Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2014 |
| 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/26040 |
Resumo: | CNPq (grant 471461/2011-3 to A.C.L.L. and 477435/2012-2 to R.S.F.) and FACEPE |
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Moreira, Diogo Rodrigo MagalhaesOliveira, Ana Daura Travassos deGomes, Paulo André Teixeira de MoraesSimone, Carlos Alberto deVillela, Filipe SilvaFerreira, Rafaela SalgadoSilva, Aline Caroline daSantos, Thiago André Ramos dosCastro, Maria Carolina Accioly Brelaz dePereira, Valéria Rego AlvesLeite, Ana Cristina Lima2018-04-23T18:13:22Z2018-04-23T18:13:22Z2014MOREIRA, D. R. M. et al. Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death. European Journal of Medicinal Chemistry, v. 75, p. 467-478, 2014.0223-5234https://www.arca.fiocruz.br/handle/icict/2604010.1016/j.ejmech.2014.02.001CNPq (grant 471461/2011-3 to A.C.L.L. and 477435/2012-2 to R.S.F.) and FACEPEFundação Oswaldo Cruz. Centro de Pesquisas 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 de São Paulo. Instituto de Física de São Carlos. São Carlos, SP, 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, 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, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilChagas disease, caused by Trypanosoma cruzi, is a life-threatening infection leading to approximately 12,000 deaths per year. T. cruzi is susceptible to thiosemicarbazones, making this class of compounds appealing for drug development. Previously, the homologation of aryl thiosemicarbazones resulted in an increase in anti-T. cruzi activity in comparison to aryl thiosemicarbazones without a spacer group. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new aryl thiosemicarbazones (9a-x), designed as more conformationally restricted compounds. By varying substituents attached to the phenyl ring, substituents were observed to retain, enhance or greatly increase the anti-T. cruzi activity, in comparison to the nonsubstituted derivative. In most cases, hydrophobic and bulky substituents, such as bromo, biphenyl and phenoxyl groups, greatly increased antiparasitic activity. Specifically, thiosemicarbazones were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting mouse splenocytes viability. The most potent anti-T. cruzi thiosemicarbazones were 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 thiosemicarbazones induce apoptosis. In conclusion, the structural design executed within the series of aryl thiosemicarbazones (9a-x) led to the identification of new potent anti-T. cruzi agents, such as compounds (9h) and (9r), which greatly inhibited epimastigote proliferation, and demonstrated a toxicity for trypomastigotes, but not for splenocytes. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process.engElsevierDoença de ChagasTrypanosoma cruziThiosemicarbazonesHydrazonesChagas diseaseTrypanosoma cruziThiosemicarbazonesHydrazonesConformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds 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/26040/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALMoreira DRM Conformational restriction....pdfMoreira DRM Conformational 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14:33:55.611oai:www.arca.fiocruz.br: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ório 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| dc.title.pt_BR.fl_str_mv |
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death |
| title |
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death |
| spellingShingle |
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death Moreira, Diogo Rodrigo Magalhaes Doença de Chagas Trypanosoma cruzi Thiosemicarbazones Hydrazones Chagas disease Trypanosoma cruzi Thiosemicarbazones Hydrazones |
| title_short |
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death |
| title_full |
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death |
| title_fullStr |
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death |
| title_full_unstemmed |
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death |
| title_sort |
Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death |
| author |
Moreira, Diogo Rodrigo Magalhaes |
| author_facet |
Moreira, Diogo Rodrigo Magalhaes Oliveira, Ana Daura Travassos de Gomes, Paulo André Teixeira de Moraes Simone, Carlos Alberto de Villela, Filipe Silva Ferreira, Rafaela Salgado Silva, Aline Caroline da Santos, Thiago André Ramos dos Castro, Maria Carolina Accioly Brelaz de Pereira, Valéria Rego Alves Leite, Ana Cristina Lima |
| author_role |
author |
| author2 |
Oliveira, Ana Daura Travassos de Gomes, Paulo André Teixeira de Moraes Simone, Carlos Alberto de Villela, Filipe Silva Ferreira, Rafaela Salgado Silva, Aline Caroline da Santos, Thiago André Ramos dos Castro, Maria Carolina Accioly Brelaz de Pereira, Valéria Rego Alves Leite, Ana Cristina Lima |
| author2_role |
author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Moreira, Diogo Rodrigo Magalhaes Oliveira, Ana Daura Travassos de Gomes, Paulo André Teixeira de Moraes Simone, Carlos Alberto de Villela, Filipe Silva Ferreira, Rafaela Salgado Silva, Aline Caroline da Santos, Thiago André Ramos dos Castro, Maria Carolina Accioly Brelaz de Pereira, Valéria Rego Alves Leite, Ana Cristina Lima |
| dc.subject.other.pt_BR.fl_str_mv |
Doença de Chagas Trypanosoma cruzi Thiosemicarbazones Hydrazones |
| topic |
Doença de Chagas Trypanosoma cruzi Thiosemicarbazones Hydrazones Chagas disease Trypanosoma cruzi Thiosemicarbazones Hydrazones |
| dc.subject.en.pt_BR.fl_str_mv |
Chagas disease Trypanosoma cruzi Thiosemicarbazones Hydrazones |
| description |
CNPq (grant 471461/2011-3 to A.C.L.L. and 477435/2012-2 to R.S.F.) and FACEPE |
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2014 |
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2014 |
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2018-04-23T18:13:22Z |
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2018-04-23T18:13:22Z |
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info:eu-repo/semantics/article |
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article |
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MOREIRA, D. R. M. et al. Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death. European Journal of Medicinal Chemistry, v. 75, p. 467-478, 2014. |
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https://www.arca.fiocruz.br/handle/icict/26040 |
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0223-5234 |
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10.1016/j.ejmech.2014.02.001 |
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MOREIRA, D. R. M. et al. Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death. European Journal of Medicinal Chemistry, v. 75, p. 467-478, 2014. 0223-5234 10.1016/j.ejmech.2014.02.001 |
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Elsevier |
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