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Discovery of Plasmodium falciparum Inhibitors as Lead Candidates for Malaria

Abstract: Malaria is one of the most prevalent parasitic infections in the world. In 2020, the disease affected 2441 million people and killed over 600,000 people. Therefore, new drug candidates are extremely needed. In this talk, two strategies towards the discovery of new Plasmodium falciparum inhibitors will be presented. The first approach investigated the synthesis and antiplasmodial profiling of a series of 4(1H)-quinolone derivatives. Three compounds showed inhibitory activities in the nanomolar to submicromolar range against a panel of sensitive and resistant Plasmodium falciparum strains and neither cytotoxic nor hemolytic activities were observed. Representative compounds of the series showed slow-acting in vitro inhibition and submicromolar activity against the ookinete stage. Evaluation of the mechanism of action indicated that the frontrunner, compound 4, was a potent and selective inhibitor for the cytochrome bc1 complex of P. falciparum. Moreover, the frontrunner exhibited considerable activity against clinical field isolates of both P. falciparum and P. vivax, a noticeable synergic inhibitory behavior when combined with the antimalarial proguanil, and modest oral efficacy. Our findings indicated that the 4(1H)-quinolone derivatives are attractive chemotypes endowed with relevant in vitro, ex vivo, and in vivo activity. 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.

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