Discovery and early optimization of 1H-indole-2-carboxamides with anti-Trypanosoma cruzi activity

by de Oliveira RG, Cruz LR, Dessoy MA, Koovits PJ, dos Santos DA, de Oliveira LFN, Ferreira RA, Mollo MC, Lee E, Duarte SM, Krogh R, Ferreira LLG, Chelucci RC, Dichiara M, Simpson QJ, Feltrin C, da Silva AC, dos Santos BM, Broering MF, Pollastri MP, Ferrins L, Moraes CB, Andricopulo AD, Kratz JM, Sjö P, Mowbray CE, Dias LC. Journal of Medicinal Chemistry 2025. doi: 10.1021/acs.jmedchem.4c02942

Summary: The authors of this manuscript present the optimization of a series of substituted indoles, previously identified through phenotypic screening against T. cruzi, the causative agent of Chagas disease. Early lead compounds with balanced potency and physicochemical properties were advanced to animal studies, but had limited plasma exposure. Medicinal chemistry strategies were used to improve metabolic stability and solubility, but this failed to yield compounds with improved exposure and potency. The best compound was progressed to proof-of-concept efficacy studies using acute and chronic mouse models of Chagas disease. Despite showing antiparasitic activity, optimization work on this series was stopped due to unfavourable drug metabolism and pharmacokinetic (DMPK) properties, and a deprioritized mechanism of action (CYP51 inhibition).

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