Discovery of Plasmodium falciparum Inhibitors as Lead Candidates for Malaria: Structural Biology and Medicinal Chemistry Studies

In this seminar, two strategies towards the discovery of new Plasmodium falciparum inhibitors will be presented. The first approach relied on the investigation of a glycolytic enzyme that plays important roles in Plasmodium biology. Enolase (EC 4.2.1.11) catalyses the reversible interconversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid. In this study, we report the discovery of “ENOblock”, a non-competitive P. falciparum enolase inhibitor, with inhibitory activity in the submicromolar range. Moreover, we solved the 3D structure of the Enolase-ENOblock complex and demonstrated that the compound inhibits the in vitro growth of the parasite (sensitive and resistant strains). In vivo studies showed that the compound was well tolerated and significantly reduced the parasitemia. Our findings indicate that enolase can be explored as molecular target for the design of new lead compounds. In another work, a comprehensive study including synthesis, SAR, and parasitological profiling was conducted to discover marinoquinoline derivatives as a new class of P. falciparum inhibitors. The most promising compounds of this series showed inhibitory activity in the low nanomolar range, fast-acting inhibitory activity with noticeable activity in the early stage of intraerythrocytic cycle and liver stages of development. A representative compound showed an excellent tolerability in non-infected mice and reasonable oral efficacy in the P. berghei malaria mouse model.