Synthesis and bio-evaluation of alkylaminoaryl phenyl cyclopropyl methanones as antitubercular and antimalarial agents

Abstract

A series of 4-alkylaminoaryl phenyl cyclopropyl methanones (6a-6u and 8a-8c) were synthesized in good yields from two 4-fluorochalcones (3a and 3b) by cyclopropanation of double bond followed by nucleophilic substitution of F with different amines. The compounds were screened for their antitubercular and antimalarial activities against M. tuberculosis H37Rv and Plasmodium falciparum 3D7 strains in vitro respectively. Several compounds (6a, 6d-6h, 6p, 6q and 8a-8c) exhibited good in vitro antitubercular activities with MIC values 3.12-12.5 µg/mL and preferentially inhibited the growth of Plasmodium falciparum in vitro (4a, 4c, 6a-6d, 6f, 6s, 8a and 8c) with IC50 as low as 0.080 and 0.035 µg/mL and SI values 4975 and 6948 respectively. Molecular docking studies against FAS-II enzymes and their in vitro inhibition analysis using reporter gene assays were carried out to elucidate the mode of action of these molecules. The compounds were screened in vitro against FAS-II enzymes wherein two of the compounds (4a and 6g) showed significant inhibition at 25 µM concentration of the compound.