Structural optimization, in vitro characterization and in silico pharmacophore modeling of a new antiplasmodial chemotype

Malaria is the most common parasitic disease worldwide, and the third deadliest infection after HIV and tuberculosis. Due to the risk of diffusion of artemisinin resistance in Africa, new drugs for ensuring efficacious antimalarial treatment are urgently needed. In one of our previous communications, we reported the discovery of a new chemotype with promising antimalarial activity against both CQ-sensitive and CQ-resistant P. falciparum (Pf) strains. The IC50 were in the low nM range. Here, we present our exploration of the structural requirements for the inhibition of Pf growth by this new chemotype through a detailed SAR investigation focused, also, on the improvement of its drug-likeness parameters. Our investigation led to the identification of the potent antiplasmodial compound DC18. DC18 was deeply investigated in vitro: assays against gametocytes as transmission blocking agent, either alone or in association, its activity in the liver stage and ability to induce hemolysis and cytotoxicity on human cells are among the topics that were verified and studied. Furthermore, an in silico analysis was run to build a pharmacophore model for this new, still target-less, antiplasmodial chemotype.