Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/25616
Title: Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
Authors: 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
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
Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil
Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil
Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil
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
Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Universidade de Pernambuco. Colegiado de Nutrição. Petrolina, PE, Brasil
Universidade de São Paulo. Instituto de Física. Departamento de Física e Inform atica. São Carlos, SP, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil
Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil
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.
Keywords: Chagas disease
Trypanosoma cruzi
Nonclassical bioisosterism
Thiazoles
Pyridine derivatives
Apoptosis
keywords: Doença de Chagas
Trypanosoma cruzi
Bioisosterismo não-clássico
Tiazoles
Derivados da piridina
Apoptose
Issue Date: 2017
Publisher: Elsevier
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.
DOI: 10.1016/j.ejmech.2017.02.026
ISSN: 0223-5234
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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