2. Academic Validation
  3. Discovery and Early Optimization of 1 H-Indole-2-carboxamides with Anti- Trypanosoma cruzi Activity

Discovery and Early Optimization of 1 H-Indole-2-carboxamides with Anti- Trypanosoma cruzi Activity

  • J Med Chem. 2025 Apr 10;68(7):7313-7340. doi: 10.1021/acs.jmedchem.4c02942.
Ramon G de Oliveira 1,  Luiza R Cruz 1 2,  Marco A Dessoy 1,  Paul J Koovits 1,  Deborah A Dos Santos 1,  Luiz F N de Oliveira 1,  Rafael A Ferreira 1,  María C Mollo 1,  Eun Lee 1,  Simone M Duarte 3,  Renata Krogh 3,  Leonardo L G Ferreira 3,  Rafael C Chelucci 3,  Maria Dichiara,  Quillon J Simpson,  Clarissa Feltrin,  Adriana C da Silva,  Benedito M Dos Santos,  Milena F Broering,  Michael P Pollastri,  Lori Ferrins,  Carolina B Moraes,  Adriano D Andricopulo 3,  Jadel M Kratz 2,  Peter Sjö 4,  Charles E Mowbray 4,  Luiz C Dias 1
Affiliations

Affiliations

  • 1 Institute of Chemistry, State University of Campinas, Campinas 13083-862, Brazil.
  • 2 Drugs for Neglected Diseases initiative, Rio de Janeiro 20010-020, Brazil.
  • 3 São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, Brazil.
  • 4 Drugs for Neglected Diseases initiative, Geneva 1202, Switzerland.
PMID: 40163677 DOI: 10.1021/acs.jmedchem.4c02942
Abstract

Chagas disease (CD), caused by the flagellate protozoan Trypanosoma cruzi, is a neglected tropical disease endemic in 21 countries. The only two antiparasitic drugs approved for its treatment, benznidazole and nifurtimox, have significant drawbacks. We present herein the optimization of a series of substituted indoles that were identified through phenotypic screening against T. cruzi. Early lead compounds with balanced potency and physicochemical properties were advanced to animal studies but showed limited plasma exposure. Medicinal chemistry strategies were used to improve metabolic stability and solubility, but unfortunately, this effort failed to yield compounds with improvements in both exposure and potency. Still, the best compound was progressed for a proof-of-concept efficacy study using acute and chronic mice models of Chagas disease. Despite showing antiparasitic activity in these in vivo studies, the optimization work with this series was stopped due to unfavorable drug metabolism and pharmacokinetic (DMPK) properties and a deprioritized mechanism of action (CYP51 inhibition).

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