Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2017 |
| Outros Autores: | , , , , , , , , , , , |
| 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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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). |
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2017 |
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2017 |
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2018-04-04T17:42:18Z |
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2018-04-04T17:42:18Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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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. |
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https://www.arca.fiocruz.br/handle/icict/25616 |
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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 |
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Elsevier |
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Elsevier |
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