Author | Moreira, Diogo Rodrigo Magalhaes | |
Author | Oliveira, Ana Daura Travassos de | |
Author | Gomes, Paulo André Teixeira de Moraes | |
Author | Simone, Carlos Alberto de | |
Author | Villela, Filipe Silva | |
Author | Ferreira, Rafaela Salgado | |
Author | Silva, Aline Caroline da | |
Author | Santos, Thiago André Ramos dos | |
Author | Castro, Maria Carolina Accioly Brelaz de | |
Author | Pereira, Valéria Rego Alves | |
Author | Leite, Ana Cristina Lima | |
Access date | 2018-04-23T18:13:22Z | |
Available date | 2018-04-23T18:13:22Z | |
Document date | 2014 | |
Citation | 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. | pt_BR |
ISSN | 0223-5234 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/26040 | |
Sponsorship | CNPq (grant 471461/2011-3 to A.C.L.L. and 477435/2012-2 to R.S.F.) and FACEPE | pt_BR |
Language | eng | pt_BR |
Publisher | Elsevier | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Doença de Chagas | pt_BR |
Subject in Portuguese | Trypanosoma cruzi | pt_BR |
Subject in Portuguese | Thiosemicarbazones | pt_BR |
Subject in Portuguese | Hydrazones | pt_BR |
Title | Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.ejmech.2014.02.001 | |
Abstract | Chagas 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. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas 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 de São Paulo. Instituto de Física de São Carlos. São Carlos, SP, 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 | Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil | pt_BR |
Subject | Chagas disease | pt_BR |
Subject | Trypanosoma cruzi | pt_BR |
Subject | Thiosemicarbazones | pt_BR |
Subject | Hydrazones | pt_BR |