Synthesis and antiplasmodial activity of new heteroaryl derivatives of 7-chloro-4-aminoquinoline

Presently, the most promising and successful strategy in fighting malaria is the artemisinin-based combination therapy (ACT). Recent reports of ACT treatment failure in southeast Asia and the potential emergence of artemisinin resistance indicate that the search of new drugs or new combinations is still highly necessary. In order to develop new classes of antimalarial agents, we recently demonstrated that the replacement of the phenolic ring of amodiaquine and tebuquine with a pyrrole nucleus, still linked to the quinoline moiety through the usual NH, is associated with a good activity against both chloroquine sensitive (CQ-S) and chloroquine-resistant (CQ-R) strains of P. falciparum [1-2]. With the aim to investigate the effect of other different heterocyclic rings linked to the 4-aminoquinoline nucleus on the antimalarial activity, a set of 7-chloro-N- (heteroaryl)-methyl-4-aminoquinoline and 7-chloro-N-(heteroaryl)-4- aminoquinoline was synthesized and tested. All compounds exhibited from moderate to high antiplasmodial activities, and the most potent molecules inhibited the growth of both CQ-S and CQ-R strains of P. falciparum with IC50<30 nM. The activity was strongly influenced both by the presence of a methylenic group, as a spacer between the 4-aminoquinoline and the heterocyclic ring, and by the presence of a basic head. Moreover, preliminary data indicate that the new compounds exhibit low toxicity against a human endothelial cell line (HMEC-1). All these results confirm that the presence of an heteroaryl moiety in the side chain of 7- chloro-4-aminoquinoline is useful for the design and development of new powerful antimalarial agents.