Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity

Moreira, Diogo Rodrigo Magalhães; Leite, Ana Cristina Lima; Cardoso, Marcos Veríssimo de Oliveira; Srivastava, Rajendra Mohan; Hernandes, Marcelo Zaldini; Rabello, Marcelo Montenegro; Cruz, Luana Faria da; Ferreira, Rafaela Salgado; Simone, Carlos Alberto de; Meira, Cássio Santana; Guimarães, Elisalva Teixeira; Silva, Aline Caroline da; Santos, Thiago André Ramos dos; Pereira, Valéria Rêgo Alves; Soares, Milena Botelho Pereira

Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity

Detalhes bibliográficos
Autor(a) principal:	Moreira, Diogo Rodrigo Magalhães
Data de Publicação:	2014
Outros Autores:	Leite, Ana Cristina Lima, Cardoso, Marcos Veríssimo de Oliveira, Srivastava, Rajendra Mohan, Hernandes, Marcelo Zaldini, Rabello, Marcelo Montenegro, Cruz, Luana Faria da, Ferreira, Rafaela Salgado, Simone, Carlos Alberto de, Meira, Cássio Santana, Guimarães, Elisalva Teixeira, Silva, Aline Caroline da, Santos, Thiago André Ramos dos, Pereira, Valéria Rêgo Alves, Soares, Milena Botelho Pereira
Tipo de documento:	Artigo
Idioma:	eng
Título da fonte:	Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo:	https://www.arca.fiocruz.br/handle/icict/8406
Resumo:	Universidade Federal de Pernambuco. Departamento de Química Fundamental. Recife, PE, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil

Metadados do item

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spelling	Moreira, Diogo Rodrigo MagalhãesLeite, Ana Cristina LimaCardoso, Marcos Veríssimo de OliveiraSrivastava, Rajendra MohanHernandes, Marcelo ZaldiniRabello, Marcelo MontenegroCruz, Luana Faria daFerreira, Rafaela SalgadoSimone, Carlos Alberto deMeira, Cássio SantanaGuimarães, Elisalva TeixeiraSilva, Aline Caroline daSantos, Thiago André Ramos dosPereira, Valéria Rêgo AlvesSoares, Milena Botelho Pereira2014-09-19T17:47:58Z2014-09-19T17:47:58Z2014MOREIRA, 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, 2014.1860-7187https://www.arca.fiocruz.br/handle/icict/840610.1002/cmdc.201300354engWiley-VCH Verlag GmbH & CoStructural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activityinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversidade Federal de Pernambuco. Departamento de Química Fundamental. Recife, PE, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Química Fundamental. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrasilUniversidade de São Paulo. Departamento de Física e Inform ática. Instituto de F ísica. São Carlos, SP, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Universidade do Estado da Bahia. Departamento de Ciências da Vida. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, BrasilPharmacological 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 10â€…µM, while they did not display host cell toxicity up to 200â€…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.â€…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.â€…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.Desenho de DrogasHidrazinas/síntese químicaTiazolidinedionas/síntese químicaTripanossomicidas/síntese químicaAnimaisCélulas CultivadasCristalografia por Raios XCisteína Endopeptidases/metabolismoRetículo Endoplasmático/efeitos de drogasFemininoComplexo de Golgi/efeitos de drogasHidrazinas/químicaMacrófagos/efeitos de drogasCamundongos Endogâmicos BALB CConformação MolecularProteínas de Protozoários/antagonistas & inibidoresBaço/efeitos de drogasTiazolidinedionas/químicaTripanossomicidas/farmacologiaTrypanosoma cruzi/efeitos de drogasinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-81914https://www.arca.fiocruz.br/bitstream/icict/8406/1/license.txt7d48279ffeed55da8dfe2f8e81f3b81fMD51ORIGINALMoreira DRM Structural Design....pdfMoreira DRM Structural Design....pdfapplication/pdf1436389https://www.arca.fiocruz.br/bitstream/icict/8406/2/Moreira%20DRM%20Structural%20Design....pdfd211240c01fd9449e4ca4a110e73acb7MD52TEXTMoreira DRM Structural Design....pdf.txtMoreira DRM Structural Design....pdf.txtExtracted texttext/plain62510https://www.arca.fiocruz.br/bitstream/icict/8406/3/Moreira%20DRM%20Structural%20Design....pdf.txt8e62cf988810300ed6b91aabb8d79383MD53icict/84062023-03-15 14:33:24.032oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352023-03-15T17:33:24Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false
dc.title.pt_BR.fl_str_mv	Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
title	Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
spellingShingle	Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity Moreira, Diogo Rodrigo Magalhães Desenho de Drogas Hidrazinas/síntese química Tiazolidinedionas/síntese química Tripanossomicidas/síntese química Animais Células Cultivadas Cristalografia por Raios X Cisteína Endopeptidases/metabolismo Retículo Endoplasmático/efeitos de drogas Feminino Complexo de Golgi/efeitos de drogas Hidrazinas/química Macrófagos/efeitos de drogas Camundongos Endogâmicos BALB C Conformação Molecular Proteínas de Protozoários/antagonistas & inibidores Baço/efeitos de drogas Tiazolidinedionas/química Tripanossomicidas/farmacologia Trypanosoma cruzi/efeitos de drogas
title_short	Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
title_full	Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
title_fullStr	Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
title_full_unstemmed	Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
title_sort	Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
author	Moreira, Diogo Rodrigo Magalhães
author_facet	Moreira, Diogo Rodrigo Magalhães Leite, Ana Cristina Lima Cardoso, Marcos Veríssimo de Oliveira Srivastava, Rajendra Mohan Hernandes, Marcelo Zaldini Rabello, Marcelo Montenegro Cruz, Luana Faria da Ferreira, Rafaela Salgado Simone, Carlos Alberto de Meira, Cássio Santana Guimarães, Elisalva Teixeira Silva, Aline Caroline da Santos, Thiago André Ramos dos Pereira, Valéria Rêgo Alves Soares, Milena Botelho Pereira
author_role	author
author2	Leite, Ana Cristina Lima Cardoso, Marcos Veríssimo de Oliveira Srivastava, Rajendra Mohan Hernandes, Marcelo Zaldini Rabello, Marcelo Montenegro Cruz, Luana Faria da Ferreira, Rafaela Salgado Simone, Carlos Alberto de Meira, Cássio Santana Guimarães, Elisalva Teixeira Silva, Aline Caroline da Santos, Thiago André Ramos dos Pereira, Valéria Rêgo Alves Soares, Milena Botelho Pereira
author2_role	author author author author author author author author author author author author author author
dc.contributor.author.fl_str_mv	Moreira, Diogo Rodrigo Magalhães Leite, Ana Cristina Lima Cardoso, Marcos Veríssimo de Oliveira Srivastava, Rajendra Mohan Hernandes, Marcelo Zaldini Rabello, Marcelo Montenegro Cruz, Luana Faria da Ferreira, Rafaela Salgado Simone, Carlos Alberto de Meira, Cássio Santana Guimarães, Elisalva Teixeira Silva, Aline Caroline da Santos, Thiago André Ramos dos Pereira, Valéria Rêgo Alves Soares, Milena Botelho Pereira
dc.subject.decs.pt_BR.fl_str_mv	Desenho de Drogas Hidrazinas/síntese química Tiazolidinedionas/síntese química Tripanossomicidas/síntese química Animais Células Cultivadas Cristalografia por Raios X Cisteína Endopeptidases/metabolismo Retículo Endoplasmático/efeitos de drogas Feminino Complexo de Golgi/efeitos de drogas Hidrazinas/química Macrófagos/efeitos de drogas Camundongos Endogâmicos BALB C Conformação Molecular Proteínas de Protozoários/antagonistas & inibidores Baço/efeitos de drogas Tiazolidinedionas/química Tripanossomicidas/farmacologia Trypanosoma cruzi/efeitos de drogas
topic	Desenho de Drogas Hidrazinas/síntese química Tiazolidinedionas/síntese química Tripanossomicidas/síntese química Animais Células Cultivadas Cristalografia por Raios X Cisteína Endopeptidases/metabolismo Retículo Endoplasmático/efeitos de drogas Feminino Complexo de Golgi/efeitos de drogas Hidrazinas/química Macrófagos/efeitos de drogas Camundongos Endogâmicos BALB C Conformação Molecular Proteínas de Protozoários/antagonistas & inibidores Baço/efeitos de drogas Tiazolidinedionas/química Tripanossomicidas/farmacologia Trypanosoma cruzi/efeitos de drogas
description	Universidade Federal de Pernambuco. Departamento de Química Fundamental. Recife, PE, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
publishDate	2014
dc.date.accessioned.fl_str_mv	2014-09-19T17:47:58Z
dc.date.available.fl_str_mv	2014-09-19T17:47:58Z
dc.date.issued.fl_str_mv	2014
dc.type.status.fl_str_mv	info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv	info:eu-repo/semantics/article
format	article
status_str	publishedVersion
dc.identifier.citation.fl_str_mv	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.
dc.identifier.uri.fl_str_mv	https://www.arca.fiocruz.br/handle/icict/8406
dc.identifier.issn.none.fl_str_mv	1860-7187
dc.identifier.doi.none.fl_str_mv	10.1002/cmdc.201300354
identifier_str_mv	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. 1860-7187 10.1002/cmdc.201300354
url	https://www.arca.fiocruz.br/handle/icict/8406
dc.language.iso.fl_str_mv	eng
language	eng
dc.rights.driver.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	Wiley-VCH Verlag GmbH & Co
publisher.none.fl_str_mv	Wiley-VCH Verlag GmbH & Co
dc.source.none.fl_str_mv	reponame:Repositório Institucional da FIOCRUZ (ARCA) instname:Fundação Oswaldo Cruz (FIOCRUZ) instacron:FIOCRUZ
instname_str	Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str	FIOCRUZ
institution	FIOCRUZ
reponame_str	Repositório Institucional da FIOCRUZ (ARCA)
collection	Repositório Institucional da FIOCRUZ (ARCA)
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Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity

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