Arabian Journal for Science and Engineering https://doi.org/10.1007/s13369-021-05858-3

REVIEW-CHEMISTRY

Chromanone‑A Prerogative Therapeutic Scafold: An Overview

Sonia Kamboj1,2 · Randhir Singh1

Received: 28 September 2020 / Accepted: 9 June 2021 © King Fahd University of Petroleum & Minerals 2021

Abstract Chromanone or Chroman-4-one is the most important and interesting heterobicyclic compound and acts as a building block in medicinal chemistry for isolation, designing and synthesis of novel lead compounds. Structurally, absence of a double bond in chromanone between C-2 and C-3 shows a minor diference from chromone but exhibits signifcant variations in biological activities. In the present review, various studies published on synthesis, pharmacological evaluation on chroman- 4-one analogues are addressed to signify the importance of chromanone as a versatile scafold exhibiting a wide range of pharmacological activities. But, due to poor yield in the case of chemical synthesis and expensive isolation procedure from natural compounds, more studies are required to provide the most efective and cost-efective methods to synthesize novel chromanone analogs to give leads to chemistry community. Considering the versatility of chromanone, this review is designed to impart comprehensive, critical and authoritative information about chromanone template in drug designing and development.

Keywords Chroman-4-one · Chromone · Pharmacological activity · Synthesis · Analogues

1 Introduction dihydropyran (ring B) which relates to chromane, chromene, chromone and chromenone, but the absence of C2-C3 dou- Chroman-4-one is one of the most important heterobicyclic ble bond of chroman-4-one skeleton makes a minor difer- moieties existing in natural compounds as polyphenols and ence (Table 1) from chromone and associated with diverse as synthetic compounds like Taxifolin, also known as chro- biological activities [1]. manone or benzo-dihydropyran or benzopyran. Structurally, chroman-4-one is a fusion of benzene nucleus (ring A) with

* Randhir Singh [email protected]

1 Maharishi Markandeshwar College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Haryana 133203, India 2 Ch. Devi Lal College of Pharmacy, Jagadhri, Haryana 135003, India

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O O 4 4 4 4 3 3 3 3 2 2 2 O 2 O O O 1 1 1 1 Chromane Chromene Chroman -4-one Chromone

Natural and synthetic chromanone analogs show vari- other diseases [4]. Presently, a number of research groups ous biological activities such as anticancer, tumor necrosis are working in designing and development of more potent factor-α (TNF-α) inhibitors, antivascular, antidiabetic, anti- and signifcant chromanone analogues. So, in the present oxidant, antimicrobial, antifungal, antiviral, antileishmanial, review, recent literature available up to 2020 about chro- insecticidal, spasmolytic, analgesic, anti-infammatory, anti- man-4-one derivative and their pharmacological activities coagulant, estrogenic inhibitor, anti-acetylcholinesterase is accrued. Present review article will ofer a platform to the (AchE) inhibitor, antihuman immunodefciency virus (HIV), researchers in designing and development of novel potent anticonvulsant, antidepressants, anticoronal and antituber- chroman-4-one analogs. cular activity. Due to of these activities, several analogues of chromane are also available in market like tocopherols 2 Biological Activities of Chromanone (vitamin E), taxifolin (antidiabetic), tetrazole (antidiabetic), troglitazone (antidiabetic), ormeloxifene (anticancer) and 2.1 Anticancer Activity nebivolol (beta-blocker) [2]. Moreover, several isolated fa- vanones, favonols, homoisofavonoids like naringenin, nar- ingin, myricetin, dihydroquercetin and kaempferol are also Discovery and development of novel anticancer agents under clinical studies [3]. Therefore, among the diverse array with potent cytotoxic activity is one of the top priorities in of chromane, chroman-4-one/4-chromanone are of consider- pharmaceutical research. Several limitations like variable able interest to researchers due to potency of this clinically efcacy, poor toxicity profle and adverse efects are associ- useful pharmacophore in the treatment of cancer and several ated with the usage of currently available chemotherapeutic agents [5]. Generally, cancer can be measured by assessing

Table 1 Properties of chromanone and chromone Name Chroman-4-one Chromone

IUPAC name 4-Chromanone 4-Chromone Other names (Synonym) Chromanone, 4-chromanone, chroman-4-one dihydrobenzo pyran, Chromone, 4-Chromone, benzopyran, 2,3-dihydro-4H-1-benzopyran-4-one 4H-Chromen-4-one,4H-1-Benzo- pyran-4-one Structure O O 4 4 3 3 2 2 O O 1 1

Formula C9H8O2 C9H6O2 Formula weight 148.15 g/mol 146.14 g/mol Molecular weight 148.15 g/mol 146.14 g/mol Density 1.196 ± 0.06 g/cm3 1.248 ± 0.06 g/cm3 Xlog P3 1.4 ± 0.24 1.4 ± 0.24 Melting point 36.5 ºC 59.0 ºC Composition 72.96% 73.97% C 5.44% 4.14% H 21.60% 21.90% O

1 3 Arabian Journal for Science and Engineering

OH OH OH OH

H3CO O HO O HO O

OH O OH O OH O Naringenin Eriodictoyl Sakuranetin OH OH OH OCH3 OCH3 H3CO HO O O H HO O

O O OO H CH3 OH O

Sterubin Deguellin CH3 Hesperetin

Fig. 1 Natural favanones containing chroman-4-one as parent moiety

O O O

O HO O HO O

OH OH 4-hydroxyflavonone 5,4'-Dideoxyflavonone 5-Dideoxyflavonone OH OH OH OCH3 OH

HO O HO O H3CO O

OH

OH O OH O OH O Hesperetin (2S,3S)-trans-Dihydroquercetin Sakuranetin

Fig. 2 Chroman-4-one derived structure (under development phase) the degree of mitochondrial impairment and metabolic dys- in lipid metabolism and unbalanced pH [6]. Therefore, to functions such as cellular energy supply, cell death signal- cure such metabolic dysfunctions, naturally occurring fa- ing, irregulation of metabolic pathways, formation of reac- vonoids, favonols, favanones (2-phenyl chroman-4-one tive oxygen species (ROS), compromised enzyme actions, derivatives) and homoisofavanones exhibit good anticancer aerobic glycolysis augmented in tumor cells, alterations potential along with other pharmacological activities such

1 3 Arabian Journal for Science and Engineering = 19 µM [ 17 ] 50 IC ≤ 9.3 µg/ml) [ 18 ] 50 (IC ≤ 3.86 µg/ml [ 19 ] 50 MB-231 = 7.56 ± 2.23, KB = 25.04 ± 10.60 and = 9.64 ± 2.7 SK-N-MC series [ 16 ] of endothelial cells with ­ cell lines ­ tested ­ IC Signifcant inhibition against MDA- Signifcant inhibition against among the anticancer agent as best Marked proliferation against potency Exhibited highest anticancer activity against Exhibited highest anticancer activity with Exhibited potent activity [ 20 ] cytotoxic Exhibited potent Inference Exhibited potent cytotoxic activity [ 21 ] cytotoxic Exhibited potent cancer), KB (nasopharyngeal epidermoid - (human neuro and SK-N-MC carcinoma) cell lines using MTT assay blastoma) endothelial HUVEC (human umbilical vein cells) (MCF-7, T47D and MDA-MB-231) Cell lines SK-N-M and SK-Hepl AGS, as A549, LLC, such HA22T cancer cells cancer) cells MCF-7 (human breast Evaluation Evaluated against MDA-MB-231 (breast (breast MDA-MB-231 against Evaluated activity in antiproliferative for Evaluated cancer cell lines three breast against Evaluated and K562, MDA-MB-231 against Evaluated colorectal cells carcinoma against Evaluated activity against antiproliferative for Evaluated Apoptotic cell population = 34.89% 3 3 H H Cl OC 3 OC OH H 3 H OC 3 OC Cl Br CH OH OH O O O O O O O O O O OO O O O CO CO O O O 3 3 Structure H H H - (3-chloro-4,5-dimethoxyben derivatives derivative) zylidene vanone) (E)-3-(2 ′ -methoxybenzylidene)-4-chromanone Hydroxy favanones Hydroxy 3-Benzylidene-chroman-4-one derivatives 3-Benzylidene-chroman-4-one 6,7-Methylenedioxy-4-chromanone (E)-3-benzylidene-7-methoxychroman-4-one (E)-3-benzylidene-7-methoxychroman-4-one Compound - (4 ′ ,7-dimethoxyfa favanones Synthetic Chroman-4-one analogs exhibiting anticancer activity analogs exhibiting Chroman-4-one 2 5 4 3 1 2 Table No. Sr. 6

1 3 Arabian Journal for Science and Engineering - = 2.9 µM) against 50 (IC = 0.9 ± 0.2 (HL60), 50 [ 23 ] HL60 cells [ 25 ] inac - entirely while E-isomer was cytotoxic, tive MDA-MB-231 cell line than etoposide (refer cell line than etoposide MDA-MB-231 ence drug) [ 22 ] Very potent compound ­ compound potent Very than potency reference cytotoxic Exhibit better activity [ 24 ] signifcant cytotoxic Showed anticancer activity against highest Displayed be more to found was Z-isomer (chromanone) IC 1.6 ± 0.3 (NALM-6), 6.3 ± 0.5 (WM-115), 5.77 ± 0.17(HUVEC) [ 26 ] Inference G2, KB, SK-N-MC cells G2, KB, SK-N-MC cells human leukemia HL-60, BGC-823 and KB (human cancer cell lines) cells) and PBMC (peripheralleukemia blood mononuclear cells) using MTT assay and normal cells HUVEC cancer cell lines Evaluation Evaluated against MCF-7, LNCaP, PC3, Hep- MCF-7, LNCaP, against Evaluated in and apoptosis potential cytotoxic Examine Bel-7402, activity against cytotoxic for Tested HL60 (acute myeloblastic against Evaluated HL-60, WM115 against Screened NALM-6, Cl Cl 1 2 R 1 NO R N O O O O -NO2 O O O O O O O O -NO2 or 2' O O 2' 3 Cl or '-

CH OH O Cl '- R1=2

CO C O CO 3 3 3 O H Structure R1=2 H H H H Cl Cl 4-one compounds isomers) and 3-arylfavones 7-Methoxyisofavanone -nitro-substituted chroman- or 2 ′ -nitro-substituted 2’-Chloro- Diarylchromanone 3 ′ ,6-Dichlorofavanone Halogenated favanones 3 ′ ,7-dichlorofavanone favanones Halogenated Compound 7, 8-Methylenedioxyfavanones (E, Z and chromanone 3-Arylidenefavanone (continued) 10 9 7 2 Table No. Sr. 8 11

1 3 Arabian Journal for Science and Engineering 1) < = 20.45 mM) 50 (IC = 5.62 ± 1.33 μM 50 IC 0.11 μM (A2780), and 20.1 mM), HeLa cell lines ± =

50 ­ (IC 0.17 μM (HT-29), respectively [ 30 ] respectively 0.17 μM (HT-29), = 42.8 mM), whereas 3-benzylchroman- ± 50 used in treatment of breast cancer [ 31 ] of breast used in treatment was found to be the most active against against be theactive to most found was BT549 [ 28 ] observed in mice was tumor growth anticancer as active and marked lines tested [ 29 ] agent the most spacer shows with a sulfonyl tives activity with potent ­ (combination indices therapeutic value 4-one derivatives (b) showed signifcant (b) showed 4-one derivatives HeLa cells ­ activity against ­ (IC 0.47 (MCF-7) 0.31 only [ 27 ] only 3-Benzylchroman-4-one derivatives (a) derivatives 3-Benzylchroman-4-one ascites carcinoma 80% inhibition of Ehrlich all cell signifcant inhibition against Showed 4 ′ -piperidin]-4-one- deriva [chroman-2, Spiro have may Combination of Silibinin and chrysin Inference BT549 (human breast carcinoma), HeLa carcinoma), BT549 (human breast (human cervical and one carcinoma) (normal kidney cell line Vero noncancerous MTT assay epithelial cells) by tumor growth lines human cancer cell lines; MCF-7 (human A2780 (human ovarian carcinoma), breast (human colorectal adeno - cancer) and HT-29 using MTT assay carcinoma) MTT assay by Evaluation Examined against two cancerous cell lines cancerous two against Examined ascites carcinoma Ehrlich against Tested and CNS cell lung, breast against Examined three activity against cytotoxic Examined cancer cell lines) T47D (breast against Tested 3 CH H H OH O 3 CH OH H OO O 2 S O O N CH O O O OH 2 SO O O O OO O O O O OO O OH OH ) O ) (b O (a O Structure H H compounds tives Novel tricyclic heterocyclic chromanone chromanone tricyclic heterocyclic Novel 4 ′ -piperidin]-4-one- deriva [chroman-2, Spiro Chrysin Silibinin 3-Benzylchroman-4-ones Compound 3-Methenylthiochroman-4-one-l, 1-dioxide 3-Methenylthiochroman-4-one-l, (continued) 14 15 16 12 2 Table No. Sr. 13

1 3 Arabian Journal for Science and Engineering 0.3( MCF7), ± 0.9 (A498) [ 32 ] ± 0.5 (HT29), 5.7 ± all the tested cell lines, 7.3 all the tested antiproliferative activity for breast cancer and breast activity for antiproliferative [ 7 ] lung carcinoma 64.6 ± 7.1( HL-60), 68.4 ± 3.9 (MCF7), 33.2 ± 2.1( MOLT-4) [ 33 ] 4.9 Found to possess very potent activity against activity against potent possess very to Found Selective Sirtuin 2 (SIRT2) inhibitors exhibited exhibited inhibitors Sirtuin 2 (SIRT2) Selective activity against cytotoxic highest Showed Inference - - cinoma), HT29 (human colon adenocarci - adenocarci noma) and A498 (human kidney B dye noma) cell lines using sulforhodamine (breast cancer) and A549 (lung carcinoma) cancer) and A549 (lung carcinoma) (breast cell lines MCF-7 cancer cell lines Evaluation Tested antiproliferative activity against MCF-7 activity against antiproliferative Tested MCF7 mammary against adenocar Screened activity on HL-60, MOL T -4, and Cytotoxic 3 3 CH N CH O O O N N N O O O O O O O O O O O O O 3 3 O O CH CH C C 3 3 N Structure H H F chromane-2,4-dione (series II) derivatives chromane-2,4-dione analog opyran-4-one Chromone-2-carboxamide (series I) and Chromone-2-carboxamide 3-(Pyridin-3-yl) chroman-4-one 1,2,4-Oxadiazole containing benzopyran 1,2,4-Oxadiazole - ethyl]-benz 6,8-Dimethyl-2-[2-(pyridin-3-yl) 6-Flurobenzopyran-4-one 6-Methoxy-3-phenyl chroman-4-one 6-Methoxy-3-phenyl Compound methoxy]-benzopyran-4-one 2-[(Furan-2-yl) (continued) 19 17 2 Table No. Sr. 18

1 3 Arabian Journal for Science and Engineering zylidene] thiochroman-4-one was found to be to found was thiochroman-4-one zylidene] signifcant and possessed very potent most all thecancer cell lines tested activity against [ 34 ] cell lines [ 37 ] tested 3-[3-(2-(4-Chlorophenyl)-2-oxoethoxy) ben - 3-[3-(2-(4-Chlorophenyl)-2-oxoethoxy) [ 35 ] Exhibited signifcant anticancer potential [ 36 ] anticancer agent Potent activity against signifcant cytotoxic Showed Inference lines), non-small cell lung cancer (NSCLC, lines), non-small cell lung cancer (NSCLC, 9 cell lines), melanoma (M, 8 or colon cancer (CC, 7 cell lines), central cancer (CNSC, 6 cell lines), system nervous - cancer (OC, 6 or 7 cell lines), pros ovarian tate cancer cancer (PC, 2 cell lines), renal cancer (BC, 6 or 8 8 cell lines), breast (RC, cell lines) cell lines carcinoma) cells of a Mediterraneanspecies, is an endophyte alga cells Evaluation Screened against leukemia (L, 4 or 6 cell leukemia against Screened adeno - MCF-7 (human breast against Tested cancer activity against cytotoxic for Examined the from fungus Nodulisporium Produced 36 cancer activity against cytotoxic for Tested 3 H Cl OC O S 3 H Br N 4 OC OH 3 O O H H 6 O O CH C O N O O S CO N NH S H OH O S O CH OH 3 3 C 3 H O O CH H OC S O O O O O O H O H O O H O H Structure S - - -one H,4 ′ H- ′′ -tetrahydrothiopyran]-4 4 ′′′ ′′ -(4-bromophenyl)-3 ′′ -Aceto-3 ′ ,3 ′′ [1, 3, 4] oxadithiin-2 chromano-[3,4-e] ′′ chroman-2 man/thiochroman-4-one derivatives man/thiochroman-4-one [1,3,4-thiadiazol]-4 ′ -one ′ ,2 ′′ ′ ,4-tetrahydropyran-3 dispiro[chroman-2 Novel noduliprevenone Novel ′ -2H- Trispiro[tetrahydrothiopyran-4,5 5 ′′ - arylidene] chro 3-[3/4-(2-aryl-2-oxoethoxy) Compound derivatives 2-hydroxy-4-chromanone (continued) 23 21 20 2 Table No. Sr. 22

1 3 Arabian Journal for Science and Engineering as anti-infammatory, antioxidative, antidiabetic, antibacte- 2.3 Anti‑infammatory Activity rial, antimicrobial, antifungal, antimutagenic, antiparasitic and anti-HIV [7, 8]. In this regard, the following naturally Localized protective reaction to infection or injury well occurring favanones such as naringenin [9], naringin [9], known as infammatory reaction plays a signifcant role in sakuranetin [10], eriodictyol [11], calyxin G, deguelin [12] the pathological mechanism of various infammation-related and sterubin [13] have been reported (Figs. 1, 2) to possess diseases like cancer, Alzheimer, diabetes, atherosclerosis potent cytotoxic profle. Moreover, these naturally occurring and cardiovascular disorders. Knowledge of etiology and favanones can also regulate cellular metabolism, scavenge mechanism of infammation progression can prevent further free radical and suppress proliferation of cancer cells [12, development of diseases [59]. 13]. However, the precise molecular mechanisms of these For treatment of infammation, diverse range of isolated favonoids accountable for cytotoxic potential have not been homoisofavanones, dihydrofavonols such as dihydromyri- completely elucidated till now. Moreover, poor yield is also cetin, hesperitin, stilbin and silybin containing chromanone a major hurdle to explore the potential of these compounds. pharmacophore are reported with vivid bioactivity and play So, synthesis of compounds containing chromanone with an exclusive role in discovery and development of new anti- efcient cytotoxic action might be a privileged approach in infammatory drugs [60]. Among the isolated compounds searching new targets for cancer treatment [14]. A number of from natural sources, chroman-4-one containing stilbin compounds are found to have signifcant anticancer activity. and silybin are used clinically as anti-infammatory drugs. For instance, several compounds containing chroman-4-one Moreover, these isolated compounds further pave the way and its natural and synthetic analogs possessing signifcant for synthesis of new anti-infammatory drugs via inhibition anticancer potential against cancer cell lines are enlisted in of cyclooxygenase 2 (COX-2). 4-Homisofavonones enlisted Table 2 [15]. in Table 4 developed as chroman-4-one analogs were found to have signifcant inhibition for COX 2 receptor binding in 2.2 Antioxidant range of 0 ± 5.4 to 0 ± 21.3(% activity) [54, 61]. Likewise, a new chromanone, violacein A produced from Streptomyces Excessive production of ROS, suppression of antioxidants violaceoruber emerged as potential therapeutic for treat- as a result of normal biochemical processes due to the efect ment of infammation-related disease by suppressing NF-kB of several environmental and endogenous factors result in (nuclear factor kappa light chain enhancer of activated B imbalance of oxidative-antioxidant. The excessive ROS cells) signaling pathways. Moreover, it can be used for the higher than physiological concentrations cause oxidative treatment of other diseases like cancer [62]. Generally, SAR stress [38, 39]. Oxidative stress afects all cellular func- studies revealed that C-2 substitution with hydroxybenzyli- tioning which may be responsible for generation of severe dine, arylidene, hydroxyphenyl, pyridine-3-yl and fuoro- diseases like diabetes complications, neurological disease, phenyl displayed the best anti-infammatory activity with atherosclerosis, skin lesions, inflammation, rheumatoid signifcant inhibition. So, exploring the substitutions at C-3, arthritis, aging, cardiovascular diseases and cancer [39, 40]. 6, 7 and 8th of chromanone nucleus yields more efcient Generally, antioxidants react or debilitate excessive level of anti-infammatory compounds which can compete isolated ROS [41]. phytochemicals as well as existing anti-infammatory drugs There are a number of isolated favanones and homoiso- [60, 62] favanones such as silymarin, pinobanksin, silybin, liquiri- tin, isointricatinol reported for their antioxidant activity in 2.4 Antidiabetic Activity 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Along with isolated components, synthetic ben- Diabetes mellitus represented as hyperglycemia is increasing zylidene chromanone derivatives also showed DPPH radical globally at very signifcant pace and has become a complex scavenging and ferric reducing antioxidant power (FRAP) chronic metabolic disease associated with diabetic compli- [42, 43]. According to structure activity relationship (SAR) cations like diabetic neuropathy and nephropathy [69]. A of chromanone analogs, C-2 and C-3 substitution with meth- number of potent antidiabetic drugs like metformin, glu- oxyphenyl, amine derivatives, aromatic groups, benzylidene cotrol, tolbutamide, acarbose, pioglitazone, gliptins, lira- and cyclohexyl carbamoyl yields more potent antioxidant glutide are available in the market, but long-term use of compounds which can produce equivalent antioxidant the antidiabetic drugs may cause serious side efects, and activity like vitamin E and Trolox [44] enlisted in Table 3. moreover, these drugs are less efective in management of Therefore, more synthetic work is required to produce new associated diabetic complications [70]. In this regard, a num- chroman-4-one scafolds as efective antioxidant compounds ber of isolated compounds as natural favonols, favanones which can be used to manage the pathogenesis of diseases in and homoisofavanones containing chromanone pharma- which oxidative stress plays a signifcant role. cophore such as naringenin, hesperitin, dihydroquercetin,

1 3 Arabian Journal for Science and Engineering - 66.4 to 66.4 to = gene expression expression gene 2 SOD 176.8 to 300 (b) DPPH 176.8 to = 213.9 [ 46 ] than vitamin E and Trolox with follow than vitamin E and Trolox inhibi - (a) lipid peroxidation ing values tion 24.30 ± 0.51 to 35 ± 0.47 (DPPH), 10.96 ± 0.34 to 14.33 ± 0.52 (FRAP) and + µM = 44.62 ± 0.48 Fe2 to 71.64 ± 0.47 [ 45 ] (TBARS) follows 30.75 ± 1.965 to 83.57 ± 0.456 (DPPH) 8.545 ± 0.545 to 39.356 ± 0.644 [ 49 ] respectively (ABTS), SOD levels and ­ SOD levels inhibition = 5.90 ± 0.150 to 0.64 ± 0.334 [ 48 ] of hyperlipidemic rats by endogenous endogenous by rats of hyperlipidemic [ 47 ] enzymes reduction antioxidant Exhibited more potent antioxidant activity antioxidant potent Exhibited more Showed following inhibition values inhibition values following Showed obtained as values Signifcant antioxidant Reduced oxidative stress, LDL level, Mn- LDL level, stress, oxidative Reduced property with antioxidant DPPH Showed Inference and ascorbic acid 2+ Fe in rat brain homogenates brain in rat zyl (DPPH) radical scavenging, ferric scavenging, (DPPH) radical zyl (FRAP) and power antioxidant reducing thiobarbituric substances acid reactive ­ tion initiated by assays DPPH and ABTS (b) DPPH scavenging activity (b) DPPH scavenging - 1,1-diphenyl-2-picrylhydra Assessed for inhibi - lipid peroxidation for (a) Assayed activity antioxidant Examined inhibition DPPH radical for Assayed activity using antioxidant Examined Evaluation 3 5 H 3 H OH OH H CH 4-CN 6 OC OH N, O OH 1 C R 2 ,2-C 3 H ut H -b NH ,4-C 3 ,C 5 ,n H 3 H O 6 ,2-C O O 2 -pro Br CH O ,n ,C 2 -N 5 r,3- 3 ,C OH H 3 2 F O O ,2-B CH O O O O CH 2 ,C OO O ,4-C 3 4-Cl 2 O 3 l, F ) 3 2 CH H ,3-C ,3-C N 3 H 2-Cl N OC OH CH F, (C N R=H, 3- 2 ,4-O 3 F, = H, CH 1 2- O CH O H CO C R CH O R O 3 3 H R=H, ,3-O R H H H Structure Chroman-4-one tives 8-methoxychroman-4-one tives 7-Hydroxy-2-(4- Hydroxy -3-Methoxyphenyl)- Hydroxy 7-Hydroxy-2-(4- - deriva 6-Hydroxy-7-methoxy-4-chromanone Benzyl-1,2,3-triazolyl hesperetin derivatives hesperetin Benzyl-1,2,3-triazolyl 3-(4’-Hydroxybenzyl)-5,7-dihydroxy-6-methyl- Compound - deriva 3-Benzylidene-7-alkoxychroman-4-one Chroman-4-one analogs exhibiting antioxidant potential antioxidant analogs exhibiting Chroman-4-one 3 2 5 4 3 Table Sr. No. Sr. 1

1 3 Arabian Journal for Science and Engineering 6.2 (DPPH) 5.80 U/mg), ± ± 3.8(DPPH) [ 50 ] ± and (b) 212.4 tive antioxidant activity with following activity with following antioxidant tive (a) 273.1 signifcant values signify good antioxidant values (ABTS) [ 52 ] potential. ischemia/reperfusion (I/R) by cerebral inhibition of SOD (75.11 ± 0.48U/mg) CAT(7.62 and GSH-Px (887.24 ± 79.23U/mg) [ 53 ] reported more potent antioxidants than reported antioxidants potent more [ 51 ] vitamin E and Trolox [ 51 ] values - respec (a) and (b) showed Both compounds 85.50 mM (DPPH) and 44.13 mM Showed focal efect against neuroprotective Showed Inhibited lipid peroxidation, and has been Inhibited lipid peroxidation, DPPH inhibition with signifcant Showed Inference DPPH radical and β-carotene/linoleic and β-carotene/linoleic DPPH radical acid system radicals DPPH and ABTS against anion (SOD), catalase (CAT) superoxide (GSH-Px) and glutathione peroxidase in mice Assayed for antioxidant property against property against antioxidant for Assayed process lipid peroxidation Evaluate DPPH inhibition Examined efect scavenging radical free Assayed inhibition of enzymes for Examined Evaluation 1 R 3 O CH OH OH O 2 CH =OH(b) OH 1 O O OH 3 3 CH H 3 N 3 R OC H CH O =OCH3 (a) ,R NH OC 1 2 O R OH h C CH O O O 3 O O H O OH O O O O O O H O OH OH H R= O, N-P C 3 C H 3 O O H H H Structure → 6)-β-glucopiranosyl]- → 6)-β-glucopiranoside]- 6-(hydroxymethyl) oxan-2-yl] oxyphenyl]- oxan-2-yl] 6-(hydroxymethyl) chroman-4-one 4-one) man-3-carboxylate ′ -hydroxybenzyl)-chroman-4- 5-hydroxy-3-(4 one rhamnopyranosyl-(1 5-hydroxy3-(4-methoxybenzyl)-chroman-4- one rhamnopyranosyl-(1 Liquiritin (7-hydroxy-2-[4-[3,4,5-trihydroxy- Chroman-4-one derivative Chroman-4-one Isointricatinol chroman- (7,8-dihydroxy-3-(4’methoxybenzyl) - carbamoyl)-4-oxochro 2-(cyclohexyl Methyl 7-O-[α- Compound Homoisofavanone7-O-[α- (continued) 10 8 9 7 (b) 3 Table Sr. No. Sr. 6 (a)

1 3 Arabian Journal for Science and Engineering nifcant inhibition of CV (524 Epa mV), DPPH (1745 ± 65) and LPx (33.6 ± 1.2). [ 54 ] group contributes activi - the to antioxidant ties [ 56 ] vascular defects, cancer and other diseases defects, vascular capacity [ 55 ] its high antioxidant due to Exhibited antioxidant potential with potential sig - Exhibited antioxidant efect signifcant antioxidant Showed 7–OH Among all the mainly compounds, NBT = 8.5 µM DPPH = 4.5 µM [ 57 ] 33% Approximately Inhibition of DPPH [ 58 ] - cardio efects against Exhibited protective Inference - metry (CV), DPPH scavenging and metry (CV), DPPH scavenging (LPx) lipid Peroxidation microsomal and SPLET mechanisms SET-PT HAT, scav radical and DPPH free scavenging enging inhibition DPPH - voltam inhibition of Cyclic for Evaluated capacity antioxidative for Examined by analyzed capacities were Antioxidant NBT superoxide activity by Antioxidant activity reported against Antioxidant Evaluation 3 H 3 OC OH CH 3 H O OH H OH 2 OH OC CH OH O O O O OH OH O O OH O O O O O O O O OH OH OH OH CO 3 O O O O H H H HO H Structure 4-one chroman-4-one ylene] Silymarin 7-Methoxy-3-(4-methoxyphenyl)-chroman- - meth 7,8-Dihydroxy-3-[(3,4-dihydroxyphenyl) Pinobanksin Compound Silybin (continued) 15 12 14 13 3 Table Sr. No. Sr. 11

1 3 Arabian Journal for Science and Engineering - value for pro-infammatory cytokine: for value 50 activity by decreasing IL-6, decreasing activity by TNF-a with –0.26 (a), 0.76 (b) and − minus log P values [ 63 ] 0.75(c), respectively [ 64 ] ity [ 65 ] infammation anti-infammatory activity and cytotoxicity [ 65 ] ILβ = 32.5 ± 3.5 μg/mL, IL-6 = 13.4 ± 2.3 μg/ anti-infammatory potent showed mL which activity [ 59 ] Exhibited signifcant anti-infammatory IC signifcant anti-infammatory potential Showed Exhibited signifcant anti-infammatory activ IL-1β,Decreased IL-6, and TNF-α cells signifcant most showed These 3 derivatives Inference IL-6, TNF-a cells IL-6 and phosphorylation of ERK1/2 and to JNK in MAPK signaling pathways production and cytokines NO decrease study edema in rats IL-1β, IL-6, and TNF-α cells Anti-infammatory activity was tested against against tested Anti-infammatory activity was Inhibited pro-infammatory ILβ, cytokine oil-induced edema in animal in croton Tested in Carrageenan induced paw Evaluated anti-infammatory activity in for Tested Evaluation 3 OH CH O OH OH OH F 1 OH N R s ve ti OH O O va OH O O 3 OH OH deri O O 5 CH e O O O O 2H en O O O O 3 O OH H R2=CH(CH3)2 b) R1=H, R2= C(CH3)3 ylid , OC R3=C ar OH OH OH O N, H R1= C O 3 H a) R1=H c) X= CO N CO 2 1 3 H O 3 O O O R H R H H H H H Structure chroman-4-one 4-one zylidene) chroman-4-one zylidene) dihydroxyphenyl) chroman-4-one dihydroxyphenyl) -O-Demethylophiopogonanone E 4 ′ -O-Demethylophiopogonanone 3-Arylidene-7-methoxychroman-4-one ′ -fuorophenyl) 3,5,7-Trihydroxy-2-(4 3,5,7-Trihydroxy-2-(pyridin-3-yl) chroman- 3,5,7-Trihydroxy-2-(pyridin-3-yl) - (E)-5,7-dimethoxy-3-(4’-hydroxyben Novel ′ ,4 - 3,5,6,7-Tetrahydroxy-2-(3 Name of compound Name Hesperetin derivatives Hesperetin Chroman-4-one analogs exhibiting anti-infammatory activity analogs exhibiting Chroman-4-one 2 4 5 3 4 Table No. Sr. 1

1 3 Arabian Journal for Science and Engineering 5.4 [ 61 ] ± 0 = = 7.8 ± 0.2 µM [ 67 ] 50 inhibition value 1.96 mM [ 66 ] inhibition value ­ IC against COX-2 with % activity COX-2 against [ 62 ] disorders ment of infammation-related Showed anti-infammatory with potential Showed anti-infammatory activity withPotent % activity = 0 ± 8.3 [ 61 ] % activity = 0 ± 21.3 % activity = 0 ± 7.8 Showed signifcant anti-infammatory activity Showed the- treat therapeutic candidate for A potential Inference (iNOS) protein expression protein (iNOS) (5-LO) Evaluated for COX-2 receptor binding receptor COX-2 for Evaluated synthaseInhibited inducible nitric oxide inhibited 5-lipoxygenase Signifcantly NF-kBSuppressed signaling pathways Evaluation 3 H CH OH H O OH H OH H OH 6 OH 3 7 3 O O H CH 5 H 8 O C O 3 OH H O O 3 H OC O OH CH OO O O O OO O 3 O O O OO O H 3 1 4 H 2 OH H OH O 3 OC c CH OC 2 CH OH 3 OA O O O O H H CO H C O 3 3 O O O O O H H H H H H H H Structure - then-9-one droxy-5-methoxychroman-4-one 5-methoxychroman-4-one Myricitrin - 1,3,6-Trihydroxy-2-methoxy-8-methylxan acetate Ovatifolionone Streptomyces violaceoruber ) A ( Streptomyces Violacin (E)-3-(3,4-dihydroxybenzylidene)-7-hy Name of compound Name Pruinosanone A (R)-3-(3,4-Dihydroxybenzyl)-7-hydroxy- (continued) 8 9 4 Table No. Sr. 7 6

1 3 Arabian Journal for Science and Engineering

eriodictyol, sakuranetin, aromadendrin, butin, pinocembrin, nymphaeol A, sophorafavanone G and sterubin (Fig. 3) are already reported for their excellent potency in the treat- ment of diabetic mellitus and diabetes associated compli- cations [2]. These chromanone containing favanones treat diabetes through inhibition of receptors like glucagon-like peptide 1 (GLP-1), dipeptidyl peptidase-IV (DPP4), per- oxisome proliferator receptor gamma (PPAR-γ), Alpha glucosidase (α-glucosidase), phosphatidylinositol 3-kinase (PI3K) in both in vivo and in vitro experimentation [71]. Moreover, several synthetic chromanone analogs are also reported (enlisted in Table 5) for antidiabetic potential via Showed anti-infammatory activity [ 68 ] Showed Inference α-glucosidase inhibition and DPPH radical scavenging activity. Zhu et al. 2019 isolated various chromanone ana- logs from the seeds of Psoralea corylifolia and evaluated for diglyceride acyltransferase (DGAT), protein-tyrosine phosphatase 1B(PTP1B) and α-glucosidase activity. Out of theses isolated compounds, (2S)-7-methoxy-6-(2-hydroxy- 3-methyl but-3-en-1-yl)-2-(4-hydroxyphenyl)chroman- 4-one, (2S)-4′-hydroxyl-7-hydroxy methylene-6-(2′′,3′′- epoxy-3′′- methyl butyl) flavanone and bavachinone B exhibited good antidiabetic efect by inhibition of DGAT, PTP1B and α-glucosidase. Takao K. et al. introduced ben- zylidene-4-chromanone derivatives as the lead compound for the development of novel α-glucosidase inhibitors as Tested for anti-infammatory potential for Tested Evaluation well as signifcant antioxidative agent due to its potential in signifcantly inhibiting the level of DPPH. By the virtue of SAR studies, substitution at C-2, 3, 6 and ­7th position of parent chromanone provide efective antidiabetic drugs which might help in the synthesis of more efcient novel compounds for the cure of diabetes and its complications [72, 73]. But, the research and published data about the synthetic chromanone containing medicinal compounds as

O O antidiabetic are very less as compared to isolated favanones, favonols and homoisofavanones. Therefore, a very efective

3 synthetic approach is required for the synthesis and evalua- N CH

C tion of more chromanone analogs as antidiabetics [72, 74]. 3 H Structure 2.5 Antibacterial and Antifungal Agents

Increased prevalence of pathogenic microbial infections necessitates the need for new antibacterial agents with dis- tinct mechanism of action and broad spectrum of activity over a wide range of bacterial and fungal strains. Consider- ing this viewpoint, several naturally occurring favonoids and heterobicyclic compounds containing chromanone pharmacophore were found to have diverse activities rang- ing from antibacterial to antiviral activity. But these com- pounds were found to have two major limitations like poor yield and resistance against the general bacterial and fungal Name of compound Name 7-Dimethylamino-4-chromanone (continued) strains such as Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Aspergillus 4 Table No. Sr. 10 niger, Fusarium oxysporum, Penicillium italicum, Pythium

1 3 Arabian Journal for Science and Engineering

OH OH OH OH OH OCH 3 OH HO O HO O HO O HO O

OH OH O OH O OH O OH O Narigenin Hesperitin Taxifolin(dihydroquercetin) Eriodictoyl(tetrahydroxyflavanone) OH OH OH OH

HO O H3CO O HO O HO O

OH OH O OH O O OH O Sakuranetin Aromadendrin(dihydrokaempferol) Butin pinocembrin H C CH 3 2 OH OH OH OH H3C HO O OH HO O H CO O CH3 3

H3C OH

CH3 CH3 OH O OH O OH O Nymphaeol A Sophoraflavonone G sterubin

Fig. 3 Natural chromanones exhibiting antidiabetic activity ultimum, Sclerotinia sclerotium, Phytophthora capsici, E. 2.6 Anti TB Agents Faecalis, C. albicans, C. Krusei, C. Glabrata and A. fumi- gates [81]. Therefore, there is a need for new synthetic anti- Among the available treatments for tuberculosis, frst-line bacterial and antifungal compounds containing chromanone and second-line antituberculosis (TB) drugs, DOTS (directly moiety. observed treatment short-course) is one of the most compe- It was found that substitution at C-2 with pyrazol-4-yl tent multidrug efective strategy developed by WHO against derivatives, methoxyphenyl, alkyl, vinyl, hydroxyl methyl Mycobacterium tuberculosis. However, the success rate for and chlorophenyl group displayed broad spectrum anti- cure of TB patients struggles to achieve 85% [99]. There- bacterial activity against tested bacterial strains, whereas fore, more research is required for the development of novel azolyl and benzylidene derivatization yields good antifun- potent antimycobacterial agents with promising efcacy gal agents as shown in Table 6 [82]. Moreover, C-2, 3, 4, and less side efects. From the series of heterobicyclic com- 6 and 7 substitutions also predicted efcient antibacterial pounds, isolated as well as synthetic chroman-4-one analogs and antifungal compounds with broad spectrum activity as were reported to inhibit M. tuberculosis [100, 101]. Chro- well as low or no resistance. Likewise, most important series manone analogs having signifcant potential for the treat- of benzylidene derivatives C-3-substituted 3-(benzo[1,3] ment of TB with greater efcacy and less side efects are dioxol-5-ylmethylene)-7-hydroxychroman-4-one, a 3-ben- enlisted in Table 7. This will provide us a new framework in zylidene-4-chromanone exhibited signifcant antibacterial designing and development of chromanone derivatives and activity against gram positive and gram negative bacteria, their potent multidrug combinations like spiro chromanones while 3-azolyl-4-chromanone phenyl hydrazones exhibited as novel antiTB agents [102]. antifungal potential against C. albicans, S. cerevisiae, A. niger and M. gypseum pathogens [83]. Hence, more exhaus- 2.7 Antiviral Agents tive approach for the chromanone scafold may lead medical chemist to synthesize more potent antibacterial and anti- A number of viral diseases in human ranging from mild fungal compounds with maximum efcacy and minimum upper respiratory infection to fatal cardiac and neurological resistance. illnesses are caused by numerous picornaviruses particularly rhinoviruses (HRVs) and enteroviruses (EVs). A diverse

1 3 Arabian Journal for Science and Engineering level, HOMA-IR value and PEPCK gene gene and PEPCK value HOMA-IR level, [ 76 ] rats in diabetic expression α-glucosidase inhibition [ 75 ] α-glucosidase DGAT, PTP1B and α- glucosidase with PTP1B and α- glucosidase DGAT, [ 73 ] signifcant values Increased insulin and decreased blood glucose blood glucose insulin and decreased Increased Exhibited antidiabetic activity with Exhibited antidiabetic Showed antidiabetic activity inhibiting antidiabetic Showed Inference cosidase inhibition Tested for antidiabetic activity antidiabetic for Tested Evaluated for α-glucosidase inhibition α-glucosidase for Evaluated corylifolia seeds of Psoralea Isolated from - PTP1B and α- glu DGAT, for Examined Evaluation OH OH OH 3 H OH OC O O O O OH Hb Ha O O O O 3 O O CH OH C 3 2 CO 3 H 3 CH OH H O 3 2 O H CH O HO H CH CH C O 3 H H C C C C 3 3 O 3 3 H H H H H Structure - - methyl butyl) butyl) - methyl ′′ - epoxy—3 ,3 ′′ methyl but- 3- en—1- yl)- 2- (4- hydroxy but- 3- en—1- yl)- methyl one chroman-4- phenyl) ene-6- (2 ′′ hydroxy-2-(4-hydroxyphenyl) chroman- hydroxy-2-(4-hydroxyphenyl) 4-one)] chroman-4-one favanone (2S)- 7- methoxy—6- (2- hydroxy—3- (2- hydroxy—3- (2S)- 7- methoxy—6- - methyl (2S)-4 ′ -hydroxyl—7-hydroxy - [(E)-8-(3,7-dimethylocta-2,6-dienyl)-5,7-di Name of compound Name B Bavachinone 7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)- Chroman-4-one analogs exhibiting antidiabetic activity antidiabetic analogs exhibiting Chroman-4-one 2 (a) (b) 1 5 Table No. Sr. (c) 3

1 3 Arabian Journal for Science and Engineering with IC50 = 0. 060 ± 0.3 mM and displayed [ 77 ] potential antidiabetic mice by diabetic streptozotocin-induced enzymes digesting inhibiting carbohydrate [ 78 ] hemi diaphragm isolated rat by cose uptake model) [ 79 ] ( in vitro dant efect [ 80 ] Showed highest α-glucosidase inhibition α-glucosidase highest Showed in hyperglycemia postprandial Improved efect using the- glu good antidiabetic Showed Showed signifcant antioxidant potential [ 72 ] potential signifcant antioxidant Showed - activity with antioxi Exhibited antidiabetic Inference α-glucosidase inhibition α-glucosidase inhibitoryα-glucosidase activity Evaluated for α-glucosidase assay α-glucosidase for Evaluated and scavenging DPPH radical for Assayed activity antidiabetic for Evaluated efect antidiabetic for evaluation in vitro and scavenging radical free for Evaluated Evaluation OH OH OH O OH N N 3 CH O O O O O 2 3 O O Cl O H OH OC O ON – Cu O H O O CO C O CO 2 C 3 3 3 3 H Ac H H H H Structure chromanone ′ -hydroxybenzyl)-4- 5,7-Dimethoxy-3-(2 3-Benzylidene-4-chromanone derivatives 3-Benzylidene-4-chromanone 6-Methyl-4-chromanone derivatives 2H-Chromenylphenyloxazolones 2-Methoxy-4-chromanones ligated Cu (II) ligated 2-Methoxy-4-chromanones Name of compound Name (continued) 6 5 7 8 4 5 Table No. Sr.

1 3 Arabian Journal for Science and Engineering - S. K. A. P. K. P. aer P. P. cap - P. E. coli = 33.8 mm E. coli = 30.5 mm E. coli = 4.17lg/mL = 20.5 mm S. aureus = 20 mm S. aureus = 14.5 mm oxysporum F. Escherichia coli = 33 mm Escherichia B. subtilis = 15 mm = 17.5 mm oxysporum F. = 30 mm oxysporum F. P. ultimum = 54.99 ppm P. for ppm values 50 = 20 mm italicum [ 84 ] uginosa = 11 mm [ 84 ] = 7.30lg/mL aureus [ 86 ] pneumonia = 34.8 mm = 10.2 mm niger [ 85 ] pneumonia = 33.5 mm = 15 mm A. niger [ 85 ] = 52.03 ppm S.sclerotiorum sici = 35.77 ppm [ 87 ] = 14 mm A. niger = 32 mm S. aureus B. subtilis = 31.5 mm, B. Subtilis = 4.17lg/mL ED Inference B. subtilis = 33 mm, - - gillus niger, Fusarium oxysporum and oxysporum Fusarium gillus niger, using griseofulvin italicum Penicillium (standard drug) against Staphylococcus aureus, Bacil - aureus, Staphylococcus against lus subtilis, Pseudomonas aeruginosa coli using ampicillin and Escherichia drug) -zone of inhibition (mm) (reference difusion using cup plate agar measured method the meas - medium used for (PDA) Agar of antibacterialurement and antifungal as in zone of inhibition (mm) potential activities coli and Staphy lus Subtilis, Escherichia capsici and P. mum, S. sclerotiorum benzopyranones thesis efective of more -Vinyl group at carbon -Vinyl lococcus aureus the biological activity C-2 is necessary for group the increases and Chloro activity Showed antibacterial activity evaluated antibacterial activity evaluated Showed Asper activity against Exhibited antifungal Dextrose media and Potato Nutrient agar Exhibited antibacterial and antifungal Bacil - activity against antimicrobial Showed - ulti P. activity against Exhibited antifungal the syn - also used as intermediate for It was Evaluation 3 H 3 H H OC 2 OC CH 2 CH O N N O O N S OH N O O O O S O O O O O O O O C C C 3 C 3 CO 3 3 3 H H Structure H H H Cl chroman-4-one derivatives chroman-4-one 2,2-Dimethylchroman-4-one derivatives 2,2-Dimethylchroman-4-one 2-Hydroxymethyl-chroman-4-one 2-(1-Phenyl-3-(2-thienyl)-1H-pyrazol-4-yl) 2-(1-Phenyl-3-(2-thienyl)-1H-pyrazol-4-yl) Name of compound Name 6-Chloro-2-vinyl chroman-4-one 6-Chloro-2-vinyl Chroman-4-one analogs exhibiting antibacterial values and antifungal analogs exhibiting Chroman-4-one 2 4 1 6 Table No. Sr. 3

1 3 Arabian Journal for Science and Engineering E. S. aureus S. aureus S. aureus S. aureus A. E. coli = 1.5 µg/ml C. albi - coli = 21.5 ± 0.7 mm cans = 20.0 ± 0.0 mm = 20.0 ± 0.0 mm niger [ 92 ] = 3.13 MSSA (µg/ml), = 3.13 MRSA (µg/ml) [ 91 ] and via inhibition of B. subtilis, S. aureus E. coli [ 90 ] 88 ] [ (MRSA) S. aureus cillin resistant Displayed signifcant antimicrobial activity signifcant antimicrobial Displayed = 6.25(µg/ml) E. Faecalis = 15.5 ± 0.7 mm S. aureus Exhibited potent antimicrobial activity [ 89 ] antimicrobial Exhibited potent - methi Exhibited signifcant activity against Inference -Antimicrobial activity assay activity assay -Antimicrobial verticillatum using nutrient plate medium agar and E. MRSA MSSA, S. aureus S. aureus coli (µg/ml) E. coli, C. Albicans and S. aureus, against difusion using agar niger Aspergillus technique resistant S. resistant ( methicillin MRSA ated for assay aureus) Evaluated for antimicrobial activity antimicrobial for Evaluated theIsolated from of Polygonatum rhizomes E. Faecalis, against Antibacterial evaluation activity antimicrobial Exhibited potent - evalu antibiotics potent natural These are Evaluation 3 A) 3 B) CH H rin rin OC 3 CH 3 CH Cl =H(Aposphae 3 =OH(Aposphae 3 2 Ph 3 CH O O 3 R CH N H , S O 3 CH O O N O =H, R H 2 3 O R R O O =C 3 , 2 5 O O R O H CH OH 2 1 OH C R O 2 =OH, =O CO R 1 1 O 3 O R Structure H H R H - thyl chroman-4-one thyl 4-ylidene)-2-phenylhydrazine droxychroman-4-one man-4- one - 5,7–Dihydroxy-3-(4-methoxybenzyl)-8-me 1-(2-(4-Chlorophenyl)-6-methoxychroman- 2-(2,6-Dimethylhept-5-en-1-yl)-5,7-dihy - chro 3-Phenylsulfonyl-3-(2-propenyl) Aposphaerin A and B Name of compound Name (continued) 7 9 8 6 5 6 Table No. Sr.

1 3 Arabian Journal for Science and Engineering F. S. aureus S. aureus P. aerugi - P. A. favus = 4.5 No E. coli = No inhibi - = 19.5 S. aureus E. coli = 21.0 = 18.7 μg/mL [ 82 ] 50 Krusei [ 93 ] GO3 strain signifcant inhibition [ 95 ] nosa = 22.5 Staphylococcus aureus, Bacillus subtilis, aureus, Staphylococcus Bacillus sphaericus, Klebsiella aerogenes, C. violaceum, Pseudomonas aeruginosa [ 92 ] P. aeruginosa = 0.25 mg/mL tion P. (MRSA = 0.125 mg/mL Positive) = 6.5[ 94 ] oxysporum = 0.52 mM S. aureus = 0.125 mg/mL S. aureus C. a clear zone of inhibition against Observed B. subtilis = 21.0 activity with antimicrobial potent Showed Signifcant antibacterial activity against IC Inference ve and –ve bacteria’s bacteria’s and –ve ve + aureus bacteria using and gram-negative positive method micro-dilution broth albicans, C. Krusei GO3, C. Glabrata strains HO5 and A. fumigates number of gram and amphotericin B using streptomycin (as standard drugs) C. B. subtilis, M. tuberculosis, S. aureus, strains albicans and S. cerevisiae Evaluated against gram-negative bacteria gram-negative against Evaluated antibacterialS. activity against Tested gram- Exhibited antibacterial activity for C. against activity evaluated Antifungal a Exhibited high antibacterial activity for against potential antimicrobial for Evaluated Also showed antioxidant potential antioxidant Also showed Evaluation H S 3 OH H 3 OC S N H O O OC 3 2 CH O NH NH OO CO O O OH O O NH C 3 N O O H O O O O O O O OH OH O O O OH OH O O C O H 3 C H O 3 O H Cl O H Structure H H H 4,5-dihydroxy-2-(((S)-5-hydroxy-2-(4- ′ - [1, [chroman-4,2 spiro hydroxyphenyl) oxy)-6-(hydroxymethyl) 3] dioxolan]-7-yl) - oxy)-6-methyl tetrahydro-2H-pyran-3-yl) tetrahydro-2H-pyran-3,4,5-triol -(3,4-Dimethoxybenzylidene) (Z)-2 ′ -(3,4-Dimethoxybenzylidene) ′ -furo[3,2-g] spiro{cyclo-hexane-1,7 ′ ,5 (2 H,6 H)-dione chromene}-3 chroman-4-one moiety derivatives moiety chroman-4-one 7-hydroxychroman-4-one, a 3-ben - 7-hydroxychroman-4-one, zylidene-4-chromanone semi carbazone derivative (2S,3R,4R,5R,6S)-2-(((2S,3R,4R,5S,6R)- 3-benzylidene-4-chromanones derivatives 3-benzylidene-4-chromanones Novel spiro chromanone–aurone hybrids hybrids chromanone–aurone spiro Novel 2-MBT(2-mercaptobenzothiazole) with2-MBT(2-mercaptobenzothiazole) 3-(Benzo-[1, 3] dioxol-5-ylmethylene)- Name of compound Name (Spiro[chroman-2,1’-cyclohexan]-4-one) (Spiro[chroman-2,1’-cyclohexan]-4-one) (continued) 11 13 14 10 6 Table No. Sr. 12

1 3 Arabian Journal for Science and Engineering M. gypseum = 16 μg/ = 16 μg/mL, S. cerevisiae ± 25 mM) [ 81 ] 50 pathogen strains [ 97 ] strains pathogen cans = 8 μg/mL, = 16 μg/mL, A. niger [ 83 ] potential mL Exhibited Antifungal ­ (MIC MIC = 16 µg/mL value [ 96 ] than potent standard drugMore oxacillin Showed signifcant inhibition against tested tested signifcant inhibition against Showed C. albi - (μg /mL) are: MICs values Showed signifcant inhibition [ 98 ] Showed activity signifcant antifungal Showed Inference strains including MRSA strains activities and M. gypsum pathogens niger S. aureus Antibacterial activity against Evaluated for antifungal and antibacterial antifungal for Evaluated A. C. albicans, S. cerevisiae, against Tested C. albicans activity against Antifungal C. albicans activity against Antifungal Evaluation 3 3 3 CH CH 3 3 CH CH OH C O 2 2 H 3 R N R1= H, R2=OCH CH N 1 O O R NH 3 C O O O H O O O O , R2=H b. N 3 OC N OH OH CO 3 O O H H Structure a. R1=OCH H - nylpyrrolidine-3,3’-chroman-4-one] manone phenyl] ~ phenyl] loxy) chroman-4-one{selinone) - Spiro[2-benzoyl-cyclohexyl-4,5-diphe - (E)-5,7-dimethoxy-3-benzylidene-4-chro 3-Azolyl-4-chromanone phenylhydrazones 3-Azolyl-4-chromanone 5,7-Dihydroxy-2-[4-(3-methyl-but-2-eny Novel favanone derivatives favanone Novel Name of compound Name (continued) 16 19 17 18 15 6 Table No. Sr.

1 3 Arabian Journal for Science and Engineering 155 [ 106 ] 2 = 55.8 µM [ 103 ] 50 1.11 and 2.94 [ 105 ] = ­ IC

10 and M. tuberculosis against the and decreased bacte - mL, respectively, rial load in lung and spleen tissues with ­ log 12.5 µg/mL and considered as most potent potent as most 12.5 µg/mL and considered [ 104 ] agents antitubercular with Mycobacterium Mycobacterium against inhibitors pump smegmatis mc study revealed anti TB activity revealed study in vitro with MICs of 0.22 and 0.07 μg/ MDR-TB H37Rv with MIC Inhibited M. tuberculosis (MbtI) of M. tuberculosis inhibitors Potential Inference Exhibited signifcant inhibition as efux 155 for anti TB potential 155 for 2 losis and mc Inhibition - M. tubercu anti TB activity against Tested in vitro MDR-TB smegmatis Mycobacterium against Screened Evaluated for M. tuberculosis for Evaluated H37Rv M. tuberculosis for Examined Evaluation 2 F 3 CH H 5 OC r H 2 B C O F O O 3 CH O O O N NH O O O O N O O C 3 H O O O O O O O O H O O O O H H H Structure H ylene] chroman-4-one ylene] ene] chroman-4-one 6-fuorochroman-4-one ylene] chroman-4-one ylene] 6-bromochroman-4-one 2H-benzopyran-5-carboxylic acid 2H-benzopyran-5-carboxylic - meth 7-Hydroxy-(E)-3-[(3-allyloxyphenyl) - methyl 7-Hydroxy-(E)-3-[(2-fuorophenyl) (E)-3-(dibenzo [b, d] furan-2-ylmethylene)- - meth 7-Hydroxy-(E)-3-[(4-methoxyphenyl) (E)-3-(dibenzo [b, d] furan-2-ylmethylene)- Chromane-4-one analogs Chromane-4-one Name of compound Name 7-Hydroxy-2-methyl-4-oxo-3,4-dihydro- Chroman-4-one analogs exhibiting antitubercular activity antitubercular analogs exhibiting Chroman-4-one 4 2 3 7 Table No. Sr. 1

1 3 Arabian Journal for Science and Engineering 0 = 20.3 µM) and PknG 5 [ 107 ] ­ (IC of 3.13 µg/ with MIC value (ATCC27294) mL [ 108 ] M. phlei (16 µ g/mL), aurum (32 µ g/ (128 µ g/mL) and M. mL), M. fortuitum smegmatis (256 µ g/mL) [ 109 ] with 27,294) strain H37Rv (ATCC MIC = 3.125 μg/mL [ 110 ] The % growth inhibition was 75.1 at 100 µM. inhibition was The % growth Inhibited mycobacterial FAS-II FAS-II Inhibited mycobacterial H37Rv Inhibited M. tuberculosis activity against antimycobacterial Displayed activity against Exhibited antimycobacterial Inference PknG inhibition cells growth (ATCC27294) tum and M. smegmatis inhibition potential antimycobacterial 27,294) for Examined for mycobacterial FAS-II and FAS-II mycobacterial for Examined H37Rv M. tuberculosis for Tested M. phlei, aurum,- M. fortui for Evaluated H37Rv (ATCC strain against Examined Evaluation r B 3 H OC O O O O O O OH O O O OH O O NH NN N OO O O 1 R O Structure chroman-4-one Amino alcohol-linked spiro chromones spiro Amino alcohol-linked 3-(4 ′ -Methoxybenzyl)-7,8-methylenedioxy- chromanones Bis-spiro Name of compound Name Triazolyl methoxy favanones methoxy Triazolyl (continued) 6 7 8 7 Table No. Sr. 5

1 3 Arabian Journal for Science and Engineering

Table 8 Chroman-4-one analogs exhibiting antiviral activity Sr. No. Name Structure Evaluation Inference

1 5′′-Aceto-3′′-phenyl-3′′H,4′H- CH3 Examined for Showed considerable antiviral dispiro[chroman-2′,4- adenovirus activity against strained adenovi- tetrahydropyran-3′,2′′-[1,3,4- type-7 inhibi- rus type 7 with signifcant inhibi- thiadiazol]-4′-one tion for antivi- tion [35] O S ral activity N N

O O 5′′-Aceto- 3′′-(4-bromophenyl)- O CH 3′′H, 4′H-dispiro[chroman- 3 O 2′,4-tetrahydrothiopyran-3′,2′′- S [1,3,4-thiadiazol]-4′-one N N Br

O S

2 2 Chroman-4-one derivatives O R Evaluated against Displayed antiviral potency against human rhinovi- tested HRV 1B and 14 strains rus (HRV) 1B [114] 1 R and 14 inhibi- tion O

3 3-Benzylchroman-4-one’s deriva- R3 O R Tested for antivi- Showed antiviral activity against tives ral activity Coxsackie virus B1, B3, B4, A9 and echovirus 30 [115] [113] R2

R1 O

range of efective antipicornavirus agents are developed and and further prevent the decapsidation of infected viral some are in clinical phase study [111]. Literature evidence segments and release of corresponding RNA within cells has established that natural and synthetic favonoids contain- [112]. Tait S et al. (2006) examined antiviral activity of ing chromane obstruct the replication step of picornavirus homoisofavonoids (3-benzylchroman-4-ones derivatives)

Table 9 Chroman-4-one analogs exhibiting anti-HIV activity

Sr. No. Name of compound Structure Evaluation Inference

CH3 1 Calanolide A CH3 Examined AZT- Showed signifcant anti-HIV resistant strains for activity against AZT-resist- H C O O 3 anti-HIV potency ant strains [118] [121]

CH3 H3C OH O

O 2 1,3-Diketo acids, new chromone OO Evaluated for anti-HIV Exhibited anti-HIV activity by 1 and R OH activity inhibition of HIV-1 IN strand chromanone derivatives transfer ­(IC50, µM = 168.2 O and 100.6 for a and b respec- O tively) [122] R1=H,3-Chromonyl-2-oxo-propionic acid(a) R1=benzyl,6-Benzylchromone-3-yl)-2-oxo-p ropionic acid (b)

O 3 3-Benzylidene derivatives of O Tested for anti-HIV Showed signifcant anti-HIV chromanone efect activity [120] Ph Ph

O S

1 3 Arabian Journal for Science and Engineering on enteroviruses replication, and these chromanone ana- Dawood et al. (2005) tested a series of 3-benzylidene logs showed signifcant activity against coxsackie virus B1, derivatives of chromanone and substitution of thio (S) group B3, B4, A9, echovirus 30 and substitution at C-3 of parent at the place of oxo(-O) at I­st position displayed impressive chromanone exhibited good efcacy against HRVs growth. anti-HIV activity. Consequently, SAR studies revealed that Moreover, introduction of thiopyran at C-2 by Hegab, MI C-2 and 6 substitution with oxo propionic acid and benzyl et al. (2015) showed considerable antiviral activity against group exhibited anti-HIV activity by inhibition of HIV-1 strained adenovirus type 7 with signifcant inhibition as IN strand transfer with good inhibitory values as shown in shown in Table 8. So, following these substitutions, more Table 9. So, more research and development on chromanone antiviral chromanone analogs may be designed and synthe- analogs can be a prominent approach for synthesis of novel sized with signifcant antiviral activity [35, 113]. HIV1 inhibitors against the treatment of AIDS [120].

2.8 Anti‑HIV Compounds 2.9 Antileishmanial Agents

Chromanone derivatives have attained much potential A group of parasites of genus Leishmania causes tropical against treatment of Acquired Immune Defciency Syn- disease known as Leishmaniasis, which spreads in living drome (AIDS) caused by HIV-1 [116]. In 1994, an iso- beings by the bite of infected sandfies [123]. These fies lated calanolide A and inophyllums from calophyllum have a multifarious life cycle which exhibits an amastigote genus reported as a novel anti-HIV chemotype inhibited phase in the host cell as well as a promastigote phase in HIV-1-specifc nonnucleoside RT [117]. Furthermore, an vector fies. A number of clinical representations, especially enantioselective designing of 2, 3-dimethyl-4-chromanone cutaneous, visceral and mucosal forms, attain the most seri- ring attachment was attempted for the synthesis of potent ous grade for Leishmaniasis [124]. Although diverse treat- calophyllum coumarins as anti-HIV 1 and it showed signif- ment for Leishmaniasis or cutaneous leishmaniasis (CL) cant efect which can compete with currently available pro- exists, less potency, toxicity and cost issues are some of tease inhibitors (atazanavir, ritonavir, lopinavir, nelfnavir, the signifcant limitations associated with the present treat- saquinavir etc.) approved by Food and Drug Administration ment options. So, development of more effective novel (FDA) [118, 119]. compounds against Leishmaniasis remains an important

Table 10 Chroman-4-one analogs exhibiting antileishmanial activity Sr. No. Name of compound Structure Evaluation Inference

NH NH2 1 Thiochroman-4-one’s deriva- N Evaluated for in vitro These compounds showed tives antileishmanial activ- good antileishmanial X ity against the intracel- activity with signifcant lular amastigote inhibition [128] S form of Leishmania panamensis IfX=O,(E)-2-(2-Phenylthiochroman-4-ylidene) hydrazinecarboxamide(IC50=5.4 µM) IfX=S,(E)-2-(2-Phenylthiochroman-4-ylidene) hydrazinecarbothioamide(IC50=5.1 µM) 2 Benzoic acid, 2-(2,3-dihydro- In vitro evaluation using Showed combined actions 4H-1-benzopyran-4-ylidene) NH macrophage intracel- of antileishmanial with hydrazide N lular mastigotes of infammatory and wound O Leishmania (Viannia) healing properties [129] panamensis and L. (V) X braziliensis by fow If X=S, Benzoic acid, cytometry antileish- 2-(2,3-dihydro-4H-1-benzothiopyran-4-ylidene) hydrazide manial activity If X=O, Benzoic acid, 2-(2,3-dihydro-4H-1-benzopyran-4-ylidene) hydrazide

3 2,2-Dimethyl-6-(octyl amino) CH3 Evaluated in romastig- Exhibited antileish- O CH3 methyl chroman-4-one otes, axenic amastig- manial potency with otes and Leishmania- ­IC50 = 24.6 ± 0.4 μM infected macrophages [130] H3C NH O

1 3 Arabian Journal for Science and Engineering stratagem. A wide range of natural favonoids having chro- 30–40% epilepsy patients [140]. Therefore, MDT (multiple- manone pharmacophore and synthetic oxygenated hetero- drug therapies) is preferred for the control of seizures. But cyclic compounds such as hydrazones, thiosemicarbazones still no MDT or single drug can prevent the development or and semicarbazones have been reported to exhibit antileish- treat epilepsy for longer time interval without development manial potential. Among these, semicarbazone and thio- of resistance [141]. Considering this viewpoint, more potent semicarbazone derivatives of favanone and thiofavanone compounds which can cure or prevent epilepsy with high could be considered a potential privileged structure [125]. efcacy and less side efects are need of the hour. Using this approach, derivatization of chroman-4-one and A series of chroman-4-one derivatives such as azolylchro- thiochroman-4-ones with acyl hydrazones resulted in sig- manones, azolylchromanone oximes and imidazolyl chro- nifcant enhancement of antileishmanial potential [126]. As manone oxime ethers were tested for their anticonvulsant thiochroman-4-one derivatives showed immense similarity potential in lithium, pilocarpine induced seizure and pentyl- with the chroman-4-one compounds so could be considered enetetrazol (PTZ) kindling model of epilepsy [142]. Among as potential scafold with wide range of bioactivity like anti- these tested compounds, some analogs (Enlisted in Table 12) viral, antitumoral, antimalarial, antibacterial and antileish- showed good anticonvulsant activity with signifcant seizure manial [127]. Therefore, more research in thiochromanone latency and seizure duration. SAR studies showed that pres- derivatization is required for more novel antileishmanial ence of azolyl ring at 3-postion, halogen (Chloro) group at compounds, and some relevant compounds are reported in the 7-position and/or an alkyl (especially methyl) group at Table 10. the 2-position of the chromane ring resulted in an enhance- ment of anti-seizure efciency in O-(2,4-dichlorobenzyl) 2.10 Anti‑Acetyl Cholinesterase (AchE) Agents oxime series and no signifcant diference in efcacy was for Alzheimer Treatment observed for both (Z)- and (E)-isomers against the seizure durations and seizure latency [143]. Therefore, efective Alzheimer is a complicated neurodegenerative disease that report of promising chroman-4-one analogs (Table 11) in poses severe threat to human health and characterized by epileptic models can predict potential clinical worth in treat- memory loss, behavioral abnormalities and cognitive def- ment of adequate epileptic disorder. cits [131]. Alzheimer’s Association reported that the num- ber of patients sufering from Alzheimer’s disease (AD) is 2.12 Antidepressants now approximately 47 million and this fgure is projected to increase around 100 million by 2050 entire over the world Depression, a mental disorder, seeks a major concern in [132]. So, demand of a better treatment for AD around the medical practice, and it is more common in patient than world is a challenge for the medical science. reported. Its generation is associated with amino acid metab- Polyphenolic compounds like favonoids, favones, isofa- olism in which tryptophan, an essential amino acid metabo- vone exhibit broad range of biological properties including lizes amines and releases various amine neurotransmitters inhibition of AchE enzymes and its catalytic steps [133]. In like serotonin, epinephrine, norepinephrine (NE), melanin this review, we included a number of chroman-4-one con- and dopamine (DA) controlling the autonomic nervous sys- taining favonoids which exhibit AchE inhibition potential tem (ANS) and central nervous system (CNS) functioning [134]. This study presents that presence of an amino group, under the catalysis of favoenzyme monoamine oxidases piperidinyl of chromanone derivatives and novel dithiocar- (MAOs). It exists as in two isomeric forms MAO-A and bamates show potent AchE inhibition in comparison with the MAO-B, from which MAO-A selectively metabolizes NE, standard drugs like Tacrine (Table 11). Therefore, designing epinephrine, 5-HT, whereas MAO-B specifcally deactivates and development of new efective chromanone hybrids as β-phenethylamine, benzylamine and inactivated by the fol- AchE inhibitors provide a new framework to the treatment lowing inhibitors such as rasagiline and selegiline with many of AD and other neurodegenerative disorders [135]. side efects and resistance [146, 147]. So, new MAOs inhibi- tors are required for developing new antidepressant drugs. 2.11 Anticonvulsants For the development of more efective novel MAO inhibi- tors, the chromanone scafolds from natural and synthetic Epilepsy is a chronic neurological disease in which patient sources displayed a promising efect and exhibited their sufers from seizures, transient attacks that afect at least 70 potency for MAO-B inhibition selectively [148]. In par- million people around the world. A number of therapeutic ticular, chromanone derivatives substituted with benzyloxy agents are available in the market as antiepileptic drugs such group at C-7 are more potent MAO-B inhibitors and after as phenytoin, phenobarbital, benzodiazepines, carbamaz- searching of more chromanone derivatives, DSP-1053, a epine, ethosuximide and sodium valproate exhibit accept- novel compound examined for serotonin reuptake in vivo able management on seizures, but resistance is observed in with 5-HT1A partial agonistic activity and inhibited serotonin

1 3 Arabian Journal for Science and Engineering - - = 2.49 ± 0.08 nM = 0.10 μM) and 50 50 5 showed best activ best 5 showed = (IC (IC 1.18 μM) and also showed 1.18 μM) and also showed - aggrega induced Ab1-42 =

2+− 50 0.0581lM, respectively), good 0.0581lM, respectively), Cu ± ­ (IC = 0.27 µM [ 135 ] = 9.9 ± 1.6 mM [ 136 ] 50 50 ity to inhibit AchE ­ inhibit AchE ity to benzylidene)-6,7-dimethoxychroman- and MAO-B AchE excellent 4-one showed inhibitory activities ­ ­ IC activity omone ring showed potent AchE inhibition AchE potent omone ring showed drug, with Tacrine the reference against ­ IC AchE-induced Aβ aggregation (33.02% at Aβ aggregation AchE-induced inhibit self- 100 μM) and could efectively (38.25%at 25 μM) induced Aβ aggregation [ 138 ] remarkable interactions with interactions theremarkable binding But - of the ChE enzymes against pockets in the and AchE, (BuchE) rylcholinesterase [ 137 ] study molecular docking tion inhibitory potency, antioxidant activity, activity, antioxidant tion inhibitory potency, ability and high BBB biometal chelating [ 139 ] permeability. and 1.74 self- and ­ A novel hybrid with hybrid n A novel (E)-3-(3-Hydroxy-4-(piperidin-1-ylmethyl) An amino group on the 2-position of chr inhibitory activity withExhibited AchE anti-acetylcholinesterase potent most Showed Inhibition aggregation inhibition aggregation of homoisofa - dual inhibitors bases were Mannich vonoid Alzheimer’s against screened disease esterase (AchE) inhibition (AchE) esterase assay potential and anti-amnestic fnding efective for docking binding pockets Evaluated for AchE-induced Aβ AchE-induced for Evaluated and MAO-B AchE Selective Evaluated for acetylcholine acetylcholine for Evaluated inhibition AchE for Evaluated activity and AchE for Evaluated Evaluation N N OH S OH S n 3 NH H O OC O O O O 3 O H OC O O N 2 H O O O 3 O O H OC N OO O CO CO CO 3 3 3 Structure H H H - and 4-hydroxyben side chain ethoxy nyl substitution zylidene benzylidene)-6,7-dimethoxychroman- 4-one (n = 5) Chroman-4-one analogs exhibiting anti-AchE inhibition anti-AchE analogs exhibiting Chroman-4-one Flavonoid derivative with carbamate moiety derivative Flavonoid with the piperidi derivative Chroman-4-one - (E)-3-(3-Hydroxy-4-(piperidin-1-ylmethyl) (E)-3-(3-Hydroxy-4-(piperidin-1-ylmethyl) Novel chromanone-dithiocarbamate hybrids hybrids chromanone-dithiocarbamate Novel Chromone-chromanone hybrid Chromone-chromanone Name of compound Name 2 3 5 4 1 11 Table No. Sr.

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Table 12 Chroman-4-one analogs exhibiting anticonvulsant activity Sr. No. Name of compound Structure Evaluation Inference

1 7-Chloro-3-(1H-imidazol-1-yl) O N Investigated for both Efective against lithium and chroman-4-one anticonvulsive and pilocarpine induced status N antiepileptogenic epilepticus with seizure properties using latency = 32.12 ± 3.04 and Cl O lithium pilocarpine seizure duration = 12.50 ± 1.87, induced seizure and whereas in PTZ-kindling PTZ-induced kindling model of epilepsy, seizure models latency and seizure index were observed as 3.75 ± 0.14 and 3.43 ± 0.14, respectively [144] 2 3-(1H-1,2,4-triazol-1-yl) chroman- O N Evaluated for PTZ- Produced signifcant action in 4-one kindling model of delaying seizures as well as N epilepsy efective protection against N PTZ-induced seizures (seizure latency = 22.00 ± 4.11 min) and deaths [145] O

Cl 3 Imidazolyl chromanone oxime Tested in PTZ-kindling Exhibited anticonvulsant Cl O N N model of epilepsy activity with Seizure latency N (s) = 715 ± 153 Seizure dura- Cl O tion (s) = 40.3 ± 4.7 Cl Seizure latency(s) = 776 ± 97

Cl Seizure duration (s) = 342 ± 4.9 O N N [143] N

Cl O CH3

reuptake and considered as fast antidepressant drug in clini- compound ANS-118 (commercial insecticide containing cal practice (Table 13) [149]. Consequently, after reviewing chroman moiety) [156]. the clinical data of DSP-1053, a probability comes out that more research in chromanone compounds might add a new 2.14 Diagnostic agents class of antidepressant drugs. Ganand et al. synthesized a series of (E)-3-benzylidenechro- 2.13 Insecticides man-4-one’s derivatives (homoisofavonoids) and evaluated for their diagnostic imaging potential for pathogenesis of AD As per the literature, it is reported that for the development by targeting β-amyloid (Aβ) plaques. In vitro studies revealed and metamorphosis regulation in insect, mainly 20-hydroxy- that (E)-3-(4-methoxybenzylidene)-6-bromo-chroman-4- ecdysone and juvenile hormones are necessary and play pro- one and (E)-3-(4-dimethylamino-benzylidene)-6-bromo- moting roles in endocrine systems of insects as growth regu- chroman-4-one derivatives exhibited high binding afnities lators [153]. In 1988, 1-tert-Butyl-1, 2-dibenzoyl hydrazine, to Aβ plaques with 9.98 and 9.10 nM (Ki values), respec- frst non-steroidal ecdysone agonist, was reported. Further, tively, as compared to [­125I] 2-(4′- dimethylaminophenyl)- a variety of ecdysone agonists were identifed among them 6-iodoimidazo[1,2-α] pyridine (IMPY) (reference com- diacyl hydrazine compounds produced signifcant response pound) [1, 158], whereas fuorescent staining test (applied for the growth and regulation of the insect structure [154, on the brain sections of AD patients) and biodistribution 155]. In 2007, Zhao et al. have introduced new design of data revealed that (E)-3-(4-dimethylamino-benzylidene) insecticidal agents as chromanone derivatives of diacyl- derivatives can selectively label Aβ plaques in brain sec- hydrazines in which chromafenozide group was attached tions and [125I]-radio labeled compound showed adequate on a chromanone moiety instead of chromane structure brain uptake for brain scanning (Table 15) [1]. Chroman- (Table 14). This study provided signifcant evidence that 4-one derivatives may be helpful diagnostic imaging agent chromanone derivatives of diacylhydrazines exhibited more for early fnding of Aβ plaques in AD brain. Hence, further potency for insecticidal activity as compared to reference research and development of novel chromanone derivatives

1 3 Arabian Journal for Science and Engineering - 6.3%

± 50 IC = 8.62 nM 50 IC > 3431) [ 150 ] receptors of 70.0 receptors 50 1A ­ IC 0.41 nmol/L and had an intrin - ± - neurotox low 11,627.9-fold-Showed > = 10.58 nM) and selectivity (SI > 9452) = 19.60 nM, 50 50 fast antidepressant efect [ 149 ] antidepressant fast ­ (IC [ 151 ] HT1A receptors ities, with IC50 value of 3.94 and 3.44 mM, ities, with IC50 value [ 147 ] respectively icity in SH-SY5Y cells in vitro-Used to treat treat to cells in vitro-Used icity in SH-SY5Y disease [ 152 ] neurodegenerative and SI with the to respect selegiline inhibitor standard ­ (IC value of 2.74 value 5-HT sic activity for Inference -A novel serotonin reuptake inhibitor showed showed inhibitor reuptake serotonin novel -A Showed highest hMAO-B potency potency hMAO-B highest Showed of the dual inhibitors SERT/5- Exhibit as novel transporterInhibited serotonin with an ­ inhibition with ­ Inhibit MAO-B enzymes activ and hMAO-B Inhibition of AchE action of both human monoamine oxidase action of both human monoamine oxidase and B as hMAO-A such isoforms (hMAO) and 5-HT1A receptor porter (SERT) with 5-HT1A partial activity in agonistic study vivo vitro (MAO-B) and monoamine oxidase (AchE) inhibition Evaluation In vitro investigation to inhibit the to enzymatic investigation In vitro - trans the inhibition of serotonin for Evaluated Inhibition reuptake serotonin for Examined inhibitory activity in hMAO-B for Evaluated cholinesterase dual acetyl for Evaluation 3 H CH 3 3 SO O O 3 CH . CH N O O O NN O O N N O O O O O O 3 O Br Cl OR N O C 3 F Structure Cl X H (piperidin-1-yl) propoxy) chroman- (piperidin-1-yl) propoxy) 4-one Chroman-4-one analogs displaying antidepressant potential antidepressant analogs displaying Chroman-4-one Chroman-4-one derivatives Chroman-4-one (E)-3-Heteroarylidenechroman-4-ones Name of compound Name 7-((4-Fluorobenzyl) oxy) chroman-4-one oxy) 7-((4-Fluorobenzyl) DSP-1053 (Novel compound) (Novel DSP-1053 (E)-3-(4-methoxybenzylidene)-7-(3- 2 1 13 Table No. Sr. 4 3 5

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Table 14 Insecticidal evaluation of chroman-4-one analogs Sr. No. Name of compound Structure Evaluation Inference

1 Chromanone derivatives CH3 Tested killing property Showed insecticidal H3C Mythima separata Mythima of diacylhydrazines H3C CH3 against potency against O O separata [156] N H3C NH CH3 O OCH3

2 Rotenone CH2 Evaluated for insecticide Exhibited impressive insec- H C 3 activity ticidal efect [157] H O O O

H O OCH 3

OCH 3 for their diagnostic potential creates a great interest in the feld of medicinal chemistry. HO OH

3 Miscellaneous HO O

3.1 Antidengue CH3

M. M. V. Ramana et al. (2015) reported a docking study of OH O isolated favanones and designed chroman-4-one compounds 2-(2, 4-dihydroxy-6-methylphenyl)-5, against NS2B/NS3 protease (dengue virus protein). As per 7-dihydroxychroman-4-one literature survey, naringenin and pinocembrin are known to have efective potential as antidengue agent with good dock score. Similarly, in-silco experimentation revealed the antidengue activity of isolated eriodictyol having Leu 3.2 Antiparasitic 149 and Asn 152 hydrogen bonding and 2-(2, 4-dihydroxy- 6-methylphenyl)-5, 7-dihydroxychroman-4-one [designed Chroman-4-one analogs 6-hydroxy-2-(3-hydroxyphenyl) compound] also showed interactions with Asp 75 and Asn chroman-4-one, 6-hydroxy-2-(4-hydroxyphenyl) chroman- 152 with a comparable glide score -7.31 that characterizes 4-one and 2-(3,4-dihydroxyphenyl)-6-hydroxychroman-4-one its antidengue activity [159]. displayed antiparasitic activity by targeting pteridine reduc- tase-1 and showed signifcant inhibition against T. brucei and L. infantum at 10 µM and 50 µM. Therefore, more research on chroman-4-one derivatives as antiparasitic may provide a new platform for the development of new antiparasitic agents. [160].

O O O

HO HO HO

OH OH O O O

OH OH 6-hydroxy-2-(3-hydroxyphenyl) 6-hydroxy-2-(4-hydroxyphenyl)chr 2-(3,4-dihydroxyphenyl)-6-hydr chroman-4-one oman-4-one oxychroman-4-one

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3.3 Anti‑aging

Chroman-4-one derivatives were used as active compound in cosmetic preparations for care, improvement and refresh- ment of texture of the skin and hairs, for treatment of skin as well as hair-related defects like infammation, allergies or wound healing process. Furthermore, cosmetic formulations containing vitamin A and its derivatives like retinol esters, retinoic acid have shown their action on the diferentiation process of epithelial cells and therefore used against psoria- sis, acne, skin spotting, wrinkles and discoloration. There- fore, chroman-4-one scafolds have signifcant cosmetic value along with pharmacological activities [160]. 9.98 and 9.10 nM (Ki values), respectively, against against respectively, (Ki values), 9.98 and 9.10 nM Helpful compound) [125I] IMPY (reference fnding of Aβ early for imaging agent diagnostic [ 158 ] disease brain in Alzheimer’s plaques Exhibited high binding afnities to Aβ plaques with Aβ plaques Exhibited high binding afnities to Inference R6 O

R5

R1

R4 O R2

R3 Diagnosis of Alzheimer’s disease Diagnosis of Alzheimer’s Evaluation chroman-4-one derivatives 2 ) 2 3 ) 3 3 H CH CH N( OC N( 3.4 Anticoronal

Kwon Dur-Han, et al. proposed inhibitory potential of an isolated favanone, quercetin-7-rhamnoside against viral O O O O propagation. Furthermore, experimentation showed efec- O O tive results against inhibition of coronavirus via specifc inhibition of PEDV (porcine epidemic diarrhea virus) pro- liferation in Vero cells with good inhibitory activity = -7.143 1 Br Br R Structure ­CC50/IC50 = > (100 g/mL) as compared to standard antiviral drug (ribavirin). Accordingly, in vitro inhibiting activity of quercetin-7-rhamnoside against PEDV, a number of favo- noids such as quercetin, luteolin, apigenin showed efective inhibition in vero cells. In spite of PEDV inhibition, querce- tin-7-rhamnoside also exhibited antiviral potential against porcine transmissible gastroenteritis virus (TGEV) with inhibition value > 1.58 ­[CC50/IC50 = > (100 g/mL/63.3 µg/ ml)] and porcine respiratory coronavirus (PRCV) with inhi- I bition value > 1.67 ­[CC50/IC50 = > (100 g/mL/59.8 µg/ml)]. 125 Therefore, quercetin-7-rhamnoside displayed better antiviral inhibition potential against three types of coronaviruses like TGEV, PEDV and PRCV than reference drug (ribavirin) in vitro. In conclusion, more experimentation on chromanone chroman-4-one derivative, derivative, R1 = 4-one

Chroman-4-one analogs evaluated as diagnostic agents as diagnostic analogs evaluated Chroman-4-one containing favonoids as anticoronal for the inhibition of (E)-3-(4-Dimethylamino-benzylidene)-6-bromo- Iodine labeled 3-benzylidenechroman-4-one’s Iodine labeled 3-benzylidenechroman-4-one’s Name of compound Name (E)-3-(4-Methoxybenzylidene)-6-bromo-chroman- other classes of corona virus might be led a new frame for drug discovery and development [161] 15 Table No. Sr. 1

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OH OH OH OH

O O O O rhamnose rhamnose

OH OH OH O OH O Quercetin-7-rhamnoside dihydroquercetin-7-rhamnoside

4 Conclusion 5. Jaracz, S.; Chen, J.; Kuznetsova, L.V., et al.: Recent advances in tumor-targeting anticancer drug conjugates. Biomed. Pharmaco- Chroman-4-one/chromanone pharmacophore is a privileged ther. 13, 5043–5054 (2005) 6. Schindler, R.; Mentlein, R.: Flavonoids and vitamin E reduce the scafold in medicinal research, consisting of two rings in release of the angiogenic peptide vascular endothelial growth which 2, 3-dihydro-γ-pyranone fused with an aromatic ben- factor from human tumor cells. J. Nutr. 136, 1477–1482 (2006) zene nucleus and derivatization at 2, 3 and 4-positions of 7. Piyush, K.; Kuldeep, S.; Azizur, R.M., et al.: A review of ben- chromanone skeleton yields more efective families of fa- zopyran derivatives in pharmacotherapy of breast cancer. Asian J. Pharm. Clin. Res. 11(7), 43–46 (2018) vonoids like 3-benzylidene-chromanones, spirochromanone, 8. Raj, V.; Lee, J.: 2H/4H-Chromenes-A versatile biologically hydrazones, oximes, favanones, homisofavonones and iso- attractive scafold. Front. Chem. 8, 623 (2020) favanones. This structural diversifcation of chromanone 9. Felgines, C.; Texier, O.; Morand, C., et al.: Bioavailability of the occupied an important role in pharmaceutical feld as they favanone naringenin and its glycosides in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 279(6), 1148–1154 (2000) owe numerous biological activities like anticancer, anti- 10. Kodama, O.: Sakuranetin, a favanone ultraviolet-irradiated phy- oxidant, antidiabetic, anti-infammatory, antiviral, antitu- toalexin from rice leaves. Phytochemistry 31(11), 3807–3809 bercular, antibacterial, antifungal, antiparasitic, anti-AchE, (1992) anticonvulsant, anti-HIV and antileishmanial properties. As 11. Ley, J.P.: Evaluation of bitter masking favanones from herba santa (Eriodictyon californicum (H. & A.) Torr., Hydrophyl- chromanone scafolds exhibit numerous potent biological laceae ). J. Agric. Food Chem. 53, 6061–6066 (2005) activities, even some derivatives are novel like DSP-1053 12. Kumar, D.; Sharma, P.; Singh, H., et al.: The value of pyrans as (novel serotonin reuptake inhibitor and fast antidepressant), anticancer scafolds in medicinal chemistry. RSC Adv. 7(59), calanolide A (anti-HIV), Silibinin and chrysin(anticancer), 36977–36999 (2017) 13. Gordo, J.; Cabrita, E.; Oliva, A., et al.: Thymus mastichina: taxifolin (antidiabetic), tetrazole (antidiabetic), troglita- chemical constituents and their anti-cancer activity. Nat. Prod. zone (antidiabetic), ormeloxifene (anticancer) and nebivo- Commun. 7(11), 1491–1494 (2012) lol (beta-blockers); nevertheless, the market proportion of 14. Lopez-Lazaro, M.: Flavonoids as anticancer agents: structure- potent chromanone analogs is fewer. Therefore, for future activity relationship study. Curr. Med. Chem. - Anti-Cancer Agents. 2(6), 691–714 (2002) prospective, more consideration is required for designing 15. Kopustinskiene, D.M.; Jakstas, V.; Savickas, A., et al.: Flavo- and developing potent synthetic chromanone analogs which noids as anticancer agents. Nutrients 12(2), 1–24 (2020) may provide better therapeutic value. 16. Noushini, S.; Alipour, E.; Emami, S., et al.: Synthesis and cyto- toxic properties of novel (E)-3-benzylidene-7- methoxychroman- 4-one derivatives. DARU J. Pharm. Sci. 21(1), 1–10 (2013) 17. Ivanova, L.; Varinska, L.; Pilatova, M., et al.: Cyclic chalcone References analogue KRP6 as a potent modulator of cell proliferation: An in vitro study in HUVECs. Mol. Bio. Rep. 40(7), 4571–4580 (2013) 1. Emami, S.; Ghanbarimasir, Z.: Recent advances of chroman- 18. Alipour, E.; Mousavi, Z.; Safaei, Z., et al.: Synthesis and cyto- 4-one derivatives: synthetic approaches and bioactivities. Eur. J. toxic evaluation of some new[1,3]dioxolo[4,5-g]chromen-8-one Med. Chem. 93, 539–563 (2015) derivatives. DARU J. Pharm. Sci. 22, 41 (2014) 2. Panche, A.N.; Diwan, A.D.; Chandra, R.: Flavonoids: an over- 19. Bahram, L.: Synthesis and in vitro cytotoxic activity of novel view. J. Nutr. Sci. 5(47), 1–15 (2016) chalcone-like agents. Iran J. Basic Med. Sci. 16, 1155–1162 3. Christophe Carola H., Ralf Rosskopf M.: Use of chroman-4-one (2013) derivatives.: United States Patent application publication., US 20. Shen, S.; Ko, H.; Tseng, S., et al.: Structurally related antitumor 2010/0028278 A1,1, 1–24 (2010). efects of favanones in vitro and in vivo: involvement of caspase 4. Cotelle, N.: Role of favonoids in oxidative stress. Curr. Top. 3 activation, p21 gene expression, and reactive oxygen species Med. Chem. I(2001), 569–590 (2001) production. Toxicol. Appl. Pharmacol. 197, 84–95 (2004)

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