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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.)

Synthesis, Biological Evaluation, and Structure-Activity Relationships of Potent Noncovalent and Nonpeptidic Cruzain Inhibitors as Anti-Trypanosoma cruzi Agents

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Ferreira, Rafaela S. [1] ; Dessoy, Marco A. [2] ; Pauli, Ivani [3] ; Souza, Mariana L. [3] ; Krogh, Renata [3] ; Sales, Ana I. L. [3] ; Oliva, Glaucius [3] ; Dias, Luiz C. [2] ; Andricopulo, Adriano D. [3]
Total Authors: 9
[1] Univ Fed Minas Gerais, Dept Bioquim & Imunol, BR-31270901 Belo Horizonte, MG - Brazil
[2] Univ Estadual Campinas, Inst Quim, BR-13084971 Campinas, SP - Brazil
[3] Univ Sao Paulo, Lab Quim Med & Computac, Ctr Pesquisa & Inovacao Biodiversidade & Farmacos, Inst Fis Sao Carlos, BR-13563120 Sao Carlos, SP - Brazil
Total Affiliations: 3
Document type: Journal article
Source: Journal of Medicinal Chemistry; v. 57, n. 6, p. 2380-2392, MAR 27 2014.
Web of Science Citations: 24

The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagas' disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously cocrystallized with the enzyme (K-i = 0.8 mu M). With the goal of achieving a better understanding of the structure-activity relationships, we have synthesized and evaluated a series of over 40 analogues, leading to the development of a very promising competitive inhibitor (8r, IC50 = 200 nM, K-i = 82 nM). Investigation of the in vitro trypanocidal activity and preliminary cytotoxicity revealed the potential of the most potent cruzain inhibitors in guiding further medicinal chemistry efforts to develop drug candidates for Chagas' disease. (AU)

FAPESP's process: 12/02230-0 - Total synthesis of bioactive compounds: biological tests and design of new analogs
Grantee:Luiz Carlos Dias
Support type: Regular Research Grants
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
FAPESP's process: 10/16778-2 - Design of inhibitors of cruzain and phosphoglycerate mutase against trypanosomiasis
Grantee:Rafaela Salgado Ferreira
Support type: Scholarships in Brazil - Post-Doctorate