Busca avançada
Ano de início
Entree
(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Structure-Based and Molecular Modeling Studies for the Discovery of Cyclic Imides as Reversible Cruzain Inhibitors With Potent Anti-Trypanosoma cruzi Activity

Texto completo
Autor(es):
Mostrar menos -
Ferreira, Rafael A. A. [1] ; Pauli, Ivani [2] ; Sampaio, Thiago S. [1] ; de Souza, Mariana L. [2] ; Ferreira, Leonardo L. G. [2] ; Magalhaes, Luma G. [2] ; Rezende Jr, Celso de O. ; Ferreira, Rafaela S. [3] ; Krogh, Renata [2] ; Dias, Luiz C. [4] ; Andricopulo, Adriano D. [2]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Univ Estadual Campinas, Inst Quim, Campinas, SP - Brazil
[2] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Pesquisa & Inovacao Biodiversidade & Farmacos, Lab Quim Med & Computac, Sao Carlos - Brazil
[3] Univ Fed Minas Gerais, Dept Bioquim & Imunol, Belo Horizonte, MG - Brazil
[4] Rezende Jr, Jr., Celso de O., Univ Estadual Campinas, Inst Quim, Campinas, SP - Brazil
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN CHEMISTRY; v. 7, NOV 25 2019.
Citações Web of Science: 0
Resumo

Chagas disease causes 10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of Trypanosoma cruzi, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (3a, IC50 = 2.2 mu M), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 mu M), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 mu M). Moreover, most compounds were selective toward T. cruzi over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents. (AU)

Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
Beneficiário:Glaucius Oliva
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs