Novel chemical starting points for drug discovery in leishmaniasis and Chagas disease

Visceral leishmaniasis (VL) and Chagas disease (CD) are caused by kinetoplastid parasites that affect millions of people worldwide and impart a heavy burden against human health. Due to the partial efficacy and toxicity-related limitations of the existing treatments, there is an urgent need to develop novel therapies with superior efficacy and safety profiles to successfully treat these diseases. Herein we report the application of whole-cell phenotypic assays to screen a set of 150,000 compounds against Leishmania donovani, a causative agent of VL, and Trypanosoma cruzi, the causative agent of CD, with the objective of finding new starting points to develop novel drugs to effectively treat and control these diseases. The screening campaign, conducted with the purpose of global open access, identified twelve novel chemotypes with low to sub-micromolar activity against T. cruzi and/or L. donovani. We disclose these hit structures and associated activity with the goal to contribute to the drug discovery community by providing unique chemical tools to probe kinetoplastid biology and as hit-to-lead candidates for drug discovery. [Display omitted] •An open source drug discovery screen between The Tres Cantos Open Lab Foundation and Calibr at Scripps Research.•High-throughput phenotypic screen of a 150,000-compound library against T. cruzi and L. donovani.•Identification and characterization of 12 novel chemical series.•7 of those 12 chemical series are active against both T. cruzi and L. donovani.•These chemical series may be valuable tools to identify new drug targets.