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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 12
[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
Total Affiliations: 5
Document type: Journal article
Source: Journal of Medicinal Chemistry; v. 61, n. 13, p. 5547-5568, JUL 12 2018.
Web of Science Citations: 7

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