NOVEL QUINAZOLINE-CHALCONE HYBRIDS AS ANTIPLASMODIUM AGENTS: SYNTHESIS, BIOLOGICAL EVALUATION AND MOLECULAR DOCKING

Abstract

Development of new antiplasmodial molecular scaffold is an urgent need to overcome the problem of resistance against the malaria parasite. A series of quinazoline-chalcone hybrids, covalently linked by amine linkage were synthesized in a convenient way starting from commercially available 2-amino benzoic acid in a five step process. Synthesized hybrids evaluated for in vitro antimalarial activity against CQ-sensitive (MRC-2) and CQ-resistant (RKL-9) P. falciparum strains. Nine out of sixteen compounds found to be more potent to chloroquine against CQ-sensitive strain (MRC-2) and six compounds observed to be more or equipotent to chloroquine against CQ-resistant strain RKL-9. The in vitro cytotoxicity study performed on the human HepG2 cell line and the selectivity index found in ranges from 4 to 203 against CQ-resistant strain RKL-9. In vitro heme crystallization inhibition assay was carried out where most of the synthesized hybrids showed considerable inhibition of β-hematin formation suggesting that compounds are strongly interfering with the hemozoin formation in parasites. Further, molecular docking study against the cysteine protease falcipain-2 was performed to explore the binding affinity and orientations between between the hybrids and the target enzyme. ASN21 and CYS22 amino acids of protein act as hydrogen bond donor region facilitate hydrogen bonding with ligand. Overall, findings support the antimalarial potential of quinazoline-chalcone hybrids.