1,3-Thiazole derivatives as privileged structures for anti-Trypanosoma cruzi activity: Rational design, synthesis, in silico and in vitro studies.

Abstract

Chagas disease is a deadly and centenary neglected disease that is recently surging as a potential global threat. Approximately 30% of infected individuals develop chronic Chagas cardiomyopathy and current treatment with the reference benznidazole (BZN) is ineffective for this stage. We presently report the structural planning, synthesis, characterization, molecular docking prediction, cytotoxicity, in vitro bioactivity and mechanistic studies on the anti-T. cruzi activity of a series of 16 novel 1,3-thiazoles (2-17) derived from thiosemicarbazones (1a, 1b) in a two-step and reproducible Hantzsch-based synthesis approach. The anti-T. cruzi activity was evaluated in vitro against the epimastigote, amastigote and trypomastigote forms of the parasite. In the bioactivity assays, all thiazoles were more potent than BZN against epimastigotes. We found that the compounds presented an overall increased anti-tripomastigote selectivity (Cpd 8 was 24-fold more selective) than BZN, and they mostly presented anti-amastigote activity at very low doses (from 3.65 μM, cpd 15). Mechanistic studies on cell death suggested that the series of 1,3-thiazole compounds herein reported cause parasite cell death through apoptosis, but without compromising the mitochondrial membrane potential. In silico prediction of physicochemical properties and pharmacokinetic parameters showed promising drug-like results, being all the reported compounds in compliance with Lipinski and Veber rules. In summary, our work contributes towards a more rational design of potent and selective antitripanosomal drugs, using affordable methodology to yield industrially viable drug candidates.

• Authors: Mabilly Cox Holanda de Barros Dias, Mayara Souza Barbalho, Gevanio Bezerra de Oliveira Filho, Marcos Veríssimo de Oliveira Cardoso, Ana Cristina Lima Leite, Aline Caroline da Silva Santos, Ana Catarina Cristovão Silva, Maria Carolina Accioly Brelaz de Castro, Danielle Maria Nascimento Moura, Luiz Felipe Gomes Rebello Ferreira, Marcelo Zaldini Hernandes, Rafael de Freitas E Silva, Valéria Rêgo Alves Pereira
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 257 Pg. 115508 (Sep 05 2023) ISSN: 1768-3254 [Electronic] France
• PMID: 37267753 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Chemical References

• Thiazoles
• Trypanocidal Agents

Topics

• Humans
• Trypanosoma cruzi
• Molecular Docking Simulation
• Structure-Activity Relationship
• Thiazoles (chemistry)
• Trypanocidal Agents (chemistry)
• Drug Design
• Chagas Disease (drug therapy)