The Role of Chromenes in Drug Discovery and Development

Chromene and its Importance: Chemistry and Biology

Nitin Verma¹, *, Parul Sood¹, Jitender Singh², Niraj Kumar Jha³, Mahesh Rachamalla⁴, Kamal Dua⁵

¹ School of Pharmacy, Chitkara University, Himachal Pradesh, India

² School of Pharmaceutical Sciences, IEC University, Solan, Himachal Pradesh, India

³ Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, 201310, India

⁴ Department of Biology, University of Saskatchewan, Saskatoon, Canada

⁵ Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia

Abstract

Chromene (benzopyrans) is one of the privileged scaffold molecules that are widely distributed in natural products and possesses a wide variety of pharmacological activities such as anticoagulant, antioxidant, anti-inflammatory, anti-spasmolytic, antitumor, antihepatotoxic, diuretic, estrogenic, antiviral, antifungal, antimicrobial, anthelminthic, anti-HIV, antitubercular, herbicidal, anticonvulsant and analgesic. Their low toxicity combined with their broad pharmacological properties has inspired researchers to obtain new chromenes and derivatives possessing considerable pharmacological action. The present review article attempts to summarize the natural source of chromene and its derivatives along with updated knowledge on its biological activities.

Keywords: Benzpyrans, Biological activity of Chromenes, Chemistry of Chromenes, Chromenes, Natural compounds.

* Corresponding author Nitin Verma: School of Pharmacy, Chitkara University, Himachal Pradesh, India; E-mail: [email protected]

INTRODUCTION

Chromene belonging to the family of lactones is a well-known, naturally occurring aromatic bicyclic heterocyclic compound. It consists of a benzene ring that is fused to an oxygen-containing pyran heterocyclic ring. It exists as mainly four structural isomers (Fig. 1) resulting from the multiple relative positions of the oxygen atom and the tetrahedral carbon atom, namely, 2H-chromene, 4H-chrome-

ne, 1H-isochromene, and 3H-isochromene [1]. Out of these isomeric forms of chromenes, 2H-chromene and its benzo fused derivatives are widely distributed in various plant species including fruits and vegetables and seem to be important for the chemical defense of plants as well as for the treatment of a wide range of pharmacological activities like anti-inflammatory, antipyretics, antioxidant, bronchodilator, vasodilator, anti-amoebic, antibacterial and antifungal activities as well as for the management of neurodegenerative disorders including Alzheimer’s and Schizophrenia [2, 3]. For thousands of years, various chromenes and chromene derivatives have been used in different traditional systems of medicine. This important chemical moiety encompasses the fundamental skeleton structure for various phytoconstituents such as natural alkaloids, coumarins, flavonoids, polyphenols, anthocyanins, and tocopherols [4, 5]. The published literature review states that, to date, several bioactive chromenes and their various derivatives have been isolated and separated from various natural sources as well as have been well studied for their biogenetic pathway and biosynthesis. This chemical moiety has been recognized by research scientists due to its low toxicity profiles in addition to broad biological activities [6, 7].

CHROMENE-CONTAINING PLANTS

Table 1 indicates the list of various plant sources from which chromenes and their derivatives were separated and isolated and were found to possess marked pharmacological activities. Fig. (1) shows the structure of some important chromenes derived from plants.

Table 1 List of plants containing chromenes and their derivatives.

Fig. (1))

Structure of Some important chromenes.

PHARMACOLOGICAL ACTIVITY

Anti-Alzheimer Activity

The alkaloid Taspine, a chromene derivative isolated first time from the leaves of Magnolia x soulangiana showed a more significantly long-lasting and dose-dependent effect on acetylcholinesterase enzyme (AChE) inhibition than the positive control galanthamine with an IC50 value of 0.33 ± 0.07 μM [42]. Oral administration of chromene derivatives such as glabridin, a major active isoflavone, isolated from the roots of Glycyrrhiza glabra significantly ameliorated scopolamine (0.5 mg kg-1, i.p.) induced amnesia and was evaluated by both elevated plus maze test and passive avoidance test at tested dosages of 2 and 4 mg kg-1. These derivatives also significantly decreased the brain AChE activity in mice in comparison to the control group [43]. Furthermore, glabridin reversed the learning and memory defects in diabetic rats in a dose-dependent manner, thus, proving to be a promising drug candidate for memory and learning improvement in the management of demented diabetic patients [44]. In vitro AChE and butyrylcholinesterase (BuChE) enzyme inhibitory activity showed that Macluraxanthone isolated from non-polar fractions of the methanolic extract of the root bark of Maclurapomifera is a specific non-competitive inhibitor of AChE with an IC50 value of 8.47 µM and competitive inhibitor of BuChE with an IC50 value of 29.8 µM [45].

Antimicrobial

Qualitative and quantitative antimicrobial screening by agar well diffusion and broth dilution assay showed that cannabichromene and its homologues, as well as isomers isolated from Cannabis sativus, have strong antibacterial activity against Gram +ve, Gram –ve, and acid-fast bacteria. However antifungal activity against yeast-like and filamentous fungi and dermatophytes was found to be mild to moderate [46].

Cannabinoids isolated from Cannabis sativa showed a potent antimicrobial effect against different methicillin-resistant strains of S. aureus (XU-212, ATCC-25923, RN-4220, EMRSA-15, EMRSA-16, and SA-1199B) in a MIC range of 2–0.5 μg/ ml [22].

Cumanensic acid isolated from aerial parts of Piper cf. Cumanense Kunth. (Piperaceae) showed promising antifungal activity against F. oxysporum f. sp. this is similar to that of the control positive (< 1 mg) evaluated by using direct bio-autography in a TLC bioassay while the minimum amount was found to be 100 µg for fungal growth inhibition of B. cinerea [40].

Anticancer

A bioassay of the chromene 6-acetyl-7,8-dimethoxy-2,2-dimethylchromene from Eupatorium toppingianum indicated its high cytotoxic, antimutagenic, and antimicrobial properties [24]. In addition, 7,3',5'-Tri-O-methyltricetin, precocene II, 3,5,7,4'-tetrahydroxyflavone and 5,6,7,3',4',5'-hexamethoxyflavone exhibited inhibitory activity on the P-388 cancer cell line with IC50 values of 12.8, 24.8, 3.5 and 7.8 µM respectively, while compound 9 exhibited inhibitory activity on the HT-29 cancer cell line with an IC50 value of 61µM.

Isodispar B, Disparpropylinol B, and disparinol B isolated from the ethyl-acetate soluble fraction of Callophyllum dispar inhibited 50% of the cellular growth of KB cell lines at a concentration ranging from 4 to 8 µg/ml [47].

Neo-tans lactone, isolated as a minor component from the ethanol extract of the root of Salvia miltiorrhiza, was found to be active against the MCF-7 breast cancer cell line at 0.6~1.2 µg/mL and exhibited low ED50 values of 0.6 µg/mL and 0.3 µg/mL against estrogen receptor-positive (ER+) human breast cancer cell lines (MCF-7 and ZR-75-1) respectively, but was found to be inactive against two ER- cell lines (MDA MB-231, and HS 587- T) with ED50 > 10 µg/mL [48]. However, flemingin A and C isolated from Flemingia grahamiana (Leguminosae) showed a cytotoxic effect against MCF-7 human breast cancer cells with IC50 values of 8.9 and 7.6 μM respectively [25].

About 17 chromene derivaties were isolated from powdered leaves of Marilapluricostata Standl.& L.O. Williams (Clusiaceae) and were tested in cytotoxicity assays against breast (MCF-7), Lungs (H-460), and CNS (SF-268)

human cancer cell lines. Out of these mammesin, Mammea A/AB, and mesuolandmammea A/AB were found to be the most cytotoxic [49].

Two novel prenylated benzoquinones such as thiaplidiaquinone A and B isolated from Aplidiumconicum induced a strong production of intracellular reactive oxygen species (ROS) in the Jurkat cell line which is derived from a human T lymphoma and induced cell death by apoptosis [50].

Out of four new chromone alkaloids, chrotacumines A-D and known compound rohitukine isolated from leaves and bark of Dysoxylumacutangulum, rohitukine showed moderate cytotoxicity against human HL-60 promyelocytic leukemia and HCT-116 colon cancer cells [51].

Malloapelta A-F isolated from Mallotus apelta significantly inhibited the ovarian cancer cell line, TOV-21G. Moreover, Malloapelta B, C, and F significantly induced apoptosis and significantly inhibited the NF-κB signaling pathway [28].

Anti-inflammatory

Cannabichromene, one of the major chromenes isolated from Cannabis sativus, its homologue as well as its isomers showed more superior anti-inflammatory activity as compared to the standard drug in both carrageenan-induced rat paw edema model and the erythrocyte heat stabilization assay [46].

Rohitukine, chromone alkaloid isolated from the stembark of Dysoxylum Binectariferum (Roxb.) Hook. F. ex Hiern (a synonym of D. gotadhora (Buch.-Ham.) Mabb., Meliaceae displayed anti-inflammatory activity in the carrageen-induced rat paw edema assay (ED50=9 mg/kg., p.o.) and inhibited the reverse passive Arthus reaction in rats, (50.8±5.9% inhibition at 2.5 mg/kg., p.o) [52].

The inhibitory effect of Anthopogochromene and Anthopogochromene A isolated from the Chinese medicinal plant Rhododendron anthopogonoides on compound 48/80-induced histamine release from rat peritoneal mast cells was found to be comparable to that of potent anti-inflammatory drug indomethacin with IC50 value 63 µM [40].

Antioxidant

A chromone alkaloid with unique structural features called cassiadinine isolated from the flowers of Cassia siamea showed its effects to reduce the levels of free radicals, thus can be used as valuable drug development leads for antioxidants [53]. Mojabanchromanol, a novel chromene, isolated from the ethyl-acetate fraction of brown alga Sargassumsiliquastrum ethanol extract exhibited the strongest antioxidant activity by 96.07±0.1% and 84.08±2.7% inhibition evaluated by DPPH scavenging assay and TBARS assay [41]. In addition, Sargachromenol, isolated from Sargassummicracanthum showed strong DPPH scavenging activity of 78.85% at a concentration of 250 µM [54]. Wittifuran P. isolated from Chinese mulberry Moruswittiorum was found to inhibit 99% inhibition in a Fe2+/cysteine-induced microsomal lipid peroxidation assay as compared to Wittifuran R and Q [31]. The chalcones flemingin A, B, C, G, and H isolated from the leaves of Flemingiagrahamiana (Leguminosae) were found to show antioxidant effect against DPPH radical scavenging assay with an ED50 value in the range of 4.4−8.9 μM [25].

Anti-plasmodial Activity

Crude root extract from the roots of traditionally used antimalarial plant Pentasbussei showed only marginal activities against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum [35].

Nine new compounds containing either a chromane or chromene ring moiety were isolated from the monotypic plant Koeberlinia Spinosa. Compounds 2, 5, 6, and 7 had weak antiplasmodial activity, while none of the compounds exhibited antiproliferative activity [55].

Leishmanicidal Activity

Four well-known chromenes namely 6-acetyl-7-hydroxy2,2-dimethylchromene, 6-(1-hydroxyethyl)-7-methoxy-2,2-dimethylchromene, 6-acetyl-7-methoxy-2,2- dimethyl chromene and 6-(1-ethoxyethyl)-7-methoxy-2,2-dimethylchromene were first time isolated from the leaves of Caleapinnatifida (R. Br.) Less. (Asteraceae) and were tested for the leishmanicidal screening against intracellular L. amazonensis amastigotes, THP-1 cells (ATCC TIB202). The first two compounds showed moderate leishmanicidal activity while the other two isolated chromenes were found to be inactive [18]. Out of isolated Lindbergin E-I, isolated from the Fern Elaphoglossumlindbergii, Lindbergin E showed the most effective in-vitro leishmanicidal activity against Promastigotes of Leishmania braziliensis and L. Amazonensi with IC50 value 13.6±1.3 µM and 16.3±1.3 µM [56].

6,6-dimethyl-2-methoxy-6H-benzo[c]chromen-9-yl) methanol sequestered from the roots of Bourreriapulchra (Boraginaceae) showed significant antiprotozoal activity against Leishmania Mexicana and Trypanosoma cruzi parasites (IC50 4.6 μg/mL and 7.5 μg/mL, respectively) while another benzochromene isolated from the root of Bourreria pulchra was found to be inactive [16].

Anti-trypanocidal Activity

Gaudichaudianic acid [(2S)-2-methyl-8-(3-methylbut-2-enyl)-2-(4-methylpent- 3’-enyl)-2H-chromene-6-carboxylic acid] isolated from ethanolic extract of Piper gaudichaudianum stems exhibited dose-dependent toxicity against epimastigotes of T. Cruzi with an IC50value of 33.8 µM while its benzopyran ester obtained by methylation proved to be four times more toxic as compared to benznidazole with an IC50 value 2.82 µM. Natural chromene obtained from the leaves of P. Aduncum along their series of semi-synthetic derivatives prepared by reduction, acetylation, and methylation has also been shown to exhibit potential trypanocidal activities against epimastigotes of T. Cruzi [37]. Another study of trypanocidal assays of Gaudichaudianic acid enantiomers indicated that the (+)-enantiomer was a more potent trypanocidal compound against the Y-strain of Trypanosoma cruzi than its antipode. Interestingly, mixtures of enantiomers showed a synergistic effect, with the racemic mixture being the most active [57].

CONCLUSION

Chromenes constitute a large group of various biologically active important molecules such as alkaloids, polyphenols, flavonoids, etc. that are widely distributed in a variety of different herbs, shrubs, and trees, worldwide including fruits and vegetables. Various naturally occurring chromene derivatives, such as ageratochromene, alloevodionol, lonchocarpin, millepachine, flemiphilippinones C, busseihydroquinones B − D, β-lapachone, mollugin, wittifurans A-F, cassiadinine, soulamarin, gramniphenol C–D, (+)-psiguadial B, fleminginsA-C, empetrikarinens, anthopogochromane and anthopogochromene A–C have been found to possess promising pharmaceutical and biological activity. Taking into account the immense therapeutic potential of chromene-based phytomolecules and their derivatives, they can be considered new bioactive molecules for the discovery of better therapeutically active lead molecules with low toxicity. Thus, more intensive efforts are required for the isolation and screening of novel and more potent bioactive chromene-based phytocompounds with unique mechanisms of action for the treatment of various disorders especially cancer and drug-resistant bacterial diseases.

ACKNOWLEDGEMENT

The authors acknowledge all the support provided by Chitkara University to complete the book chapter.

REFERENCES

Recent Trends of Chromene Syntheses

Samarpita Das¹, Pulkit Asati¹, Harish K. Indurthi¹, Ashutosh Kumar Dash², Deepak K. Sharma¹, *

¹ Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi-221005, U.P., India

² Department of Medicinal Chemistry, Devsynthesis India Pvt. Ltd., Hyderabad, India

Abstract

2H/4H-chromenes (2H/4H-Ch) structural scaffolds have been widely employed in the synthesis of many natural products and