Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya
A significant amount of research has been done on plants of Kenya resulting in the isolation of thousands of natural products, but data on these natural products is not systematically organized in a readily accessible form. This has necessitated the construction of a web-based database of natural products of 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 that were subjected to structure based drug design using Fred (OpenEye) docking utility program with 1TV5 PDB structure of the PfDHODH receptor to identify 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 co-crystallized with PfDHODH receptor) using ROCS and EON programs, respectively, of OpenEye suite. There was an above average similarity among the top performing ligands in the docking studies with shape and electrostatic comparison. This led to the identification of compounds of interest which were targeted for synthesis and antiplasmodial assay. 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. Whereas 45 showed strong activity, 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 need for further computational refinement of these compounds to optimize their antiplasmodial activity.