Identifying inhibitors of Trypanosoma cruzi nucleoside diphosphate kinase 1 as potential repurposed drugs for Chagas' disease.

Trypanosoma cruzi is the causative agent of Chagas' disease, an endemic and neglected disease. The treatment is limited to only two drugs, benznidazole (BZL) and nifurtimox (NFX), introduced more than fifty years ago and no new advances have been made since then. Nucleoside diphosphate kinases (NDPK) are key metabolic enzymes which have gained interest as drug targets of pathogen organisms. Taking advantage of the computer-assisted drug repurposing approaches, in the present work we initiate a search of potential T. cruzi nucleoside diphosphate kinase 1 (TcNDPK1) inhibitors over an ∼ 12,000 compound structures database to find drugs targeted to this enzyme with trypanocidal activity. Four medicines were selected and evaluated in vitro, ketorolac (KET, an anti-inflamatory), dutasteride (DUT, used to treat benign prostatic hyperplasia), nebivolol and telmisartan (NEB and TEL, used to treat high blood pressure). The four compounds were weak inhibitors and presented different trypanocidal effect on epimastigotes, trypomastigotes and intracellular stages. NEB and TEL were the most active drugs with increased effect on intracellular stages, (IC

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.