Discovery and Early Optimization of 1H-Indole-2-carboxamides with Anti-Trypanosoma cruzi Activity.

Chagas disease (CD), caused by the flagellate protozoan Trypanosoma cruzi, is a neglected tropical disease endemic in 21 countries. The only two antiparasitic drugs approved for its treatment, benznidazole and nifurtimox, have significant drawbacks. We present herein the optimization of a series of substituted indoles that were identified through phenotypic screening against T. cruzi. Early lead compounds with balanced potency and physicochemical properties were advanced to animal studies but showed limited plasma exposure. Medicinal chemistry strategies were used to improve metabolic stability and solubility, but unfortunately, this effort failed to yield compounds with improvements in both exposure and potency. Still, the best compound was progressed for a proof-of-concept efficacy study using acute and chronic mice models of Chagas disease. Despite showing antiparasitic activity in these in vivo studies, the optimization work with this series was stopped due to unfavorable drug metabolism and pharmacokinetic (DMPK) properties and a deprioritized mechanism of action (CYP51 inhibition).