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

Nicole McNamara; Raphael Rahmani; Melissa L Sykes; Vicky M Avery; Jonathan Baell

doi:10.1039/d0md00058b

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

RSC Med Chem. 2020 May 29;11(6):685-695. doi: 10.1039/d0md00058b. eCollection 2020 Jun 1.

Authors

Nicole McNamara¹, Raphael Rahmani¹, Melissa L Sykes², Vicky M Avery², Jonathan Baell¹

Affiliations

¹ Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences , Monash University , Parkville , Victoria 3052 , Australia . Email: jonathan.baell@monash.edu.
² Discovery Biology , Griffith Institute for Drug Discovery , Griffith University , Brisbane Innovation Park, Don Young Road , Nathan , Queensland 4111 , Australia.

Abstract

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.