New Class of Antitrypanosomal Agents Based on Imidazopyridines

ACS Med Chem Lett. 2017 Jun 27;8(7):766-770. doi: 10.1021/acsmedchemlett.7b00202.

Daniel G Silva ¹, J Robert Gillespie ², Ranae M Ranade ², Zackary M Herbst ², Uyen T T Nguyen ², Frederick S Buckner ², Carlos A Montanari ¹, Michael H Gelb ² ²

Affiliations

1 Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos 13566-590, Universidade de São Paulo, São Carlos, São Paulo Brazil.
2 Departments of Chemistry, Medicine, and Biochemistry, University of Washington, Seattle, Washington 98195, United States.

PMID: 28740614 DOI: 10.1021/acsmedchemlett.7b00202

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 μM 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.

Keywords

Anti-infectives; Trypanosoma brucei; Trypanosoma cruzi; Trypanosomiasis; imidazopyridine.

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