Author | Moreira, Diogo Rodrigo Magalhães | |
Author | Leite, Ana Cristina Lima | |
Author | Cardoso, Marcos Veríssimo de Oliveira | |
Author | Srivastava, Rajendra Mohan | |
Author | Hernandes, Marcelo Zaldini | |
Author | Rabello, Marcelo Montenegro | |
Author | Cruz, Luana Faria da | |
Author | Ferreira, Rafaela Salgado | |
Author | Simone, Carlos Alberto de | |
Author | Meira, Cássio Santana | |
Author | Guimarães, Elisalva Teixeira | |
Author | Silva, Aline Caroline da | |
Author | Santos, Thiago André Ramos dos | |
Author | Pereira, Valéria Rêgo Alves | |
Author | Soares, Milena Botelho Pereira | |
Access date | 2014-09-19T17:47:58Z | |
Available date | 2014-09-19T17:47:58Z | |
Document date | 2014 | |
Citation | MOREIRA, D. R. M. et al. Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity. ChemMedChem, v. 9, n. 1, p. 177-188, 2014. | pt_BR |
ISSN | 1860-7187 | |
URI | https://www.arca.fiocruz.br/handle/icict/8406 | |
Language | eng | pt_BR |
Publisher | Wiley-VCH Verlag GmbH & Co | pt_BR |
Rights | open access | pt_BR |
Title | Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity | pt_BR |
Type | Article | pt_BR |
DOI | 10.1002/cmdc.201300354 | |
Abstract | Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 µM, while they did not display host cell toxicity up to 200 µM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death. | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Departamento de Química Fundamental. Recife, PE, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Departamento de Química Fundamental. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil | pt_BR |
Affilliation | Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil | pt_BR |
Affilliation | Universidade de São Paulo. Departamento de Física e Inform ática. Instituto de F ísica. São Carlos, SP, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Universidade do Estado da Bahia. Departamento de Ciências da Vida. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, Brasil | pt_BR |
DeCS | Desenho de Drogas | pt_BR |
DeCS | Hidrazinas/síntese química | pt_BR |
DeCS | Tiazolidinedionas/síntese química | pt_BR |
DeCS | Tripanossomicidas/síntese química | pt_BR |
DeCS | Animais | pt_BR |
DeCS | Células Cultivadas | pt_BR |
DeCS | Cristalografia por Raios X | pt_BR |
DeCS | Cisteína Endopeptidases/metabolismo | pt_BR |
DeCS | Retículo Endoplasmático/efeitos de drogas | pt_BR |
DeCS | Feminino | pt_BR |
DeCS | Complexo de Golgi/efeitos de drogas | pt_BR |
DeCS | Hidrazinas/química | pt_BR |
DeCS | Macrófagos/efeitos de drogas | pt_BR |
DeCS | Camundongos Endogâmicos BALB C | pt_BR |
DeCS | Conformação Molecular | pt_BR |
DeCS | Proteínas de Protozoários/antagonistas & inibidores | pt_BR |
DeCS | Baço/efeitos de drogas | pt_BR |
DeCS | Tiazolidinedionas/química | pt_BR |
DeCS | Tripanossomicidas/farmacologia | pt_BR |
DeCS | Trypanosoma cruzi/efeitos de drogas | pt_BR |