Author | Silva, Elany Barbosa da | |
Author | Silva, Dayane Albuquerque Oliveira e | |
Author | Oliveira, Arsênio Rodrigues | |
Author | Silva Mendes, Carlos Henrique da | |
Author | Santos, Thiago André Ramos dos | |
Author | Silva, Aline Caroline da | |
Author | Castro, Maria Carolina Acioly de | |
Author | Ferreira, Rafaela Salgado | |
Author | Moreira, Diogo Rodrigo Magalhães | |
Author | Cardoso, Marcos Veríssimo de Oliveira | |
Author | Simone, Carlos Alberto de | |
Author | Pereira, Valéria Rêgo Alves | |
Author | Leite, Ana Cristina Lima | |
Access date | 2018-04-04T17:42:18Z | |
Available date | 2018-04-04T17:42:18Z | |
Document date | 2017 | |
Citation | 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. | pt_BR |
ISSN | 0223-5234 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/25616 | |
Sponsorship | Conselho Nacional de Desenvolvimento Científico e Tecnol ogico, Fundaç~ao de Amparo a Ci^encia e
Tecnologia de Pernambuco (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 | Bioisosterismo não-clássico | pt_BR |
Subject in Portuguese | Tiazoles | pt_BR |
Subject in Portuguese | Derivados da piridina | pt_BR |
Subject in Portuguese | Apoptose | pt_BR |
Title | Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.ejmech.2017.02.026 | |
Abstract | Chagas 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. | pt_BR |
Affilliation | 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, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. 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 / Universidade Federal de Pernambuco. Centro Acadêmico de Vit oria. Laborat orio de Parasitologia. Vit oria de Santo Antão, PE, 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 Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Universidade de Pernambuco. Colegiado de Nutrição. Petrolina, PE, Brasil | pt_BR |
Affilliation | Universidade de São Paulo. Instituto de Física. Departamento de Física e Inform atica. São Carlos, SP, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil | pt_BR |
Affilliation | Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil | pt_BR |
Subject | Chagas disease | pt_BR |
Subject | Trypanosoma cruzi | pt_BR |
Subject | Nonclassical bioisosterism | pt_BR |
Subject | Thiazoles | pt_BR |
Subject | Pyridine derivatives | pt_BR |
Subject | Apoptosis | pt_BR |