In vitro Antimalarial Activity of Flavonoids and Chalcones

Malaria is one of the most common infectious diseases in tropical and subtropical countries, including parts of the Americas, Asia, and Africa. Each year, it affects nearly 400900 million people and causes approximately one to three million deaths annually. Human malaria is caused by Plasmodium falciparum, P. malariae, P. ovale, and P. vivax, however, P. falciparum is the most prevalent for the disease and it is responsible for about 80% of infections and 90% of deaths. The first effective treatment (17 century) against the P. falciparum parasite was the bark of cinchona tree, which contains quinine, a quinoline alkaloid. A number of medicines have been developed to treat malaria with chloroquine and its derivatives as the mainstay therapy. In recent years, P. falciparum has become increasingly resistant to conventional antimalarial drugs, and the search for new antimalarial compounds by combining natural sources and synthetic approaches is still underway. As a part of our search for novel antimalarial agents from plants or via chemical synthesis, we prepared twenty derivatives of flavonoids and chalcones. Flavonoids comprise a large group of polyphenolic secondary metabolites in plants. They are based on the flavan skeleton, consisting of two aromatic rings (ring A and B) interconnected by a threecarbon-atom, heterocyclic C ring, and classified into six main groups, flavanones, flavones, isoflavones, flavonols, flavanols, and anthocyanins. Many natural and synthetic flavonoids possess antimalarial activity. Chalcones have a diverse array of substituents on the two aromatic rings of 1,3-diphenyl-2-propen-1-one, which was derived by the cleavage of the C ring in flavonoids. Depending on the substitution pattern on the two aromatic rings, chalcones have a wide range of biological activities, including antimalarial activity. However, there has not been a direct comparison of flavonoids and chalcones and their structureactivity relationships. In the present study, four derivatives for each of flavones (1-4), flavanones (5-8), chalcones (9-12), dihydrochalcones (13-16), and 3'-chloro-chalcones (17-20) (Fig. 1) were synthesized and evaluated for in vitro antimalarial activity against P. falciparum strain FCR-3 and cytotoxicity against FM3A cells (a mouse mammary tumor cell). The aim of this paper is to derive predictive structure-activity relationships to guide lead compound design. Among the flavonoids and the related chalcones tested, the most active compounds were 3'-methyl-substituted flavanones (5) and 4'-methoxy-substituted dihydrochalcones (15), showing 100% inhibition against P. falciparum at the final concentration of 5.0 μg/mL and 5.4 μg/mL, respectively (EC50 = 1.6 μg/mL and 1.0 μg/mL, respectively) (Table 1). These compounds also showed strong cytotoxicity against FM3A cells, a model of the host, with relatively low EC50 values (>4.8 μg/mL and 3.3 μg/mL, respectively) and low selectivity indices (>3 and 3.3, respectively), indicating that these compounds have non-selective antimalarial activity. The selective toxicity index of quinine, a well-known antimalarial drug, was 450 in our previous report. Eight compounds were weakly antimalarial, ten compounds were not cytotoxic, and five compounds showed no activity, but without cytotoxicity.