Synthesis, antimalarial activity, heme binding and docking studies of 4-aminoquinoline–pyrimidine based molecular hybrids

Abstract

A series of novel 4-aminoquinoline–pyrimidine hybrids was synthesized and evaluated for their antimalarial activity. Several compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains of P. falciparum with no cytotoxicity against Vero cell lines. The selected compound 7f, when evaluated for in vivo activity showed mild suppression of parasites in the P. berghei-mouse malaria model. The heme binding studies were conducted to determine the probable mode of action of these hybrids. Compound 8d formed a stable 1 : 1 complex with hematin suggesting that these hybrids act on a heme polymerization target. The binding of most active hybrids was studied by molecular docking analysis in the active site of Pf-DHFR-TS. The top scoring compounds with low binding energy, interact in the active site of Pf-DHFR-TS in a similar way to the natural protein substrate dihydrofolate. The pharmacokinetic properties of the most active compounds were also assessed using ADMET prediction.