Discovery of IID432 for Chagas Disease: A Cyanotriazole Inhibitor of <i>Trypanosoma cruzi</i> Topoisomerase II Achieves Sterile Cure After Short-Term Treatment in a Chronic Infection Model

Chagas Disease is a neglected tropical disease caused by the parasite <i>Trypanosoma cruzi</i>, affecting millions worldwide. Current treatments suffer from variable efficacy, long duration, and safety concerns, highlighting the need for better therapies. A phenotypic screening of the Novartis compound library against <i>Trypanosoma brucei</i> identified cyanotriazole (CT) compounds with rapid sterilizing activity across kinetoplastids via selective inhibition of parasite topoisomerase II. First-generation CTs had safety liabilities, including lymphopenia and neutrophilia due to sphingolipid pathway modulation. Medicinal chemistry optimization led to a tailored aminopyrrolidine core structure for Chagas Disease, improving ADME properties and reducing off-target effects. <b>IID432</b> showed potent activity against <i>T. cruzi</i> (EC₅₀ = 8 nM) and achieved a relapse-free cure in a chronic mouse model of infection with shorter treatment duration. These findings support <b>IID432</b> as a promising fast-acting, curative therapy for <i>T. cruzi</i> infections.