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.