PROGRAMA DE SEMINÁRIOS DO LASSBio
Mensalmente um palestrante será convidado para compartilhar sua experiência profissional com os alunos do laboratório

Summary:

Malaria is one of the most prevalent parasitic infection in the world. The disease affects 216 million people each year, and in 2016 it was estimated to have caused 445,000 deaths. In this work, we conducted a comprehensive study to discover marinoquinoline derivatives as a new class of compound with antiplasmodial activity. We synthesized and evaluated the inhibitory activity against P. falciparum 3D7 strain and conducted a structure−activity relationship study, focusing on the improvement of potency and maintaining low cytotoxicity. Next, we devised 2D and 3D QSAR models, which we prospectively validated, to discover new marinoquinoline derivatives with enhanced potency. The most potent compound 50 (IC503d7 = 39 nM; IC50K1 = 41 nM) is a fast-acting inhibitor with noticeable activity in the early stage of intraerythrocytic cycle and liver stages of development. Moreover, the compound showed considerable selectivity index (SI > 6410) and additive effect in combination with artesunate. Mechanism of action investigation indicated concentration-dependent interference in heme species sequestration. Compound 50 showed an excellent tolerability in non-infected mice (all mice survived up to 30 days) and interesting oral efficacy at 50 mg/Kg in the P. berghei malaria mouse model (62 % of parasitemia reduction on day 5 and 56 % on day 9 post-infection) thus being considered as a lead compound for the discovery of new antimalarial agentes.