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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

New Class of Antitrypanosomal Agents Based on Imidazopyridines

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

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 type: Research Projects - Thematic Grants
FAPESP's process: 16/10362-5 - Synthesis of cruzain inhibitors for dipeptidyl nitriles warhead exchange
Grantee:Daniel Gedder Silva
Support type: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 13/01128-0 - Molecular design and synthesis of reversible cruzain inhibitors
Grantee:Daniel Gedder Silva
Support type: Scholarships in Brazil - Doctorate