Artículos de revistas
Synthesis, Biological Evaluation, and Structure-Activity Relationships of Potent Noncovalent and Nonpeptidic Cruzain Inhibitors as Anti-Trypanosoma cruzi Agents
Registro en:
Journal Of Medicinal Chemistry. Amer Chemical Soc, v. 57, n. 6, n. 2380, n. 2392, 2014.
0022-2623
1520-4804
WOS:000333578400015
10.1021/jm401709b
Autor
Ferreira, RS
Dessoy, MA
Pauli, I
Souza, ML
Krogh, R
Sales, AIL
Oliva, G
Dias, LC
Andricopulo, AD
Institución
Resumen
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 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. 57 6 2380 2392 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) FAPESP [2013/07600-3, 2012/02230-0] FAPESP [2010/16778-2]