De novo lead optimization of triazine derivatives identifies potent antimalarials.

Malaria is a life-threatening disease caused by Plasmodium parasites among which Plasmodium falciparum is the most deadly. Due to the widespread resistance of the current antimalarial drugs, intense research efforts are focused on identification of new and potent antimalarials. We report here, a structure based drug discovery strategy for design of a series of effective and novel triazine based antimalarials. The X-ray structure of P. falciparum methyl transferase (PfPMT) is used as a target as it is unique to the parasite. The triazine molecules designed and synthesized showed low micro-molar activity against malarial parasite cell lines. Molecular dynamics simulations on the PfPMT-inhibitor complex shed light on the inhibition mechanism for further optimization of the lead compounds.