Autor(es)

Silva, Daniel G. ; Gillespie, J. Robert ; Ranade, Ranae M. ; Herbst, Zackary M. ; Nguyen, Uyen T. T. ; Buckner, Frederick S. ; Montanari, Carlos A. ; Gelb, Michael H.

• Tipo de documento: Artigo Científico
• Fonte: ACS Medicinal Chemistry Letters; v. 8, n. 7, p. 766-770, JUL 2017.
• Citações Web of Science: 6

Resumo

The present work describes the synthesis of 22 new imidazopyridine analogues arising from medicinal chemistry optimization at different sites on the molecule. Seven and 12 compounds exhibited an in vitro EC50 <= 1 mu M against Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) parasites, respectively. Based on promising results of in vitro activity (EC50 < 100 nM), cytotoxicity, metabolic stability, protein binding, and pharmacokinetics (PK) properties, compound 20 was selected as a candidate for in vivo efficacy studies. This compound was screened in an acute mouse model against T.cruzi (Tulahuen strain). After established infection, mice were dosed twice a day for 5 days, and then monitored for 6 weeks using an in vivo imaging system (IVIS). Compound 20 demonstrated parasite inhibition comparable to the benznidazole treatment group. Compound 20 represents a potential lead for the development of drugs to treat trypanosomiasis. (AU)

• Processo FAPESP: 13/18009-4 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Carlos Alberto Montanari
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/01128-0 - Planejamento e síntese de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Daniel Gedder Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/10362-5 - Síntese de dipeptidil nitrilas como inibidores de cruzaína para realização de modificações no warhead
• Beneficiário: Daniel Gedder Silva
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado