Discovery of Marinoquinolines as Potent and Fast-Acting<i>Plasmodium falciparum</i>Inhibitors with in Vivo Activity

Abstract

We report the discovery of marinoquinoline (3H-pyrrolo[2,3-c]quinoline) derivatives as new chemotypes with antiplasmodial activity. We evaluated their inhibitory activities against P. falciparum and conducted a structure–activity relationship study, focusing on improving their potency and maintaining low cytotoxicity. Next, we devised quantitative structure–activity relationship (QSAR) models, which we prospectively validated, to discover new analogues with enhanced potency. The most potent compound, 50 (IC503d7 = 39 nM; IC50K1 = 41 nM), is a fast-acting inhibitor with dual-stage (blood and liver) activity. The compound showed considerable selectivity (SI > 6410), an additive effect when administered in combination with artesunate, excellent tolerability in mice (all mice survived after an oral treatment with a 1000 mg/kg dose), and oral efficacy at 50 mg/kg in a mouse model of P. berghei malaria (62% reduction in parasitemia on day 5 postinfection); thus, compound 50 was considered a lead compound for the discovery of new antimalarial agents.