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New Class of Antitrypanosomal Agents Based on Imidazopyridines.

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 ?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.

SUBMITTER: Silva DG 

PROVIDER: S-EPMC5512129 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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New Class of Antitrypanosomal Agents Based on Imidazopyridines.

Silva Daniel G DG   Gillespie J Robert JR   Ranade Ranae M RM   Herbst Zackary M ZM   Nguyen Uyen T T UTT   Buckner Frederick S FS   Montanari Carlos A CA   Gelb Michael H MH  

ACS medicinal chemistry letters 20170627 7

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 EC<sub>50</sub> ≤ 1 μM against <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>) and <i>Trypanosoma brucei</i> (<i>T. brucei</i>) parasites, respectively. Based on promising results of <i>in vitro</i> activity (EC<sub>50</sub> < 100 nM), cytotoxicity, metabolic stability, protein binding, and pharmacok  ...[more]

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