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

Author(s):Show less -

Campos Aguiar, Anna Caroline ^[1] ; Panciera, Michele ^[2] ; Simao dos Santos, Eric Francisco ^[2] ; Singh, Maneesh Kumar ^{[3, 4]} ; Garcia, Mariana Lopes ^[1] ; de Souza, Guilherme Eduardo ^[1] ; Nakabashi, Myna ^[4] ; Costa, Jose Luiz ^[5] ; Garcia, Celia R. S. ^[3] ; Oliva, Glaucius ^[1] ; Duarte Correia, Carlos Roque ^[2] ; Carvalho Guido, Rafael Victorio ^[1]

Affiliation

^[1] Univ Sao Paulo, Sao Carlos Inst Phys, Av Joao Dagnone, 1100 Jardim Santa Angelina, BR-13563120 Sao Carlos, SP - Brazil

^[2] Univ Estadual Campinas, Inst Chem, Josue de Castro St, BR-13083970 Campinas, SP - Brazil

^[3] Univ Sao Paulo, Fac Pharmaceut Sci, Av Prof Lineu Prestes, 580 Cidade Univ, BR-05508900 Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Dept Physiol, Rua Matao 101, Travessa 14, BR-05508090 Sao Paulo, SP - Brazil

^[5] Univ Estadual Campinas, Fac Pharmaceut Sci, Rua Oswaldo Cruz, 2 Andar, Bloco F3, Cidade Univ, BR-13083859 Campinas, SP - Brazil

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 61, n. 13, p. 5547-5568, JUL 12 2018.
• Web of Science Citations: 7

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 nMp; 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. (AU)

• FAPESP's process: 11/51295-5 - Functional genomics in Plasmodium
• Grantee: Célia Regina da Silva Garcia
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 14/25770-6 - New frontiers in cross-coupling reactions promoted by palladium: combining enantioselective catalysis, C-H activations, new materials and in flux reactions aiming at high efficiency and sustainability in synthetic processes
• Grantee: Carlos Roque Duarte Correia
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 15/18192-9 - Discovery and development of Antimalarial Drugs: Structural Biology, Medicinal Chemistry and Parasitology
• Grantee: Anna Caroline Campos Aguiar
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/25613-5 - Synthesis of molecular fluorescent diarylmaleimide probes form the Heck-Matsuda reactions and their applications in biology and biochemistry
• Grantee: Michele Panciera
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC