Design, synthesis, and in vitro antiplasmodial activity of 4-aminoquinolines containing modified amino acid conjugates

A new series of side chain-modified 4-aminoquinolines were synthesized and screened for in vitro antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Among the series, compounds 30 and 31 showed significant inhibition of parasite growth against K1 strain of P. falciparum with IC50 values 0.28 and 0.31 mu M, respectively, whereas compounds 34, 35, and 38 exhibited superior activity against K1 strain with IC50 values 0.18, 0.22, and 0.17 mu M, respectively, as compared to 0.255 mu M for chloroquine (CQ). All the compounds displayed good resistance factor between 1.54 and >34.48 as against 51.0 for CQ. All these analogues were found to form strong complex with hematin and inhibited the beta-hematin formation in vitro, suggesting that this class of compounds act on a heme polymerization target. Overall results suggest that present series of compounds appear to be promising for further lead optimization to obtain compounds active against drug-resistant parasites.