2. Academic Validation
  3. Discovery of Marinoquinolines as Potent and Fast-Acting Plasmodium falciparum Inhibitors with in Vivo Activity

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

  • J Med Chem. 2018 Jul 12;61(13):5547-5568. doi: 10.1021/acs.jmedchem.8b00143.
Anna Caroline Campos Aguiar 1,  Michele Panciera 2,  Eric Francisco Simão Dos Santos 2,  Maneesh Kumar Singh 3 4,  Mariana Lopes Garcia 1,  Guilherme Eduardo de Souza 1,  Myna Nakabashi 4,  José Luiz Costa 5,  Célia R S Garcia 3,  Glaucius Oliva 1,  Carlos Roque Duarte Correia 2,  Rafael Victorio Carvalho Guido 1
Affiliations

Affiliations

  • 1 Sao Carlos Institute of Physics , University of Sao Paulo , Av. Joao Dagnone, 1100 Jardim Santa Angelina , São Carlos , SP 13563-120 , Brazil.
  • 2 Institute of Chemistry , State University of Campinas , Josue de Castro St. , Campinas , SP 13083-970 , Brazil.
  • 3 Faculty of Pharmaceutical Sciences , University of Sao Paulo , Av. Prof. Lineu Prestes, 580 Cidade Universitária , São Paulo , SP 05508-900 , Brazil.
  • 4 Department of Physiology , University of Sao Paulo , Rua do Matão 101, Travessa 14 , São Paulo , SP 05508-090 , Brazil.
  • 5 Faculty of Pharmaceutical Sciences , State University of Campinas , Rua Oswaldo Cruz, 2° Andar, Bloco F3, Cidade Universitária , Campinas , SP 13083-859 , Brazil.
PMID: 29879353 DOI: 10.1021/acs.jmedchem.8b00143
Abstract

We report the discovery of marinoquinoline (3 H-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.

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