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

• Published in: Journal of medicinal chemistry 2018-07, Vol.61 (13), p.5547-5568
• Main Authors: Aguiar, Anna Caroline Campos, Panciera, Michele, Simão dos Santos, Eric Francisco, Singh, Maneesh Kumar, Garcia, Mariana Lopes, de Souza, Guilherme Eduardo, Nakabashi, Myna, Costa, José Luiz, Garcia, Célia R. S, Oliva, Glaucius, Correia, Carlos Roque Duarte, Guido, Rafael Victorio Carvalho
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials - chemistry; Antimalarials - pharmacology; Drug Design; Mice; Models, Molecular; Molecular Conformation; Plasmodium falciparum - drug effects; Quantitative Structure-Activity Relationship; Quinolines - chemistry; Quinolines - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00143

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 (IC50 3d7 = 39 nM; IC50 K1 = 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.