Discovery and Early Optimization of 1<i>H</i>-Indole-2-carboxamides with Anti-<i>Trypanosoma cruzi</i> Activity
Chagas disease (CD), caused by the flagellate protozoan <i>Trypanosoma cruzi</i>, 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 <i>T. cruzi</i>. 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).
Authors
- Marco A. Dessoy (ORCID: https://orcid.org/0009-0005-5731-761X)
- Carolina Borsoi Moraes (ORCID: https://orcid.org/0000-0002-0689-2770)
- María C. Mollo (ORCID: https://orcid.org/0000-0001-8040-2533)
- Adriano D. Andricopulo (ORCID: https://orcid.org/0000-0002-0457-818X)
- Ramon G. de Oliveira (ORCID: https://orcid.org/0000-0002-2407-5766)
- Luiz C. Dias (ORCID: https://orcid.org/0000-0003-0628-9928)
- Benedito Matheus dos Santos (ORCID: https://orcid.org/0000-0002-2196-260X)
- Maria Dichiara (ORCID: https://orcid.org/0000-0001-6380-7176)
- Jadel M. Kratz (ORCID: https://orcid.org/0000-0002-7681-8234)
- Peter Sjö (ORCID: https://orcid.org/0000-0002-6768-0536)
- Luiza R. Cruz (ORCID: https://orcid.org/0000-0001-6103-9345)
- Deborah A. dos Santos (ORCID: https://orcid.org/0000-0001-5677-1857)
- Lori Ferrins (ORCID: https://orcid.org/0000-0001-8992-0919)
- Rafael Augusto Alves Ferreira
- Michael P. Pollastri (ORCID: https://orcid.org/0000-0001-9943-7197)
- Milena Fronza Broering (ORCID: https://orcid.org/0000-0001-6748-882X)
- Rafael Consolin Chelucci (ORCID: https://orcid.org/0009-0008-4099-9986)
- Simone Michelan‐Duarte (ORCID: https://orcid.org/0000-0003-3132-1037)
- Renata Krogh (ORCID: https://orcid.org/0000-0002-6545-608X)
- Quillon J. Simpson (ORCID: https://orcid.org/0000-0002-1074-9838)
- Paul J. Koovits (ORCID: https://orcid.org/0000-0002-8435-9437)
- Leonardo L. G. Ferreira (ORCID: https://orcid.org/0000-0002-6947-0639)
- Clarissa Feltrin (ORCID: https://orcid.org/0000-0002-7384-7558)
- Adriana Corrêa da Silva (ORCID: https://orcid.org/0000-0002-1273-3450)
- Charles E. Mowbray (ORCID: https://orcid.org/0000-0003-3538-8116)
- Liliane de Fátima Antônio Oliveira (ORCID: https://orcid.org/0000-0002-6530-3120)
- Eun Lee (ORCID: https://orcid.org/0000-0001-6893-4799)
Institutions
- Northeastern University (US)
- Drugs for Neglected Diseases Initiative (CH)
- Universidade de São Paulo (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- FZU ‒ Institute of Physics of the Academy of Sciences of the Czech Republic (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-31
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02942
- Citations
- 3
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 4.06
Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Universidade de São Paulo
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases