3D QSAR-Based Design, Synthesis and Biologycal Evaluation of Substituted Quinolines as Antimalarial Agents

Abstract

Malaria is a fatal tropical and subtropical disease caused by the protozoal species Plasmodium. Many commonly available antimalarial drugs and therapies are becoming ineffective because of the emergence of multidrug resistant Plasmodium falciparum, which drives the need for the development of new antimalarial drugs. Antimalarial ctivity of 7-(2-phenoxyethoxy)-4(1H)-quinolones, 3-Substituted 2 methyl-4(1H)-uinolones and 1,2,3,4-tetrahydroacridine-9(10H)-ones with nanomolar EC50 against erythrocytic stage of multidrugresistance W2 (resistant to chloroquine and rimethamine). QSAR models were established from by using 178 molecules of ubstituted quinolone derivatives by 3D comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Based on the potent QSAR model provides valuable insight for optimization of quinolone derivatives for better anti-malarial therapy. Contour map analysis of best CoMFA and CoMSIA model suggested that by substituting sterically bulky group and hydrogen bond donor group, potency of the compound could be improved. Prediction of Physicochemical properties and toxicities of 36 designed compounds and showed a good drug score. . Synthesis of top 8 substituted quinoline derivatives was carried out and spectral characterization was carried out using FT-IR, Mass, 1H and 13 C-NMR spectroscopy. Synthesized derivatives were subjected for In-vitro studies.