention of scientists to this very interesting plant with high medicinal potential.

Acknowledgments: Thanks to kontroluje.me for English language corrections. Author Contributions: K.Š. and M.M. performed the literature search, wrote the manuscript and provided the final corrections. K.Z., Z.S., G.I., L.I. performed the literature search and analyzed sources in Russian language. M.Ž. performed search and provided the final corrections. Conflicts of Interest: The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

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