Discovery of IID432 for Chagas Disease: A Cyanotriazole Inhibitor of Trypanosoma cruzi 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 Trypanosoma cruzi, 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 Trypanosoma brucei 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. IID432 showed potent activity against T. cruzi (EC50 = 8 nM) and achieved a relapse-free cure in a chronic mouse model of infection with shorter treatment duration. These findings support IID432 as a promising fast-acting, curative therapy for T. cruzi infections.