Hit-to-lead optimization of novel benzimidazole phenylacetamides as broad spectrum trypanosomacides

Trypanosoma cruzi and Trypanosoma brucei are the parasitic causative agents of Chagas disease and human African trypanosomiasis (HAT), respectively. The drugs currently used to treat these diseases are not efficacious against all stages and/or parasite sub-species, often displaying side effects. Herein, we report the SAR exploration of a novel hit, 2-(4-chlorophenyl)-N-(1-propyl-1H-benzimidazol-2-yl)acetamide previously identified from high throughput screens against T. cruzi, Trypanosoma brucei brucei and Leishmania donovani. An informative set of analogues was synthesized incorporating key modifications of the scaffold resulting in improved potency whilst the majority of compounds retained low cytotoxicity against H9c2 and HEK293 cell lines. The SAR observed against T. cruzi broadly matches that observed against T.b. brucei, suggesting the possibility for a broad-spectrum candidate. This class of compounds therefore warrants further investigation towards development as a treatment for Chagas disease and HAT.