Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death

Detalhes bibliográficos
Autor(a) principal: Silva, Elany Barbosa da
Data de Publicação: 2017
Outros Autores: Silva, Dayane Albuquerque Oliveira e, Oliveira, Arsênio Rodrigues, Silva Mendes, Carlos Henrique da, Santos, Thiago André Ramos dos, Silva, Aline Caroline da, Castro, Maria Carolina Acioly de, Ferreira, Rafaela Salgado, Moreira, Diogo Rodrigo Magalhães, Cardoso, Marcos Veríssimo de Oliveira, Simone, Carlos Alberto de, Pereira, Valéria Rêgo Alves, Leite, Ana Cristina Lima
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/25616
Resumo: Conselho Nacional de Desenvolvimento Científico e Tecnol ogico, Fundaç~ao de Amparo a Ci^encia e Tecnologia de Pernambuco (FACEPE).
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spelling Silva, Elany Barbosa daSilva, Dayane Albuquerque Oliveira eOliveira, Arsênio RodriguesSilva Mendes, Carlos Henrique daSantos, Thiago André Ramos dosSilva, Aline Caroline daCastro, Maria Carolina Acioly deFerreira, Rafaela SalgadoMoreira, Diogo Rodrigo MagalhãesCardoso, Marcos Veríssimo de OliveiraSimone, Carlos Alberto dePereira, Valéria Rêgo AlvesLeite, Ana Cristina Lima2018-04-04T17:42:18Z2018-04-04T17:42:18Z2017SILVA, E. B. et al. Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death. European Journal of Medicinal Chemistry, v. 130, p. 39e50, 2017.0223-5234https://www.arca.fiocruz.br/handle/icict/2561610.1016/j.ejmech.2017.02.026Conselho Nacional de Desenvolvimento Científico e Tecnol ogico, Fundaç~ao de Amparo a Ci^encia e Tecnologia de Pernambuco (FACEPE).Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil / Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil / Universidade Federal de Pernambuco. Centro Acadêmico de Vit oria. Laborat orio de Parasitologia. Vit oria de Santo Antão, PE, BrasilUniversidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade de Pernambuco. Colegiado de Nutrição. Petrolina, PE, BrasilUniversidade de São Paulo. Instituto de Física. Departamento de Física e Inform atica. São Carlos, SP, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilChagas disease, caused by the kinetoplastid protozoan parasite Trypanosoma cruzi, remains a relevant cause of illness and premature death and it is estimated that 6 million to 7 million people are infected worldwide. Although chemotherapy options are limited presenting serious problems, such as low efficacy and high toxicity. T. cruzi is susceptible to thiazoles, making this class of compounds appealing for drug development. Previously, thiazoles resulted in an increase in anti-T. cruzi activity in comparison to thiosemicarbazones. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new thiazoles derivatives (3a-m and 4a-m), designed from molecular hybridization associated with non-classical bioisosterism. By varying substituents attached to the phenyl and thiazole rings, substituents were observed to retain, enhance or greatly increase their anti-T. cruzi activity, in comparison to the corresponding thiosemicarbazones. In most cases, electron-withdrawing substituents, such as bromine, 3,4-dichloro and nitro groups, greatly increased antiparasitic activity. Specifically, new thiazoles were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting macrophages viability. These compounds were also evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these molecules induce apoptosis. In conclusion, except for compounds 3h and 3k, all thiazoles derivatives evaluated exhibited higher cytotoxic activity against the trypomastigote forms than the reference medicament benznidazole, without affecting macrophages viability. Compounds 4d and 4k were highlights, CC50 = 1.2 e 1.6 μM, respectively. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process, being considered a good starting point for the development of new anti-Chagas drug candidates.engElsevierDoença de ChagasTrypanosoma cruziBioisosterismo não-clássicoTiazolesDerivados da piridinaApoptoseChagas diseaseTrypanosoma cruziNonclassical bioisosterismThiazolesPyridine derivativesApoptosisDesing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite deathinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/25616/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALSilva EB Desing and synthesis of potent....pdfSilva EB Desing and synthesis of 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dc.title.pt_BR.fl_str_mv Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
title Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
spellingShingle Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
Silva, Elany Barbosa da
Doença de Chagas
Trypanosoma cruzi
Bioisosterismo não-clássico
Tiazoles
Derivados da piridina
Apoptose
Chagas disease
Trypanosoma cruzi
Nonclassical bioisosterism
Thiazoles
Pyridine derivatives
Apoptosis
title_short Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
title_full Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
title_fullStr Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
title_full_unstemmed Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
title_sort Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
author Silva, Elany Barbosa da
author_facet Silva, Elany Barbosa da
Silva, Dayane Albuquerque Oliveira e
Oliveira, Arsênio Rodrigues
Silva Mendes, Carlos Henrique da
Santos, Thiago André Ramos dos
Silva, Aline Caroline da
Castro, Maria Carolina Acioly de
Ferreira, Rafaela Salgado
Moreira, Diogo Rodrigo Magalhães
Cardoso, Marcos Veríssimo de Oliveira
Simone, Carlos Alberto de
Pereira, Valéria Rêgo Alves
Leite, Ana Cristina Lima
author_role author
author2 Silva, Dayane Albuquerque Oliveira e
Oliveira, Arsênio Rodrigues
Silva Mendes, Carlos Henrique da
Santos, Thiago André Ramos dos
Silva, Aline Caroline da
Castro, Maria Carolina Acioly de
Ferreira, Rafaela Salgado
Moreira, Diogo Rodrigo Magalhães
Cardoso, Marcos Veríssimo de Oliveira
Simone, Carlos Alberto de
Pereira, Valéria Rêgo Alves
Leite, Ana Cristina Lima
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Silva, Elany Barbosa da
Silva, Dayane Albuquerque Oliveira e
Oliveira, Arsênio Rodrigues
Silva Mendes, Carlos Henrique da
Santos, Thiago André Ramos dos
Silva, Aline Caroline da
Castro, Maria Carolina Acioly de
Ferreira, Rafaela Salgado
Moreira, Diogo Rodrigo Magalhães
Cardoso, Marcos Veríssimo de Oliveira
Simone, Carlos Alberto de
Pereira, Valéria Rêgo Alves
Leite, Ana Cristina Lima
dc.subject.other.pt_BR.fl_str_mv Doença de Chagas
Trypanosoma cruzi
Bioisosterismo não-clássico
Tiazoles
Derivados da piridina
Apoptose
topic Doença de Chagas
Trypanosoma cruzi
Bioisosterismo não-clássico
Tiazoles
Derivados da piridina
Apoptose
Chagas disease
Trypanosoma cruzi
Nonclassical bioisosterism
Thiazoles
Pyridine derivatives
Apoptosis
dc.subject.en.pt_BR.fl_str_mv Chagas disease
Trypanosoma cruzi
Nonclassical bioisosterism
Thiazoles
Pyridine derivatives
Apoptosis
description Conselho Nacional de Desenvolvimento Científico e Tecnol ogico, Fundaç~ao de Amparo a Ci^encia e Tecnologia de Pernambuco (FACEPE).
publishDate 2017
dc.date.issued.fl_str_mv 2017
dc.date.accessioned.fl_str_mv 2018-04-04T17:42:18Z
dc.date.available.fl_str_mv 2018-04-04T17:42:18Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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status_str publishedVersion
dc.identifier.citation.fl_str_mv SILVA, E. B. et al. Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death. European Journal of Medicinal Chemistry, v. 130, p. 39e50, 2017.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/25616
dc.identifier.issn.pt_BR.fl_str_mv 0223-5234
dc.identifier.doi.none.fl_str_mv 10.1016/j.ejmech.2017.02.026
identifier_str_mv SILVA, E. B. et al. Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death. European Journal of Medicinal Chemistry, v. 130, p. 39e50, 2017.
0223-5234
10.1016/j.ejmech.2017.02.026
url https://www.arca.fiocruz.br/handle/icict/25616
dc.language.iso.fl_str_mv eng
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dc.publisher.none.fl_str_mv Elsevier
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