In Silico Studies and Biological Evaluation of Thiosemicarbazones as Cruzain-Targeting Trypanocidal Agents for Chagas Disease
<b>Background/Objectives:</b> Chagas disease remains a major unmet medical need due to the limited efficacy and safety of current therapies. Here, we investigated sixteen thiosemicarbazone (TSC) derivatives as cruzain inhibitors using an integrated in silico/in vitro workflow. Methods: Docking against cruzain (PDB 3KKU) guided hit prioritization and correlated with enzyme inhibition; validation by redocking supported the protocol's reliability. <b>Results</b>: The top compounds-H7, H10 and H11-showed potent cruzain inhibition (IC<sub>50</sub> = 0.306, 0.512 and 0.412 µM, respectively) and low-micromolar trypanocidal activity, with negligible cytotoxicity in human fibroblasts (CC<sub>50</sub> > 64 µM) and favorable selectivity. Structure-activity insights highlighted the role of expanded aromatic systems and electron-donating groups in enhancing binding within S2/S1' subsites, while nitro substituents were associated with higher cytotoxicity. In silico ADMET parameters supported oral drug-likeness and acceptable metabolic liabilities. <b>Conclusions</b>: Overall, these data position TSCs as promising anti-T. cruzi leads and underscore the value of rational design against cruzain.
Authors
- Sumbal Saba (ORCID: https://orcid.org/0000-0002-6134-7249)
- Larissa Sens (ORCID: https://orcid.org/0000-0003-2404-3817)
- Jamal Rafique (ORCID: https://orcid.org/0000-0002-2336-040X)
- Lidiane Meier (ORCID: https://orcid.org/0000-0003-2343-5173)
- Renata Krogh (ORCID: https://orcid.org/0000-0002-6545-608X)
- Heitor R Abreu (ORCID: https://orcid.org/0000-0002-6040-0511)
- Adilson Beatriz (ORCID: https://orcid.org/0000-0001-6864-6092)
- Adriano D. Andricopulo
- Isabella M. e Oliveira
- Milena F. C. V. de Melo
- Thiago H. Doring
- Aldo S. de Oliveira
Institutions
- Universidade Federal de Mato Grosso do Sul (BR)
- University of Lisbon (PT)
- Institute of Physics (PL)
- Institute of Mathematics and Computer Science (MD)
- Universidade Regional de Blumenau (BR)
- Instituto Federal do Espírito Santo (BR)
- Instituto Gulbenkian de Ciência (PT)
- Universidade Federal de Goiás (BR)
Publication Details
- Journal
- Pharmaceutics
- Published
- 2026-01-04
- DOI
- https://doi.org/10.3390/pharmaceutics18010065
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de Goiás
- Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul
- Universidade Federal de Goiás
- Universidade Federal de Santa Catarina
- Universidade Federal de Mato Grosso do Sul