Rene, Olivier, Saldivia Concepcion, Manuel Alejand-1, Dauphinais, Maxime, Zhang, Lei-9, Hollingsworth, Scott, Jiricek, Jan, Koester, Dennis, Miller, Sarah, Williams, Sarah, Ng, Pearly, Patra, Debjani, Baxley, Grace, Osborne, Colin, Chen, Ying-Bo, Chen, Yen-Liang-1, Cheung, Harry, Lakshminarayana, Suresh, Galarneau, Jean-Rene, Diagana, Thierry, Sarko, Christopher, Rao, Srinivasa and Jumani, Rajiv (2026) Discovery of IID432: A Highly Efficacious and Safe Cyanotriazole Inhibitor of Trypanosoma cruzi Topoisomerase II for Short-Duration Curative Treatment of Chagas Disease. Journal of medicinal chemistry.

Abstract

Chagas Disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi affecting millions worldwide. Current therapy suffers from variable efficacy, longer treatment duration and undesirable safety profile. There is an urgent need for more effective, safer, and shorter-duration treatments. A phenotypic screen of the Novartis compound library against the bloodstream form of the closely related Trypanosoma brucei parasite identified a series of cyanotriazole (CT) compounds with rapid sterilizing activity across kinetoplastid parasites by specifically inhibiting parasite topoisomerase II. Initial CT compounds suffered from safety liabilities such as lymphopenia and neutrophilia due to modulation of the sphingolipid pathway. Subsequent medicinal chemistry optimization of the first-generation CTs led to the development of a tailored aminopyrrolidine core structure for Chagas Disease, enhancing ADME properties and mitigating sphingolipid pathway modulation. IID432 demonstrated potent activity against T. cruzi (EC50 = 8 nM) and achieved relapse-free cure in a mouse model of chronic Chagas Disease with a shorter treatment duration. These findings suggest that IID432 has the potential to serve as a fast and curative treatment for Chagas Disease.

Item Type:	Article
Date Deposited:	21 Jan 2026 00:45
Last Modified:	21 Jan 2026 00:45
URI:	https://oak.novartis.com/id/eprint/58313