Structure-Metabolism Relationships of Benzimidazole Derivatives with anti-Trypanosoma cruzi Activity for Chagas Disease.

Autor: Espinoza-Chávez RM; Laboratory of Synthetic Organic Chemistry, Institute of Chemistry, State University of Campinas (Unicamp), Campinas-SP, 13084-971, Brazil., de Oliveira Rezende Júnior C; Laboratory of Synthetic Organic Chemistry, Institute of Chemistry, State University of Campinas (Unicamp), Campinas-SP, 13084-971, Brazil.; Institute of Chemistry, Federal University of Uberlândia (UFU), Uberlândia-MG, 38400-902, Brazil., Laureano de Souza M; Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos (IFSC), University of Sao Paulo (USP), Sao Carlos-SP, 13563-120, Brazil., Consolin Chelucci R; Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos (IFSC), University of Sao Paulo (USP), Sao Carlos-SP, 13563-120, Brazil., Michelan-Duarte S; Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos (IFSC), University of Sao Paulo (USP), Sao Carlos-SP, 13563-120, Brazil., Krogh R; Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos (IFSC), University of Sao Paulo (USP), Sao Carlos-SP, 13563-120, Brazil., Gomes Ferreira LL; Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos (IFSC), University of Sao Paulo (USP), Sao Carlos-SP, 13563-120, Brazil., Valli M; Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos (IFSC), University of Sao Paulo (USP), Sao Carlos-SP, 13563-120, Brazil., Sena de Oliveira A; Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos (IFSC), University of Sao Paulo (USP), Sao Carlos-SP, 13563-120, Brazil.; Department of Exact Sciences and Education, Federal University of Santa Catarina (UFSC), Blumenau-SC, 89036-004, Brazil., Andricopulo AD; Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos (IFSC), University of Sao Paulo (USP), Sao Carlos-SP, 13563-120, Brazil., Carlos Dias L; Laboratory of Synthetic Organic Chemistry, Institute of Chemistry, State University of Campinas (Unicamp), Campinas-SP, 13084-971, Brazil.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Oct 16; Vol. 19 (20), pp. e202400293. Date of Electronic Publication: 2024 Aug 27.
DOI: 10.1002/cmdc.202400293
Abstrakt: This study introduces further insights from the hit-to-lead optimization process involving a series of benzimidazole derivatives acting as inhibitors of the cruzain enzyme, which targets Trypanosoma cruzi, the causative parasite of Chagas disease. Here, we present the design, synthesis and biological evaluation of 30 new compounds as a third generation of benzimidazole analogues with trypanocidal activity, aiming to enhance our understanding of their pharmacokinetic profiles and establish a structure-metabolism relationships within the series. The design of these new analogues was guided by the analysis of previous pharmacokinetic results, considering identified metabolic sites and biotransformation studies. This optimization resulted in the discovery of two compounds (42 e and 49 b) exhibiting enhanced metabolic stability, anti-Trypanosoma cruzi activity compared to benznidazole (the reference drug for Chagas disease), as well as being non-cruzain inhibitors, and demonstrating a satisfactory in vitro pharmacokinetic profile. These findings unveil a new subclass of aminobenzimidazole and rigid compounds, which offer potential for further exploration in the quest for discovering novel classes of antichagasic compounds.
(© 2024 Wiley-VCH GmbH.)
Databáze: MEDLINE
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