Bignoniaceae) and Their Therapeutic Value: a Review

European Journal of Medicinal Plants 6(3): 124-142, 2015, Article no.EJMP.2015.049 ISSN: 2231-0894

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Phytochemicals of Markhamia Species (Bignoniaceae) and Their Therapeutic Value: A Review

Shaimaa Ali1, Sherweit El-Ahmady1*, Nahla Ayoub1 and Abdel Nasser Singab1

1Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt.

Authors’ contributions

This work was carried out in collaboration between all authors. Authors SA and SE planned the review. Author SA wrote the first draft of the manuscript. Authors SE, NA and AS revised the written manuscript. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/EJMP/2015/15015 Editor(s): (1) Marcello Iriti, Faculty of Plant Biology and Pathology, Department of Agricultural and Environmental Sciences, Milan State University, Italy. Reviewers: (1) Fabiana Firetti Leggieri, Department of Botany, Universidade de São Paulo, São Paulo, Brazil. (2) Anonymous, Thailand. Complete Peer review History: http://www.sciencedomain.org/review-history.php?iid=913&id=13&aid=7659

Received 1st November 2014 th Review Article Accepted 16 December 2014 Published 7th January 2015

ABSTRACT

Aims: To present a compilation of data regarding the phytochemical content and pharmacological activities pertaining to genus Markhamia as one of 120 genera belonging to family Bignoniaceae. Study Design: Literature was collected from various published textbooks and scientific papers then the required data was summarized and presented in both tabulated form and concise text. Results: Phenyl propanoids, triterpenic acids and anthraquinones are the major phytochemicals reported in this genus. Traditional clinical practice demonstrated that the different species of Markhamia were used in curing anaemia and bloody diarrhoea in Africa as well as other ethnopharmacological uses. Many reports were published explaining the activity of the extracts of various species of Markhamia as potential anti-inflammatory, antiparasitic, anthelmintic, analgesic, anti-viral, antimicrobial and anti-fungal agents. Conclusion: This review presents an overview on the reported phytochemicals isolated from different Markhamia species and the biological activities associated with various Markhamia extracts and isolated compounds.

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*Corresponding author: E-mail: [email protected];

Ali et al.; EJMP, 6(3): 124-142, 2015; Article no.EJMP.2015.049

Keywords: Review; markhamia; bignoniaceae; phenyl propanoids; triterpenic acids; anthraquinones.

1. INTRODUCTION 2. PHYTOCHEMICAL CONSTITUENTS

Medicinal plants have been long used for their The key classes of compounds isolated and medicinal value, especially in developing identified from genus Markhamia vary widely. countries where natural medicine is popular and The genus constitutes phenylpropanoids, widely used for maintaining better health. Nature lignans, naphthoquinones, anthraquinones, is considered a vast source of therapeutic sterols, cycloartane triterpenes and their agents. Being safe and inexpensive, these glycoside derivatives, phenolic glycosides and natural agents are widely used in both prevention triterpene acids. These compounds are isolated and treatment of numerous human diseases. from different plant parts including roots, leaves, Genus Markhamia is one of around120 genera stem, root bark and heartwood (Table 2). belonging to family Bignoniaceae, mostly spread in the tropical and neotropical areas of Asia, 2.1 Phenylpropanoids America and Africa, although some species are cultivated in other areas as ornamentals [1]. Phenylpropanoids are a large group of Many species of this genus are traditionally used secondary plant metabolites, mainly produced in in the treatment of several diseases. In Tanzania, response to wound, infection, UV irradiation or the aqueous extract of the root bark of any other stressful condition attributed to their Markhamia lutea is used to treat anaemia and free radical scavenging capability [6]. diarrhoea however in Cameroon, M. lutea and M. Phytochemical analysis of the roots of the tomentosa are both used to cure various medicinal plant M. lutea revealed the presence of microbial and parasitic diseases [2]. It was different phenylpropanoid glycosides named reported that the wood extract of M. lutea played verbascoside and its isomer isoverbascoside in a major role in the protection of wood against addition to luteoside A, B and C [7]. From the termite and fungal attack, hence its use as a leaves and the branches of M. stipulata, different wood preservative in Uganda [3]. The foliage of verbascoside derivatives described as M. platycalyx are important food of the red markhamiosides (A-E) were isolated [8]. colobus and the black-and-white colobus monkeys in Africa [4]. Plants belonging to genus 2.2 Lignans Markhamia are either trees or shrubs. They are characterized by the presence of pseudostipules. Lignans can be described as group of dimeric The leaves are opposite, imparipinnate with phenylpropanoids formed by attachment of two terminal or axillary panicle or raceme. The corolla C6-C3 groups together. Coniferyl alcohol, p- (cup shaped) is 2-lipped, composed of 5-lobes coumaroyl alcohol and sinapoyl alcohol are longer than the calyx. The ovary is bilocular and considered the main precursors of lignans and the seeds are winged. The name "Markhamia" is lignins in plants [9]. D-sesamin and paulownin derived after Sir Clements Robert Markham an are lignans which were isolated from the English geographer and traveler. The twelve heartwood of M. lutea [10]. species of Markhamia fall into three different categories (Table 1). The first category includes 2.3 Anthraquinones and Naphtho- five different species: M. stipulata, M. caudafelina, M. lutea, M. platycalyx and M. quinones hildebrandtii. The common characters of these species include yellow corollas and foliaceous Anthraquinones are class of natural products that and orbicular pseudostipules. The second have drawn attention for quite some time. Their category includes three species: M. sessilis, M. bright colors allowed them to be used in the tomentosa and M. obtusifolia. They are synthesis of numerous dyes where pigments of characterized by yellow corollas and subulate different colors have been now characterized as pseudostipules. The third category includes four quinones. These compounds are also diversely species: M. puberula, M. stenocarpa, M. used in both food and pharmaceutical industry. zanzibarica and M. acuminata. They differ from Many derivatives of anthraquinones exist in the previously mentioned species in the nature. The biosynthesis of the main 9, 10 presence of brownish purple corolla beside the dioxoanthracene skeleton originate from either foliaceous and orbicular pseudostipules [5]. the acetate or the isoprene units which act as the main building blocks used for the de-novo

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synthesis of anthraquinones. Those, which interest in natural triterpenes has evolved due to originate from the acetate/malonate pathway are their wide pharmacological activities. They were called polyketides (emodin-type) anthraquinones, reported to possess antiviral, antimicrobial, anti- however those, which originate from the inflammatory, cardiovascular and cytotoxic isoprenoid pathway are called the isoprenoid effects [15]. From the leaf extract of M. lutea, anthraquinones [11]. It was reported that different hydroperoxy cycloartane triterpenes and lapachol, Dehydro-α-lapachone, 2- their xylose glycosides were isolated together isopropenylfurano-1,4-naphthoquinone were with 2-epitormentic acid. They exhibited isolated from the heartwood of M. lutea [10], significant in-vitro antiparasitic activity and low however tectoquinone and dehydrotectol were cytotoxicity against KB and MRC5 cells [16]. The isolated from the stem bark of M. stipulata [12]. leaf extract of M. obtusifolia showed the From the stem bark of M. tomentosa, 2- presence of different triterpenic acids namely acetylnaphtho [2,3-β]furan-4,9-dione and 2- pomolic (and its acetylated derivative), tormentic acetyl-6-methoxynaphtho[2,3-β]furan-4,9-dione (and its epimer), oleanolic and ursolic acids [17]. were isolated [2]. Also, markhamioside F which The cuticular wax obtained from the chloroform was reported to be a hydroquinone derivative leaf extract of M. acuminata was analyzed by was isolated from the leaves and the branches of GC-MS showing ursolic and oleanolic acids to be M. stipulata [8]. the major components forming the wax by 52 and 60% respectively [18]. 2.4 Sterols 2.6 Polyphenols The most abundant sterols in plants are β- sitosterol, Campesterol, and Stigmasterol. Plant Polyphenolics are a diverse group of compounds sterols have a chemical structure very similar to widely spread among plants and include at least that of cholesterol except for the presence of an one aromatic ring bearing one or more hydroxyl extra methyl, ethyl group or double bond [13]. groups. Hydroxy benzoic/cinnamic acid The main nucleus is a triterpene with a tetracyclic derivatives, stilbenes, lignans, flavonoids, cyclopentane phenanthrene structure and a side anthocyanins, catechins and phenolic alcohols chain at C17. They act by inhibiting intestinal are different polyphenols biosynthesized in absorption of cholesterol hence decreasing its plants. Research on polyphenols showed their serum concentration. Stigmasterol was isolated tremendous effect on degenerative diseases from the heartwood of M. lutea [10], however Ɣ- prevention. They are strong antioxidants with sitosterol was isolated from the root extract of M. high free radical scavenging capacity. From the zanzibarica [14], while β-sitosterol was isolated hydromethanolic leaf extract of M. platycalyx, from the stem bark of M. tomentosa [2]. various polyphenols were identified including cinaroside, luteolin, apigenin, cosmosiin, 2.5 Triterpene Acids verbascoside, isoverbascoside and jacraninoside-I [19]. Different flavonoids have Triterpenes are a large class of plant secondary been isolated from the leaves of M. acuminata. metabolites including sterols and steroids. Their Luteolin, apigenin and luteolinrutinoside are from carbon skeleton consists of 30 carbons and the isolated flavones however naringenin, biosynthesized from squalene through naringenin-7-rutinoside and eriocitrin are from cyclization, ring expansions or contractions and the isolated flavanones [20]. loss of small molecules. Sapogenin is the free triterpene aglycone however saponin is the 3. BIOLOGICAL ACTIVITIES triterpene glycoside. Triterpenes are divided into many subgroups depending on squalene Extracts prepared from various Markhamia cyclization as hopane, lupane, oleanane, ursane species showed a wide array of biological and gammacerane types. Triterpenes with activities. Many of the reported pharmacological cycloartane skeleton are common in many plants activities were aimed at verifying the traditional and they are formed by cyclization between C9 uses of Markhamia species in folk remedy. and C19. In the past few decades, a growing

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Table 1. The different synonyms and species of genus Markhamia

Species Synonyms Distribution Varities M. acuminata Spathodea acuminata Klotzsch East Africa ------K. Schum. M. caudafelina Spathodea caudafelina Hance. China ------Craib Dolichandrone caudafelina Benth. ex M. hildebrandtii Dolichandrone hildebrandtii Baker East Africa, Usambara ------Sprague M. lutea Spathodea lutea Benth. Muenteria lutea Seem. Dolichandrone lutea West Africa ------K. Schum. Benth. ex M. obtusifolia Sprague Markhamia lanata K. Schum. Congo, Central Africa ------Dolichandrone obtusifolia Baker East Africa M. platycalyx Sprague Dolichandrone platycalyx Baker Uganda, East Africa ------M. puberula Spathodea puberula Klotzsch East Africa ------K. Schum. Muenteria puberula Seem. M. sessilis Muenteria sessilis Seem. West Africa , Congo Markhamia sessilis var. Sprague Angola brachyrhyncha M. stenocarpa Muenteria stenocarpa Seem. Dolichandrone stenocarpa Baker Angola ------K. Schum. Spathodea stenocarpa Welw. ex. M. stipulata Bignonia stipulata Roxb. Hort. Beng. Bignonia campanulata Ham. ex Upper and lower Burma M. stipulata var. Kerrii Seem. Wall. Spathodea stipulata Wall. Spathodea campanulata Ham. ex Wall. Andaman Islands Spathodea velutina Kurz. Dolichandrone stipulata Benth. Ex M. tomentosa Spathodea tomentosa Benth. Muenteria tomentosa Seem. West Africa Markhamia tomentosa K. Schum. Dolichandrone tomentosa Benth. var. gracilis M. zanzibarica Muenteria zanzibarica Seem. Spathodea zanzibarica Bojer East Africa ------K. Schum.

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Table 2. List of reported compounds isolated from genus Markhamia

Compound name Structure Species Organ used Ref. O O OH

R1O

R O O OH 2 OH

O OH O OH O OH

H3C

HO OH O M. lutea Roots [7]

Luteoside A H C R1= 3 O

R2= HO O HO M. lutea Roots [7] Luteoside B

R1= HO R2= H O M. lutea Roots [7]

Luteoside C H3CO

R1= HO R2= H

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Compound name Structure Species Organ used Ref. R2 CH3

CH3

R1O

H3C COOH Musambin A R1= H M. lutea Leaves [16], H3C [33] H OOH

CH2

R2= CH3

Musambin B R1= H M. lutea Leave [16], H3C [33]

CH3 [16], OOH M. lutea Leaves [33]

R2= CH3 Musambin C R1= H H3C O

CH2

R2= CH3 Musambioside A R1= Xylose M. lutea Leaves [16], [33]

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Compound name Structure Species Organ used Ref. H3C H OOH

CH2

R2= CH3 Musambioside B R1= Xylose M. lutea Leaves [16], H3C [33]

CH3 OOH

R2= CH3 Musambioside C R1= Xylose M. lutea Leaves [16], H3C [33] O

CH2

R2= CH3 OR1

O R O 2 O OH O

OR3

O H3C OR HO 4

HO OH Decaffeoyl verbascoside R1=R2=R3=R4=H M. stipulata Leaves and [30] branches Markhamioside A R1=R2=R4=H M. stipulata Leaves and [30] R3= Apiosyl branches Verbascoside R1=R3=R4=H M. stipulata Leaves and [30] R2= Caffeoyl branches

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Compound name Structure Species Organ used Ref. Isoverbascoside R2=R3=R4=H M. stipulata Leaves and [30] R1= Caffeoyl branches 2''- R1= R4=H M. stipulata Leaves and [30] O-apiosylverbascoside R2= Caffeoyl branches R3= Apiosyl Markhamioside B R1= Feruloyl M. stipulata Leaves and [30] R2=H branches R3= Apiosyl R4= Me Markhamioside C R2= R4=H M. stipulata Leaves and [30] R1= Caffeoyl branches R3= Arabinosyl Markhamioside D R1= Acetyl M. stipulata Leaves and [30] R2= Caffeoyl branches R3= Arabinosyl R4= H Markhamioside E R1= Acetyl M. stipulata Leaves and [30] R2= Caffeoyl branches R3= Galactosyl R4= H R1

OH R2

O HO O OCH3 HO O

R3O O

OH OH

Markhamioside F R1= R3=H M. stipulata Leaves and [30] R2= OH branches khaephuoside B R1= R2= OMe M. stipulata Leaves and [30]

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Compound name Structure Species Organ used Ref. O branches

H3CO

R3= HO Sequinoside K R1= H M. stipulata Leaves and [30] R2= OH branches O

H3CO

R3= HO

Rengyoside B O M. stipulata Leaves and [30] branches

O O

HO OH

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Compound name Structure Species Organ used Ref. (+)-lyoniresinol OH M. stipulata Leaves and [30]

3α-O-β-glucopyranoside OCH3 branches OH

HO O OH

O OCH3 HO

HO H3CO OCH3

OH R5 R 4

COOH

R3O

Pomolic Acid R1= OH M. obtusifolia Leaves [17] R2= R3= R5=H R4=CH3 Tormentic acid R1= R2=OH M. obtusifolia Leaves [17] R3= R5=H R4=CH3 Ursolic acid R1= R2= R3= R5= H M. obtusifolia Leaves [17] R4=CH3 3- acetyl pomolic acid R1= OH M. obtusifolia Leaves [17] R2= R5=H R3= COCH3 R4=CH3

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Compound name Structure Species Organ used Ref. Oleanolic acid R1= R2= R3= R4 =H M. obtusifolia Leaves [17] R5= CH3 O

O O

2-acetylnaphtho R= H [2,3-β]furan-4,9-dione 2-acetyl-6-methoxy R= OCH3 M. obtusifolia Leaves [17] naphtho[2,3- β] furan-4,9-dione O

O O

O Sesamin R= H M. lutea Heartwood [10] Paulownin R= OH Lapachol O M. lutea Heartwood [10]

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Compound name Structure Species Organ used Ref. O

Dehydro-α-lapachone M. lutea Heartwood [10]

O O M. tomentosa Stem bark [10] O Dehydroiso-α-lapachone

β-lapachone O M. tomentosa Stem bark [10]

O O

O 2-isopropenyl furano -1,4- M. lutea Heartwood [10] O naphthoquinone CH2

CH3

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Compound name Structure Species Organ used Ref.

Stigmosterol M. lutea Heartwood [10]

HO O

CH3 Tectoquinone M. stipulata Stem bark [12]

O Dehydrotectol M. stipulata Stem bark [12]

O O

M. tomentosa Stem bark [2] β-sitosterol

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Compound name Structure Species Organ used Ref. H O H N M. tomentosa Stem bark [31] H Palustrine H H N N

HO Eriocitrin OH M. acuminata Leaves [20]

O O OH HO

O OH

O OH O

OH O

H3C OH

OH Naringenin OH M. acuminata Leaves [20]

HO O

OH O

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3.1 Anti-protozoal Activity The triterpene acids (ursolic, pomolic and 2-epitormentic), isolated from the acetone leaf extract Biological studies performed on the ethyl-acetate of Markhamia obtusifolia, were tested for their extract of the stem bark of M. tomentosa, activity against three different strains of C. showed promising in-vitro antimalarial activity. albicans isolated from dogs, cats and the The isolated compounds were evaluated in-vitro standard strain ATCC 90028. The results for their anti-protozoal activities against two showed that ursolic acid was the most active strains of Plasmodium falciparum, Leishmania against the three strains, with minimum inhibitory donovani amastigotes, and the bloodstream concentration (MIC) = 12.5 μg/mL (for C. trypomastigotes of Trypanosoma brucei. The albicans strain isolated from dogs) and = 25 ethyl-acetate extract showed potent antimalarial μg/mL (for standard ATCC 90028 and C. albicans activity, with low IC50 recorded for the two tested strain isolated from cats) at 24 hours strains of P. falciparum (K1 and W2 strains). The after incubation. However the MIC exceeds 400 activity of the ethyl acetate extract was attributed μg/mL for all isolated triterpenes at 48 hours to the presence of different classes of incubation. This showed that growth inhibition of phytoconstituents classified as C. albicans occurs only at the first 24 hours from naphthofuranediones (lapachol derivatives). It the start of the experiment however no growth was shown that the isolated inhibition was observed at 48 hours either from naphthofuranediones exhibited very strong the extract or from the pure isolated compounds activity against both strains of P. falciparum, the [21]. leishmanial amastigotes and the tested trypanosomes with IC50 ˂ 0.9 µg/ml however they The activity of different extracts of M. lutea was showed strong cytotoxicity when tested on L-6 tested among other Rwandan plants against both cell line with IC50 = 0.1 µg/ml. It was reported that chloroquine sensitive (3D7) and resistant (W2) naphtho- and anthraquinones (and their synthetic forms of plasmodium falciparum. The derivatives) isolated from various plants exhibit dichloromethane extract of M. lutea showed in-vitro antiprotozoal and antimalarial activity. weak antiplasmodial activity with IC50 of 29 One example is the naphthoquinone sterekunthal μg/mL, however the ethyl acetate extract showed A which was isolated from the root bark of significant antiplasmodial activity with IC50 of 10.2 Stereospermum kunthiamum (another species of μg/mL. Although the methanolic extract showed family Bignoniaceae) and exhibited in-vitro 62.1% growth inhibition against plasmodium activity against P. falciparum with IC50 = 1.3 bergheiin vivo, the extract was inactive in vitro µg/ml. Even though naphtho-and anthraquinones with IC50>50 μg/ml [22] and their derivatives posses high anti-protozoal activity but their high degree of cytotoxicity limits 3.2 Anthelmintic Activity their medical use as potent anti-protozoals unless modulation in their structure is achieved The anthelmintic activity of M. obtusifolia for a higher degree of safety [2]. aqueous and acetone leaf extracts were evaluated against the gastrointestinal nematode M. lutea ethyl acetate extract and isolated Trichostrongylus colubriformis using the in-vitro compounds were also evaluated for possible egg hatch test. The effective concentration cytotoxicity against MRC5 and KB cells. The (EC50) for the aqueous leaf extract of M. ethyl acetate leaf extract of M. lutea exhibited obtusifolia (0.5 mg/mL) was significantly lower significant in-vitro anti-parasitic activity and low than the EC50 for the acetone extract (0.8 cytotoxicity. The extract was active against T. mg/mL). This proved that the aqueous extracts brucei with EC50 1.9 µg/ml and against P. were twice as potent anthelmintic as the acetone falciparum with IC50 10.2 µg/ml however it extracts with an effect on the hatchability of the showed weak activity against L. donovani with nematode eggs. These results supported the use EC50 42.0 µg/ml. The isolated compounds of M. obtusifolia in traditional veterinary (musambin A, B and C) showed weak or no practices. In the cytotoxicity bioassay it was activity against L. donovani and P. falciparum, observed that the LD50 of the aqueous extract of however musambin C showed the best activity M. obtusifolia was too high (relatively safe 0.476 against P. falciparum with IC50 10.2 µg/ml. All the mg/ml) when compared to standard toxic isolated compounds showed weak or no berberine which had an LD50 of 9.80 µg/ml [23]. cytotoxicity against MRC5 and KB cells [16].

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3.3 Antibacterial and Antifungal Activity against RSV than standard ribavirin as well as higher selectivity than ribavirin. It is likely that the The methanolic leaf extract of M. tomentosa was mechanism by which phenylpropanoid shown to possess strong antibacterial and glycosides inhibit RSV is through an intracellular antifungal activity. Five different concentrations antiviral mechanism similar to ribavirin since the of M. tomentosa leaf extract were tested for M. lutea extract showed activity even when activity against different strains of bacteria (E.coli administered 3 hrs. after the infection with the NCTC 10418, P. aeruginosa ATCC 10145, S. cells with RSV. None of the isolated phenyl aureus NCTC 6571 and B. subtilis NCIB 3610) propanoid glycosides showed activity against and fungi (C. albicans, C. pseudotropicalis NCYC herpes simplex virus, cytomegalovirus or 6 and T. rubrum). It was observed that at varicella zoster virus [7]. concentration 5 mg/ml and 10 mg/ml of M. tomentosa methanolic extract, there was neither 3.5 Analgesic and Anti-inflammatory activity against bacteria nor fungi however at Activity concentration 20 mg/ml, the methanolic extract showed only antibacterial activity against S. The analgesic and anti-inflammatory effect of aureus (the diameter of zone inhibition was 7 different extracts of M. tomentosa (hexane, mm) without any antifungal activity. At dichloromethane, ethyl acetate, methanolic, concentration 40 mg/ml, the extract showed aqueous and aqueous residue) on rats and mice antibacterial activity against both S. aureus and were investigated using thermal noxious stimuli B. subtilis (the diameter of zone inhibition was 10 (hot plate and tail immersion tests for evaluating and 5 mm respectively). Only at extract analgesic activity) and carrageenan induced concentration of 225 mg/ml, was both acute inflammation (for assessing anti- antibacterial (against all bacterial strains tested, inflammatory activity). The aqueous, ethyl the diameter of zone inhibition for E.coli was 1 acetate, methanol and aqueous residue extracts mm, B. subtilis 8 mm, P. aeruginosa 10 mm and showed significant inhibition on writhing S. aureus 16 mm) and antifungal (against only C. response induced by acetic acid in a dose pseudotropicalis with 3 mm diameter of zone dependent manner (p ˂ 0.001) however the inhibition) activity achieved [24]. It was observed methanol and aqueous extracts (200 mg/kg) that the chloroformic leaf extract of M. tomentosa demonstrated higher inhibition response with showed an MIC at 312 µg/ml for B. subtilis when 60% and 53% inhibition, respectively. In the first compared to the standard chlorocresol which phase of formalin test, it was observed that both showed MIC at 125 µg/ml. the methanolic, aqueous and aqueous residue extracts at dose 200 mg/kg significantly reduced In another study, the acetone extract of M. the licking time by 43%, 57% and 28% obtusifolia showed the highest degree of activity respectively when compared to morphine control against Candida when compared to other which inhibited this first phase by 60% (p ˂ extracts (hexane, methanol and 0.001). In formalin second phase, all extracts dichloromethane). Three triterpene acids significantly (p ˂ 0.001) reduced formalin induced (pomolic, ursolic and 2-epitormentic acid) were pain however the methanolic extract (200 mg/kg) isolated from the leaf extract of M. obtusifolia. showed maximum inhibition by 80% when They inhibited the growth of three Candida compared to morphine (10 mg/kg) which albicans strains (two of them are clinical however inhibited the inflammatory pain by 45.22%. The the third is standard ATCC 90028). Pomolic acid hot plate test showed that both M. tomentosa was the most active with minimum inhibitory methanolic extract (50, 100 and 200 mg/kg) and concentration of 12.5 μg/mL [17]. morphine (10 mg/kg) decreased the reaction time of mice to the thermal stimuli significantly at p ˂ 3.4 Antiviral Activity 0.001 when compared to acetyl salicylic acid control (200 mg/kg) which showed no effect on Five phenylpropanoid glycosides isolated from the pain induced by the hot plate. In the tail the roots of M. lutea, exhibited potent in-vitro immersion test, both the methanolic extract of M. activity against the respiratory syncytial virus tomentosa and morphine (10 mg/kg) increased (RSV) according to the cytopathic effect assay significantly (p ˂ 0.01) the latency time when (CPE) against standard ribavirin. The isolated compared to acetyl salicylic acid control (200 compounds including verbascoside, mg/kg) which failed to affect the reaction time. isoverbascoside and luteoside A and B showed The anti-inflammatory activity of the M. similar or even better in-vitro activity (EC50) tomentosa methanolic extract (50, 100 and 200

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mg/kg) showed significant (p ˂ 0.001) reduction dependent. This suggests the use of the extract in the edema induced by carrageenan in the rat in treating sub-chronic inflammation [27]. hind paw after 2 hrs. of carrageenan injection with a maximum inhibition reached 43% after 5 3.6 Antioxidant Activity hrs. of injection (for the dose 100 mg/kg) when compared to morphine (10 mg/kg) which The generation of reactive oxygen species and inhibited rat paw edema by 37%. The acetyl free radicals are the main precursors for salicylic acid control (200 mg/kg) showed 50% oxidative stress which is implicated in the inhibition recorded after 2 hrs. of carrageenan pathogenesis of numerous diseases. The injection [25]. This data was coherent to the antioxidant assay for M. tomentosa was reported folk medicinal use of M. tomentosa in performed using rapid radical scavenging Cameroon for treatment of pain and inflammatory screening test and DPPH photometric assay test. related ailments. The results showed that the EC50 of the extract using DPPH photometric assay was 16.5 µg/ml The anti-ulcer activity of three per oral doses (50, for the M. tomentosa methanolic extract 100 and 150 mg/kg) of the ethanol leaf extract of indicating high DPPH radical scavenging M. tomentosa was evaluated in both ethanol and capacity and antioxidant activity [24]. indomethacin induced models. The extract in its different doses caused significant dose 3.7 Anti-tumor Activity dependent ulcer inhibition (p<0.05). The ethyl acetate extract was the most potent among all The reported cytotoxicity of the root wood of M. fractions causing 72-92% inhibition of zanzibarica was attributed to the presence of Ɣ- indomethacin and pylorus induced ulcers in dose sitosterol [14]. The naphthoquinone derivative, 2- 150 mg/kg. LC-MS profiling of this bioactive isopropenylfurano-1,4-naphthoquinone, which fraction revealed the presence of acteoside, was isolated from the benzene extract of M. ajugol, dilapachone, luteolin-7-rutinoside, hildebrandtii showed its powerful antitumor effect Luteolin-3′,7-di-O-glucoside, carnosol, tormentic against Hela cells. The 50% growth inhibition and oxo-pomolic acid [26]. concentration of Hela cells was 7.5 × 10-7 M [28]. The ethanolic leaf extract of M. tomentosa In another study performed on the leaf extract of was evaluated for its cytotoxic activity using the M. tomentosa to evaluate its anti-inflammatory brine shrimp lethality assay. Preliminary results activity, three different doses of the extract (50, showed cytotoxic activity of the extract towards 100 and 200 mg/kg) were enrolled in the study. brine shrimp larvae with LD50 31.62 µg/ml. further The in-vivo anti-inflammatory activity was cytotoxic assay was performed on the cancerous investigated using carrageenan, histamine, HeLa and MCF-7 cell lines and the non- serotonin, xylene and formalin induced edema. In cancerous Vero cell lines using MTT test. The carrageenan induced edema, the extract extract showed significant cytotoxic activity exhibited significant (p ˂ 0.01, 0.001, 0.0001) against HeLa cells with IC50 of 189.1±1.76 µg/ml dose dependent activity with maximum effect however no cytotoxicity was reported against obtained at 66.67% for the 200 mg/kg dose either MCF-7 (IC greater than 2000 µg/ml) or within the first 90 minutes (the first phase of 50 the non-cancerous Vero cells (IC50 greater than inflammation). This possibly indicates the 250 µg/ml) [29]. inhibiting effect of the extract on both histamine and serotonin release which mediate the first 3.8 Plant Larvicidal Activity phase of inflammation. Xylene induced edema leads to acute inflammation which is mediated The methanolic extracts of different Nigerian through phospholipase A2. M. tomentosa produced significant (p ˂ 0.05, 0.01) dose- medicinal plants were tested for their larvicidal dependent inhibition of ear edema induced by activity. The stem bark extract of M. tomentosa xylene with the highest effect produced by the was one of the tested extracts for its activity highest dose 200 mg/kg. This result suggests the against Aedes aegypti L., the main vector for extract to act through inhibition of phospholipase transmission of dengue, yellow and chikungunya fevers. According to the egg hatch and larvicidal A2. The formalin induced edema is a model for sub chronic inflammation. The ethanolic extract tests performed, the extract showed mild of M. tomentosa showed significant (p ˂ 0.05, larvicidal activity lasted for 48 hours with LC50> 0.0001) reduction in edema which is also dose 4.2 mg/ml [32].

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4. CONCLUSION London: H.M. Stationery Office. 1919;1899-1900. Phytochemical research is an ongoing process of 6. Korkina LG. Phenylpropanoids as naturally discovery. The isolation and identification of the occurring antioxidants: from plant defense chemical components comprising the to human health. Cell Mol Biol. complicated make up of various organisms 2007;53:15-25. among which are plants and recognizing their 7. Kernan MR, Amarquaye A, Chen JL, Chan biological activity seems endless. A significant J, Sesin DF, Parkinson N, et al. Antiviral part of this process relies on previous studies phenylpropanoid glycosides from the and discoveries upon which novel research is medicinal plant Markhamia lutea. J Nat built. From the review at hand, Markhamia Prod. 1998;61:564-570. species are noticeably one of the understudied 8. Kanchanapoom T, Kasai R, Yamasaki K. plant species with potential for further Lignan and phenylpropanoid glycosides phytochemical and pharmacological investigation from Fernandoa adenophylla. Phytochem. in an effort to find and reveal bioactive 2001;57:1245-1248. components with substantial weight in the field of 9. Wilson R, Márcio L, Rodrigo C, Sérgio R, medicinal plants. Jairo K. Lignans: Chemical and Biological Properties, Phytochemicals - A Global CONSENT Perspective of Their Role in Nutrition and Health. 2012;51:953-978. Not applicable. 10. Joshi KC, Singh P, Sharma MC. Quinones and Other Constituents of Markhamia ETHICAL APPROVAL platycalyx and Bignonia unguiscati. J Nat Prod. 1985;48:145. 11. Viresh M, Paul S, Bharti O. Isolation and Not applicable. characterization of anthraquinone

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