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

Autor: Nunes JA; 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., Santos-Júnior PFDS; Laboratory of Medicinal Chemistry, Institute of Pharmaceutical Sciences, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões Campus, Alagoas, Maceió, 57072-970, Brazil., Gomes MC; 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., Ferreira LAS; Laboratory of Organic and Medicinal Synthesis, Federal University of Alagoas, Campus Arapiraca, Manoel Severino Barbosa Avenue, Arapiraca, 57309-005, Brazil., Padilha EKA; 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., Teixeira TR; 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., Stanger EJ; 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., Kaur Y; 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., Silva EBD; 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., Costa CACB; Department of Chemistry, Federal Institute of Alagoas, Maceió Campus, Mizael Domingues Street, 57020-600, Maceió, Alagoas, Brazil., Freitas JD; Department of Chemistry, Federal Institute of Alagoas, Maceió Campus, Mizael Domingues Street, 57020-600, Maceió, Alagoas, Brazil., Araújo-Júnior JX; Laboratory of Medicinal Chemistry, Institute of Pharmaceutical Sciences, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões Campus, Alagoas, Maceió, 57072-970, Brazil., Mendonça-Junior FJB; Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraíba, João Pessoa, 58429-500, Paraíba, Brazil., Giardini MA; 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., Siqueira-Neto JL; 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., Caffrey CR; 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., Zhan P; 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., Cardoso SH; 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., Silva-Júnior EFD; 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.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Nov 28; Vol. 283, pp. 117109. Date of Electronic Publication: 2024 Nov 28.
DOI: 10.1016/j.ejmech.2024.117109
Abstrakt: 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 IC 50 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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