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 Chloroquine (CQ) Amodiaquine (AQ) Quinine (QN) 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 64 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]. 65 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 66 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