Discovery and pharmacophore mapping of a new low nanomolar inhibitor of P. falciparum growth

The treatment of malaria, the most common parasitic disease worldwide and the third deadliest infection after HIV and tuberculosis, is nowadays harmed by the dramatic increase and diffusion of drug-resistance among the different species of Plasmodium, especially P. falciparum (Pf). In this view, the development of new antiplasmodial agents, able to act via innovative mechanisms of action, is crucial to ensure efficacious antimalarial treatments. In one of our previous communications, we described a novel class of compounds endowed with high antiplasmodial activity, characterized by a pharmacophore never described before as antiplasmodial and identified in their 4,4'-oxybisbenzoyl amide cores. Here, through a detailed structure-activity relationship (SAR) study, we deeply investigated the chemical features of the reported scaffolds and successfully built a novel antiplasmodial agent active on both chloroquine (CQ) sensitive and CQ-resistant Pf strains in the low nanomolar range, without displaying cross resistance. Moreover, we conducted an in silico pharmacophore mapping.