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

  • J Med Chem. 2026 Jan 22;69(2):1135-1153. doi: 10.1021/acs.jmedchem.5c02459.
Olivier René ,  Manuel Saldivia ,  Maxime Dauphinais ,  Lei Zhang ,  Scott A Hollingsworth ,  Jan Jiricek ,  Dennis C Koester ,  Sarah L Miller ,  Sarah L Williams ,  Pearly S Ng ,  Debjani Patra ,  Rajiv S Jumani ,  Grace M Baxley ,  Colin S Osborne ,  Ying-Bo Chen ,  Yen-Liang Chen ,  Harry Cheung ,  Suresh B Lakshminarayana ,  Jean-René Galarneau ,  Thierry T Diagana ,  Christopher Sarko ,  Srinivasa P S Rao
PMID: 41499305 DOI: 10.1021/acs.jmedchem.5c02459
Abstract

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.

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