Structure-activity relationships of 1,5-dihydro-2H-benzo[b][1,4]diazepine-2,4(3H)-diones as inhibitors of Trypanosoma cruzi
Abstract
Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi), is responsible for a large health burden with around 6-8 million people infected globally. The current drug development pipeline is sparsely populated and there is an urgent need for new treatments. In this paper we describe the identification of a series of benzodiazepinediones with antiparasitic activity, and the platform we utilised to demonstrate that they act via a novel mechanism of action. Two distinct sub-series were identified, and the medicinal chemistry program identified compounds from both with pIC50's >6.4 which were progressed to a T. cruzi washout assay. This assay showed that neither sub-series was suitable for further development. This work demonstrated the value of a robust Chagas disease discovery platform for focusing the limited resources available for neglected disease drug discovery onto the most promising series.
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