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 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 (EC₅₀ < 100 nM), cytotoxicity, metabolic stability, protein binding, and pharmacokinetics (PK) properties, compound <b>20</b> was selected as a candidate for <i>in vivo</i> efficacy studies. This compound was screened in an acute mouse model against <i>T.cruzi</i> (<i>Tulahuen</i> strain). After established infection, mice were dosed twice a day for 5 days, and then monitored for 6 weeks using an <i>in vivo</i> imaging system (IVIS). Compound <b>20</b> demonstrated parasite inhibition comparable to the benznidazole treatment group. Compound <b>20</b> represents a potential lead for the development of drugs to treat trypanosomiasis.