دورية أكاديمية
1,3-Thiazole derivatives as privileged structures for anti-Trypanosoma cruzi activity: Rational design, synthesis, in silico and in vitro studies.
| العنوان: | 1,3-Thiazole derivatives as privileged structures for anti-Trypanosoma cruzi activity: Rational design, synthesis, in silico and in vitro studies. |
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| المؤلفون: | Cox Holanda de Barros Dias M; Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, Pernambuco, Brazil. Electronic address: mabillycox@gmail.com., Souza Barbalho M; Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670- 420, Recife, Pernambuco, Brazil., Bezerra de Oliveira Filho G; Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, Pernambuco, Brazil., Veríssimo de Oliveira Cardoso M; Universidade de Pernambuco, 56328-903, Petrolina, Pernambuco, Brazil., Lima Leite AC; Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, Pernambuco, Brazil., da Silva Santos AC; Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670- 420, Recife, Pernambuco, Brazil., Cristovão Silva AC; Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670- 420, Recife, Pernambuco, Brazil., Accioly Brelaz de Castro MC; Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670- 420, Recife, Pernambuco, Brazil., Maria Nascimento Moura D; Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670- 420, Recife, Pernambuco, Brazil., Gomes Rebello Ferreira LF; Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, Pernambuco, Brazil., Zaldini Hernandes M; Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, Pernambuco, Brazil., de Freitas E Silva R; Universidade de Pernambuco, 50100-010, Recife, Pernambuco, Brazil., Rêgo Alves Pereira V; Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, 50670- 420, Recife, Pernambuco, Brazil. Electronic address: valeria.hernandes@fiocruz.br. |
| المصدر: | European journal of medicinal chemistry [Eur J Med Chem] 2023 Sep 05; Vol. 257, pp. 115508. Date of Electronic Publication: 2023 May 19. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Paris : Editions Scientifiques Elsevier Original Publication: Paris, S.E.C.T. [etc.] |
| مواضيع طبية MeSH: | Trypanosoma cruzi* , Trypanocidal Agents*/chemistry , Chagas Disease*/drug therapy, Humans ; Molecular Docking Simulation ; Structure-Activity Relationship ; Thiazoles/chemistry ; Drug Design |
| مستخلص: | 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. 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 © 2023 Elsevier Masson SAS. All rights reserved.) |
| فهرسة مساهمة: | Keywords: 1,3-thiazoles; ADME prediction; Bioisosterism; Chagas disease; Cruzain; Trypanocidal agents |
| المشرفين على المادة: | 0 (Thiazoles) 0 (Trypanocidal Agents) |
| تواريخ الأحداث: | Date Created: 20230602 Date Completed: 20230619 Latest Revision: 20230619 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/j.ejmech.2023.115508 |
| PMID: | 37267753 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1768-3254 |
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| DOI: | 10.1016/j.ejmech.2023.115508 |