2. Academic Validation
  3. Nanomolar activity of coumarin-3-thiosemicarbazones targeting Trypanosoma cruzi cruzain and the T. brucei cathepsin L-like protease

Nanomolar activity of coumarin-3-thiosemicarbazones targeting Trypanosoma cruzi cruzain and the T. brucei cathepsin L-like protease

  • Eur J Med Chem. 2025 Feb 5:283:117109. doi: 10.1016/j.ejmech.2024.117109.
Jéssica Alves Nunes 1,  Paulo Fernando da Silva Santos-Júnior 2,  Midiane Correa Gomes 1,  Luiz Alberto Santos Ferreira 3,  Emanuelly Karla Araújo Padilha 1,  Thaiz Rodrigues Teixeira 4,  Emily J Stanger 4,  Yashpreet Kaur 4,  Elany Barbosa da Silva 4,  Clara Andrezza Crisóstomo Bezerra Costa 5,  Johnnatan Duarte de Freitas 5,  João Xavier de Araújo-Júnior 2,  Francisco Jaime Bezerra Mendonça-Junior 6,  Miriam A Giardini 4,  Jair L Siqueira-Neto 4,  Conor R Caffrey 4,  Peng Zhan 7,  Sílvia Helena Cardoso 8,  Edeildo Ferreira da Silva-Júnior 9
Affiliations

Affiliations

  • 1 Biological and Molecular Chemistry Research Group, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões Campus, Alagoas, Maceió, 57072-970, Brazil.
  • 2 Laboratory of Medicinal Chemistry, Institute of Pharmaceutical Sciences, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões Campus, Alagoas, Maceió, 57072-970, Brazil.
  • 3 Laboratory of Organic and Medicinal Synthesis, Federal University of Alagoas, Campus Arapiraca, Manoel Severino Barbosa Avenue, Arapiraca, 57309-005, Brazil.
  • 4 Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
  • 5 Department of Chemistry, Federal Institute of Alagoas, Maceió Campus, Mizael Domingues Street, 57020-600, Maceió, Alagoas, Brazil.
  • 6 Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraíba, João Pessoa, 58429-500, Paraíba, Brazil.
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 8 Laboratory of Organic and Medicinal Synthesis, Federal University of Alagoas, Campus Arapiraca, Manoel Severino Barbosa Avenue, Arapiraca, 57309-005, Brazil. Electronic address: silvia.cardoso@arapiraca.ufal.br.
  • 9 Biological and Molecular Chemistry Research Group, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões Campus, Alagoas, Maceió, 57072-970, Brazil. Electronic address: edeildo.junior@iqb.ufal.br.
PMID: 39653622 DOI: 10.1016/j.ejmech.2024.117109
Abstract

Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) urgently demand innovative drug development due to their impact on public health worldwide. Their cysteine proteases, Cruzain (CRZ) and the T. brucei Cathepsin L-like protease (TbrCATL) are established drug targets for these parasites. In this study, our coumarin-3-thiosemicarbazones demonstrated nanomolar IC50 values (22-698 nM) toward these proteases. Against T. cruzi amastigotes and T. brucei trypomastigotes, LASF-01 displayed a promising result. Herein, MCG-02, the most potent TbrCATL inhibitor, underwent comprehensive analyses, including cytotoxicity assessments and in vitro tests. Molecular dynamics (MD) simulations and a multiscale Quantum Mechanics/Quantum Mechanics (QM/QM) approach were used to generate insights into their binding modes. These suggested that MCG-02 could be a reversible, competitive covalent inhibitor. Further, confirmatory assays were experimentally performed changing different parameters to prove its efficacy. Additionally, the predicted pharmacokinetic profile showed that there is no violation of the Lipinski rule of five. Notably, coumarin-3-thiosemicarbazone hybrids emerged as promising candidates for designing highly active inhibitors against CRZ and TbrCATL. Overall, the integration of in silico and experimental approaches enhanced our understanding regarding the binding modes of MCG-02, which were experimentally corroborated, providing valuable insights for future drug development.

Keywords

Carboxamides; Coumarines; Multiscale QM/QM calculations; Thiosemicarbazones; Trypanosoma.

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