New Class of Antitrypanosomal Agents Based on Imidazopyridines

Author(s)

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.

• Document type: Journal article
• Source: ACS Medicinal Chemistry Letters; v. 8, n. 7, p. 766-770, JUL 2017.
• Web of Science Citations: 6

Abstract

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)

• FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/01128-0 - Molecular design and synthesis of reversible cruzain inhibitors
• Grantee: Daniel Gedder Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/10362-5 - Synthesis of cruzain inhibitors for dipeptidyl nitriles warhead exchange
• Grantee: Daniel Gedder Silva
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate