Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya

Abstract

Abstract. Scolastica M, Ndakala AJ, Derese S. 2018. Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya. Biofarmasi J Nat Prod Biochem 16: 8-21. Despite numerous research that has been done on plants in Kenya, resulting in the isolation of thousands of natural products, data on these natural products are not systematically organized in a readily accessible form. This has urged the construction of a web-based database of natural products in Kenya. The database is named Mitishamba and is hosted at http://mitishamba.uonbi.ac.ke. The Mitishamba database was queried for chromones, chromanones, and chalcones and subjected to structure-based drug design using Fred’s (OpenEye) docking utility program with the 1TV5 PDB structure, the PfDHODH receptor, to identify complex ligands that bind with the active site. Ligand-based drug design (Shape and electrostatics comparison) was also done on the ligands against query A77 1726 (38) (the ligand that is co-crystallized with PfDHODH receptor) using ROCS and EON programs, respectively, of OpenEye suite. There was a substantial similarity among the top-performing ligands in the docking studies with shape and electrostatic comparison that identified compounds of interest targeted for synthesis and antiplasmodial assay. In this study, a chromanone (7-hydroxy-2-(4-methoxyphenyl) chroman-4-one (48)) and two intermediate chalcones (2',4'-dihydroxy-4-methoxychalcone (45) and 2’,4’-dihydroxy-4-chlorochalcone (47)), were synthesized and subjected to antiplasmodial assay. Among these substances, 45 showed vigorous activity, whereas 47 and 48 had moderate activity against the chloroquine-resistant K1 strain of P. falciparum with IC₅₀ values of 4.56±1.66, 17.62 ± 5.94, and 18.01 ±1.66 µg/ml, respectively. Since the synthesized compounds showed antiplasmodial potential, there is a need for further computational refinement of these compounds to optimize their antiplasmodial activity.