Structurally Diverse Bioflavonoids As Potential Source of Antimalarial Lead Molecules

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STRUCTURALLY DIVERSE BIOFLAVONOIDS AS POTENTIAL SOURCE OF ANTIMALARIAL LEAD MOLECULES

Dipak Chetia* and Mithun Rudrapal Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh-786 004, Assam E-mail: [email protected]

Abstract: In this article, a review on bioactive flavonoids that are abundant in medicinal and functional food (dietary) plants has been made, with special reference to antimalarial flavonoid molecules. Flavonoids have been found to exist in plants/plant medicines with a wide structural diversity consisting of numerous polyphenolic compounds and having well defined molecular target specificity. These phytoconstituents may serve as important natural lead molecules for their development as potent antimalarial therapeutic agents.

Keywords: Malaria, drug resistance, bioflavonoids, pharmacophoric scaffolds, antimalarial drugs

1. INTRODUCTION Malaria is a serious infectious disease that malaria-related deaths worldwide. Moreover, P. affects people of all ages, particularly in tropical falciparum strains produce rapid as well as varying and subtropical regions of the world. According to degree of resistance against currently available the World Health Organization (WHO), antimalarial drugs, which has become a major approximately 40% of the world population live in clinical issue in the malaria chemotherapy [1-6]. malaria endemic areas, with 300-500 million Plant-based medicines have been playing clinical cases and 1.5-2.7 million deaths per year an important role in the treatment of malaria since globally. In the South East Asian region, out of ancient times. Malaria treatment in the modern about 1.4 billion people living in 11 countries, 1.2 therapeutic form started with the discovery of billion (85.7%) are exposed to the risk of malaria. quinine (QN) from cinchona bark. The quinoline- Of the 2.5 million reported cases in the South East based synthetic antimalarial drugs (Figure I) such Asia, India alone contributes about 70% of the total as chloroquine (CQ) were successfully used in the cases. Human malaria is caused by five species of treatment of malaria for a long time [2, 3, 7]. Plasmodium, namely, P. falciparum, P. vivax, P. However, with the pace of time their clinical uses Ovale, P. malariae and P. knowlesi. Plasmodium have become limited because of the development falciparum is the most widespread and extremely of resistant strains of malarial parasites, especially dangerous species, which causes potentially fatal of P. falciparum. malaria such as cerebral malaria, and most of the

H OH

H N N N HN HN HO H3CO

N Cl N Cl N

Quinine (QN) Chloroquine (CQ) Amodiaquine (AQ) Fig. I: Quinoline-based antimalarial drugs Artemisinin (ART), isolated from the then successfully incorporated as potent drugs in plant, Artemisia annua was later introduced, and its the treatment of malaria in resistant cases [7, 8]. several semi-synthetic derivatives (Figure II) were

CH3 CH H 3 CH3 H H O O H CH3 H CH O Reduction O Derivatization 3 O H CH3 O O O O O H C O 3 O H3C H C O 3 RO OH

Artemisinin Dihydroartemisinin R=Me, Artemether R=Et, Arteether R=CO(CH2)2COONa, Sodium artesaunate R=CH2 (p-C6H4)COONa, Sodium artelinate Fig. II: Artemisinin (ART) and its semi-synthetic derivatives Currently, artemisinin-based combination xanthones, limonoids, steroids etc. and they possess therapies (ACTs) are recommended by the WHO a diverse range of activity profile in terms of health for the treatment of multidrug-resistant P. implications. Among all these, flavonoids have falciparum malaria. Some examples of ACTs are recently gained significant interest among artemether plus lumefantrine, artesunate plus medicinal chemists because of their promising mefloquine (MQ), and artesunate plus chemopreventive ∕chemoprotective potentials in pyronaridine. But, the ACTs are costlier relative to inflammatory disorders, cardiovascular diseases, CQ and QN, and also, resistance to ART and MQ- diabetes, neurodegenerative disorders, cancer, ART against P. falciparum has begun to emerge in bacterial infections and malaria [11, 12]. In tune Southeast Asia. Therefore, the treatment of malaria with the above facts, researchers have investigated has increasingly become a challenging task because many plant species for their antimalarial activities of the emergence of the resistant strains of malaria and have reported the bioactive principles including parasites, which has created an urgent need to flavonoids responsible for antimalarial develop new and therapeutically efficacious effectiveness. A number of polyphenolic flavonoids antimalarial agents [8-10]. that are abundant in dietary and medicinal plants However, in order to resolve the above have been identified to have good antimalarial challenging issue, the discovery of newer effectiveness both in-vitro and in-vivo [13]. In this antimalarial drugs from plants and/or plant-based review, plant derived flavonoids which have been traditional medicines is considered to be the most identified to possess antimalarial potential, their reliable alternative approach as nature always chemistry and structural diversity, and basis of their serves as the richest source of chemicals with a bioactivity are described. Flavonoid compounds wide range of structural- and bio- diversity. These with their pharmacophoric structural scaffolds may chemical compounds are basically secondary therefore be potential lead molecules for the metabolites of plant origin belonging to several development of flavonoid-based antimalarial drugs important phytochemical classes such as against the resistant strains of the malaria parasites. terpenoids, alkaloids, flavonoids, coumarins,

2. BIOFLAVONOIDS Flavonoids comprise of a large groups of products, so called phenylpropanoids. More aromatic organic compounds of around 10,000 precisely, the molecular framework of flavonoids structures that are ubiquitously distributed in the consists of a C6-C3-C6 unit i.e., flavonoid plant kingdom. In fact, these compounds are (phenylbenzopyrone) skeleton in which the parent secondary plant metabolites biosynthesized in C6-C3 unit is present as chromone (benzo-훾-pyrone) plants as metabolic hybrids through a combination nucleus (Figure III). The term flavonoid was of the shikimate-derived phenylpropanoid (-->C6- derived from the Latin word flavus meaning

C3) pathway and the acetate∕mevalonate polyketide yellow, and the prefix ‘bio’ denotes their biological

(-->C6) pathway. They therefore possess a carbon origin as well as their manifested biological skeleton of phenylpropanoid (C6-C3 unit), and significances (including pharmacological effects) hence constitute an important class of natural on other organisms [14-16].

O O

O C6-C3 C6-C3 C6-C3-C6 Phenylpropanoid Chromone Flavonoid Fig. III: Parent structures of flavonoids 2.1 Chemistry The chemical structure of flavonoids are are often hydroxylated in positions 3, 5, 6, 7, 3′, 4′, based on the flavonoid (C6-C3-C6) molecular and 5′. The structural skeletons of various types of framework which is a fifteen-carbon skeleton flavonoids are represented in the Figure IV [14-18]. consisting of two benzene rings (A ring and B ring) According to the oxidation state of the interconnected by a three carbon heterocyclic pyran central pyran ring, they can be broadly classified ring (C ring). The chroman ring (C ring) is into: (i) Flavonoids: These are ketone compounds connected to the second aromatic ring (ring B, that include anthoxanthins (flavones and flavonols), benzenoid substituent) at the C-2 (flavone), C-3 isoflavones and neoflavones. The skeletal (e.g., isoflavone) or C-4 (neoflavone) positions. structures of this class of compounds are based Sometimes, in place of six-membered heterocyclic upon flavone backbone. (ii) Flavanoids: These are pyran ring (ring C) an acyclic moiety (chalcone) or mostly non ketone compounds (except flavanols) a five membered heterocyclic furan ring (aurone) is having flavan backbone that include flavanones, found. Six-membered ring condensed with the flavanols, and flavanonols. Flavonoids differ from benzene ring is either a 훾-pyrone (flavones, flavanoids mainly by a C2–C3 double bond. flavonols and isoflavones) or its dihydroderivatives Individual bioactive compounds within a class (flavanones and flavanols). Flavonoids are differ primarily in the pattern of hydroxyl generally hydroxylated phenolic substances and substitution of the A and B rings [16, 17]. therefore, referred to as plant polyphenols. They 3' 2' 4' 8 1' O1 5' 7 2 6' 6 3 5 4

Flavonoid (Flavanoid) skeleton C6-C3-C6 O O O O O OH O O O O Chalcone Aurone Flavone Flavonol Isoflavone O O O O O O

OH OH O O Neoflavone Flavan Flavanol Flavanone Flavanonol

O O

OH OH OH Leucoanthocyanidin Anthocyanidin Fig. IV: Structural skeletons/backbone structures of flavonoids

In a much broader sense, the term origin that collectively includes both flavonoids bioflavonoids refers to all compounds of natural and flavanoids.

2.2 Bio- and Structural- diversity Flavonoids are widely distributed in plants as water solubility, lipophilicity and thermostability and occur virtually in all plant parts to impart a flavonoids possess favourable absorption and variety of colours such as yellow, orange, purple, distribution characteristics in human body, which blue etc. to flower petals, fruit peels, vegetables in turn responsible for their better bioavailability and certain grains. Because of their widespread and eventual therapeutic outcomes. Flavonoids are distribution in dietary plants, like fruits and also abundantly found in many medicinal and vegetables, flavonoids form an integral part of aromatic plants (Table I), and certain herbal human diet. Flavonoids consumed (in considerable remedies. For instance, the traditional use of amounts) through diet (raw forms, processed liquorice extract (rich in flavonoid content) in the products or cooked preparations) contributes treatment of peptic ulcer disease is well beneficial properties to human health. Owing to documented [13, 15, 17, 18]. their desirable biophysicochemical properties such Table I: Some medicinal plants rich in flavonoids Plant (Family) Representative flavanoid(s) Aloe vera (Asphodelaceae) Luteolin Acalypha indica (Euphorbiaceae) Kaempferol Azadirachta indica (Meliaceae) Quercetin Betula pendula (Betulaceae) Quercetin Butea monospermea (Fabaceae) Genistein Cannabis sativa (Compositae) Quercetin Citrus medica (Rutaceae) Hesperetin Glycyrrhiza glabra (Leguminosae) Liquitrin Mentha longifolia (Lamiaceae) Luteolin Mimosa pudica (Mimosoideae) Isoquercetin (a glycoside) Oroxylum indicum (Bignoniaceaea) Chrysin

Flavonoids rich in human diet constitute a nutritional and medicinal benefits are mainly common group of polyphenolic compounds (also attributed to be due to their free radical scavenging known as poplyhydroxyphenols), which are usually activity (redox property), which in turn mitigates considered as non-nutritive bioactive components oxidative stress-induced tissue damage associated that play a significant role in human health and with some chronic non communicative disorders nutrition. The dietary sources of various types of and certain infectious diseases [15, 17]. flavonoids are enumerated in Table II. Their

Table II: Subclasses of bioflavonoids and their common dietary sources Flavonoids/ Structural Representative Dietary sources Flavanoids backbone flavonoid(s)/ subclass flavanoid(s) Flavones 2-Phenylchromen-4-one Acacetin, apigenin, Buckwheat, celery, (or 2-phenylchromone) baicaclein, chrysin, parsley, red pepper, red luteolin, tangeritin wine, tomato Flavonols 3-Hydroxy-2-phenylchrmone Kaempherol, Apples, berries, broccoli, (or 3-Hydroxyflavone) myricetin, quercetin, buck wheat, cherries, tamarixetin fennel, grapes, kale, olive

oil, onions, red wine, tea, tomato Isoflavones 3-Phenylchromone Daidzein, genistein, Alfalfa, chickpea, formononetin legumes, soyabeans Neoflavones 4-phenylcoumarin Dalbergin Not found in food plants Flavanones 2,3-Dihydro-2-phenylchrmone Eriodictyol, hesperetin, Citrus fruits (lemons, (or 2,3-Dihydroflavone) naringenin oranges), grape fruits, prunes Flavanols Flavan-3-ol Catechins, theaflavin Apples, tea (2-Phenyl-3,4-dihydro-2H- chromen-3-ol)

Leucoanthocyanidi Flavan-3,4-diol Leucopelargonidin - ns

Flavanonols 3-Hydroxy-2,3-dihydro-2- Dihydrokaempferol, Aurantium, limon phenylchromen-4-one Taxifolin (or 3-Hydroxyflavanone (2,3-dihydroquercetin) (or 2,3-Dihydroflavonol) Anthocyanidins Flavylium (2-phenyl Apigenidin, cyanidin Cherry, grapes, chromenylium) ion strawberries Foods rich in flavonoids (polyphenols) structural scaffolds which have potential role in include fruits, grains, legumes, vegetables and several human ailments. It is believed that such beverages such as fruit juice, tea, coffee, red wine, structural scaffolds are the fundamental beer, dark chocolates and other cocoa-rich pharmacophoric features (nucleus/skeletal products. The skins of the fruits (apple skin, orange component) of those bioactive flavonoids and peel) or the outer edge of the vegetables (tomato hence required to be essential for their desired skin) and leaves of certain vegetables (alfalfa, pharmacological actions/medicinal benefits. broccoli) relatively contain more amount of Clinical evidences also support the phenolics than the edible portions because of their chemopreventive roles of polyphenolic flavonoids accumulation in the outer surface of plant tissues on cardiovascular diseases such as coronary heart for their functional roles in producing organisms. disease, stroke, atherosclerosis and hypertension; Flavonoids found in the highest amounts in human inflammatory disorders like osteoporosis, diet are flavonols, flavones and soy isoflavones. osteoarthritis; aging and neurologic disorders such Flavonols are the most abundant flavonoids in as Alzheimer's disease (AD), Parkinson's disease human foods. The major flavonol of our diet is (PD), multiple sclerosis (MS); cancer (of the skin, quercetin that is present either in free state or in the lung and breast); diabetes, and bacterial infections. form of its 3-O-glycoside, rutin. Flavanols like The pharmacodynamic property of their disease catechins (monomeric forms) are also commonly preventing actions is mainly due to their strong encountered in high amount in functional food antioxidant activities in moderate to severe plants like tea, coffee etc. oxidative stress induced pathologic conditions, Flavonoids are most commonly found in which in turn is brought about by virtue of their plants either as free polyhydroxylated compounds free radical scavenging actions. The redox active (polyphenols) or in the form of their derivatives pharmacophoric moiety such as phenolic hydroxy like methyl ethers and acetyl esters (Figure V). A groups (particularly of B-ring) is attributed to be wide structural diversity and a little molecular responsible in bringing out their antioxidant actions complexity in terms of the fundamental carbon by sequencing the harmful reactive oxygen species skeletons and various structural substitutions (ROS) by a free radical trapping mechanism at the (highly functionalized) exist in flavonoid group of target site. The high degree of functional specificity compounds, which are the rich source of huge for biomolecular targets is of paramount number of active compounds or flavonoid importance besides their intrinsic structural

68 properties (of pharmacophoric scaffolds) for their overall biological effectiveness [13, 15-19]. OH Flavones O OH OH HO O OH O HO O HO O

OH O OH O OH O OH O Acacetin Chrysin Apigenin Luteolin (5, 7 - OH) (5, 7, 4' - OH) (5, 7, 3', 4' - OH) (5, 7 - OH 4' -OCH3) Flavonols Flavanones OH OH OH OH OH OH OH O OH O OH O OH O OH OH OH OH O OH OH O OH O OH O Myricetin Naringenin Kaempferol Quercetin (3, 5, 7, 3', 4', 5' -OH) (5, 7, 4' -OH ) (3, 5, 7, 4' - OH) (3, 5, 7, 3', 4' - OH)

Flavanonols Isoflavones OH OH O OH OH OH O OH O OH O OH O

OH O OH OH OH O OH O OH O Daidzein Hesperetin Dihydrokaempferol Taxifolin (3, 5, 7, 3', 4' - OH) (7, 4' - OH) (5, 7, 3' - OH 4'-OCH3) (3, 5, 7, 4' - OH)

Neoflavones Anthocyanidins OH OH OH OH O O O O HO O OH O HO OH O OH OH OH OH

Genistein Dalbergin Apigenidin Cyanidin (5, 7, 4' - OH) (3, 5, 7, 3', 4'-OH) (5, 7, 4' - OH) (6-OH 7-OCH3)

Fig. V: Illustrative structure of flavonoid polyphenols including their methylated derivatives

Flavonoids also occur abundantly in plants galactose and arabinose by a condensation reaction as glycosides in which one or more phenolic with the elimination of water molecules. The hydroxyl groups are combined with sugar residues. resulting condensed products having C-O-C The basic flavonoid structure of glycosides is glycosidic linkage is called acetals (glycosides). known as aglycone. They are water soluble and Depending on the location of glycosidic linkage, thermostable compounds possessing acidic flavonoid glycosides are normally grouped into 3- property of aromatic phenols. In plants, glycosides O-glycosides of flavonol aglycones (e.g., quercitin, of flavonoid aglycones are formed with sugars quercetin-3-O-훼-L-rhamnopyranoside; (glycone moiety) such as L-rhamnose isoquercitin/isoquercetin, quercetin-3-O-β-D- (rhamnoside), D-glucose (glucoside), glucopyranoside; rutin, quercetin-3-O-(훼-L- glucorhamnose/rutinose rhamnopyranosyll-(1-->6)-β-D- (rhamnoglucoside/rutinoside), sometimes with glucopyranoside)/rutinoside) and flavanone

69 aglycone based 7-O-glycosides (e.g., hesperidin, rhamnopyranosyl-(1-->6)-β-D-glucopyranoside). hesperetin-7-O-훼-L-rhamnopyranosyl-(1-->6)-β-D- The structure of some flavonoid glycosides are glucopyranoside; naringin, naringenin-7-O-훼-L- given in the figure VI [14, 16]. Flavonol (3-O) glycosides OH OH OH OH OH OH OH O OH O OH O 3 O Glu 3 O Glu Rha 3 O Rha OH O OH O OH O

Quercitin Isoquercitin Rutin (Quercetin-3-O-rhamnoside) (Quercetin-3-O-glucoside) (Quercetin-3-O-rhamnoglucoside)

Flavanone (7-O) glycosides

OH OH O Rha Glu Rha Glu O O O O 7 7 OH O OH O

Hesperidin Naringin (Hesperetin-7-O-rhamnoglucoside) Naringenin-7-O-rhamnoglucoside Fig. VI: Structure of some flavonoid glycosides

Flavanols such as (+)-catechin (C), (-)- (EGCG) (Figure VII). These are all collectively epicatechin (EC) , (+)-gallogatechin (GC) and (-) known as tea polyphenols or polyphenolic epigallocatechin (EGC) are found largely in green antioxidants. Black tea contain theaflavin (a tea leaves in the form of their tannic acid esters (as complex dimer of polyphenol) as theaflavin-3- gallates) like (+)-catechin-3-gallate (CG), (+)- gallate, theaflavin-3'-gallate, theaflavin-3,3'- gallocatechin-3-gallate (GCG), (-)-epicatechin-3- digallate [15, 19]. gallate (ECG), (-)-epigallocatechin-3-gallate OH OH OH OH OH OH B OH O OH O OH O A C OH OH OH OH OH OH OH

(+)-Catechin (-)-Epicatechin (+)-Gallocatechin

OH OH OH OH OH OH B OH O OH O OH OH OH O O A H OH C O C OH O C D OH OH OH OH O O OH OH OH

(-)-Epigallocatechin (-)-Epicatechin-3-gallate (-)-Epigallocatechin-3-gallate (EGCG)

Fig. VII: Polyphenolic flavanols and their gallate esters

2.3 Flavonoids as antimalarial drug molecules Plant flavonoids having antimalarial naringenin and quercetin, just to name some of the potential could be identified by investigating the important compounds. The in vitro antiplasmodial plant species (extracts) or herbal medicines found activities of these compounds are well reported in in the traditional treatment of malaria, which is literature. Though the molecular mechanism of followed by a bioactivity-guided isolation of active antimalarial action of flavonoids is not fully compounds. Random screening of dietary elucidated, it is believed that flavonoids act by components (phytochemicals as biomarkers) inhibiting the fatty acid biosynthesis in the parasite provides an alternative means of investigating biochemistry. They also act probably by inhibiting antimalarial compounds widespread in our foods or the influx of L-glutamine and myoinositol into food products. Several bioflavonoids from dietary infected erythrocytes during intraerytrhocytic phase sources as well as from medicinal plants have been of Plasmodium life cyle. Unlike basic quinoline- found to possess in vitro and in vivo antiplasmodial based antimalarials, flavonoids possess acidic effectiveness in both sensitive- and resistant- character (due to phenolic –OH groups) which strains of P. falciparum. Table III depicts some impedes their entry into the acidic food vacuole of antimalarial flavonoids (Figure VI) along with their parasites and hence flavonoid based compounds sources (particularly medicinal plants). Dietary does not interfere with the haemoglobin flavonoids having antimalarial activity are acacetin, degradation process, the only site of actions for baicaclein, chrysin, genistein, hesperetin, most of the existing drugs against which malaria isoquercetin, kaempferol, luteolin, myricetin, parasites have developed resistance [13, 20-22]. Table III: Plant derived antimalarial flavonoids Medicinal plant species (Family) Flavonoids and/or their glycosides Flavonoid class Andira inermis (Fabaceae) Calycosin, genistein Isoflavones Artemisia afra (Asteraceae) Acacetin Flavones Artemisia annua (Asteraceae) Artemetin, casticin, chrysosplenetin, cirsilneol Flavones eupatorin and quercetin-3,3'-dimethylether (available as methyl rhamnoglucoside ether derivatives) Artemisia indica (Asteraceae) (-)-cis-3-Acetoxy-4,5,7-trihydroxyflavanone Flavanones Calycolpus warszewiczianus 5-Galloylquercetin-3-O-arabinofuranoside Flavonols (Myrtaceae) Camellia sinensis (Theaceae) (-)-Epigallocatechin-3-gallate (EGCG) and Flavanols other catechins (as esters of gallic acids) Erythrina abyssinica 5-Deoxyabyssinin II Flavones (Leguminosae) Erythrina sacleuxii (Leguminosae) 5-Deoxy-3'-prenylbiochanin A Isoflavones Garcinia livingstonei (Clusiaceae) Methyl ether derivative of bis-naringenin Flavanones Phlomis brunneogaleata Luteolin-7-O-glucofuranoside Flavones (Lamiaceae) Polygonum senegalense 9-Hydroxyhomoisoflavonoid, 2,3-dihydro-5- Flavanones (Polygonaceae) hydroxy-7-methoxy-2-phenylchromen-4-one

O OH O O O OH O O O O O O

O O O O O O OH O OH O OH O

Artemetin Casticin Chrysosplenetin OH O OH OH HO O Glu O O HO O O O OH O O

5-Deoxyabyssinin II 5-Deoxy-3'-prenylbiochanin A Luteolin-7-O-glufuranoside

OH OH OH HO O HO O O O

O C CH3 O Ara OH O HO O O O OH O HO O HO 2,3-Dihydro-5-hydroxy-7-methoxy-2 (-)-cis-3-Acetoxy-4,5,7-trihydroxy 5-Galloylquercetin- flavanone 3-O-arabinofuranoside -phenylchromen-4-one

OH HO O OCH3 O HO O HO

OH O Methyl ether derivative of bis-naringenin

Fig. VIII: Structure of some antimalarial flavonoids

3. CONCLUSION Plant flavonoids comprise of a vast class for antimalarial activity is not adequate or poorly of biologically active molecules that play a vital explored. The molecular basis of their antimalarial role in human ailments. Such structurally diverse action is also unclear. Further study is required to bioactive compounds are the valuable natural give a complete insight into flavonoid molecules resources of medicinal agents and may therefore and their antimalarial action. It is quite interesting provide useful lead molecules in the development to note that flavonoids act on specific biological of novel class of therapeutics. But, it needs targets which are different from that of the common scientific attention in order to explore these antimalarial drug targets. This would probably be bioactive substances for their wide applicability in the basis of further scientific investigation towards health implications. Though the antimalarial finding new flavonoid-based antimalarial drugs by potential of some medicinal and dietary plants rational design of flavonoid libraries (based on containing flavonoids is reported, but information natural leads) through virtual screening techniques. regarding flavonoid molecules that are responsible In this aspect, the optimization of their molecular

72 as well as biopharmaceutical properties is highly The specificity for molecular targets and host desired in the transformation of such lead toxicity issues are however some integral properties molecules into more effective flavonoid-based that a flavonoid drug molecule must possess for its synthetic drugs or their semi-synthetic flavonoid optimal therapeutic outcome. congeners as a novel class of antimalarial agents. 4. REFERENCES

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