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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Journal of Medicinal Chemistry; v. 57, n. 6, p. 2380-2392, MAR 27 2014.
• Citações Web of Science: 24

Resumo

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)

• Processo FAPESP: 12/02230-0 - Síntese total de produtos bioativos: testes biológicos e design de novos análogos estruturais
• Beneficiário: Luiz Carlos Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/16778-2 - Planejamento de Inibidores das Enzimas Cruzaína e Fosfoglicerato Mutase Candidatos a Fármacos contra Tripanossomíases
• Beneficiário: Rafaela Salgado Ferreira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs