Design, synthesis and evaluation of 4-aminoquinoline-purine hybrids as potential antiplasmodial agents

A novel series of 4-aminoquinoline-purine hybrids were synthesized and assessed for their anti-plasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4-aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodia( HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P. falciparum with up to six-fold better activity (compound 10i, IC50: 0.08 mu M) compared to the reference drug CQ (IC50: 0.5 mu M) against the resistant strain. The synthesized compounds were also checked for their cytotoxicity towards mammalian cells and with the exception of two compounds out of the twenty synthesized hybrids, all others were non-cytotoxic up to 11.86 mu M concentration. Mechanistic heme-binding studies were performed to identify the mechanism of action of the synthesized molecules and good binding interactions were observed. Computational docking studies showed that the most active hybrids dock well within the binding site of HGPRT protein. In silica ADME predictions of the most active hybrids showed that these compounds possess good pharmacokinetic behavior. (C) 2016 Elsevier Masson SAS. All rights reserved.