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