Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/13781
Title: Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi.
Authors: Oliveira Filho, Gevanio Bezerra de
Cardoso, Marcos Veríssimo de Oliveira
Espíndola, José Wanderlan Pontes
Ferreira, Luiz Felipe Gomes Rebello
Simone, Carlos Alberto de
Ferreira, Rafaela Salgado
Coelho, Pollyanne Lacerda
Meira, Cássio Santana
Moreira, Diogo Rodrigo Magalhães
Soares, Milena Botelho Pereira
Leite, Ana Cristina Lima
Affilliation: 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
Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil
Universidade de São Paulo. Instituto de Física. Departamento de Física e Informática. São Carlos, SP, Brasil
Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, 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
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil
Abstract: Chagas disease is an infection caused by protozoan Trypanosoma cruzi, which affects approximately 8-10million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases of Chagas disease; however, it has poor efficacy during the symptomatic chronic phase. Therefore, the development of new pharmaceuticals is needed. Here, we employed the bioisosterism to modify a potent antiparasitic and cruzain-inhibitor aryl thiosemicarbazone (4) into 4-thiazolidinones (7-21). Compounds (7-21) were prepared by using a straightforward synthesis and enabled good to excellent yields. As a chemical elucidation tool, X-ray diffraction of compound (10) revealed the geometry and conformation of this class compounds. The screening against cruzain showed that 4-thiazolidinones were less active than thiosemicarbazone (4). However, the antiparasitic activity in Y strain trypomastigotes and host cell cytotoxicity in J774 macrophages revealed that compounds (10 and 18-21) are stronger and more selective antiparasitic agents than thiosemicarbazone (4). Specifically, compounds (18-20), which carry a phenyl at position N3 of heterocyclic ring, were the most active ones, suggesting that this is a structural determinant for activity. In infected macrophages, compounds (18-20) reduced intracellular amastigotes, whereas Benznidazole did not. In T. cruzi-infected mice treated orally with 100mg/kg of compound (20), a decreased of parasitemia was observed. In conclusion, we demonstrated that the conversation of thiosemicarbazones into 4-thiazolidinones retains pharmacological property while enhances selectivity.
Keywords: Chagas disease
Trypanosoma cruzi
Thiosemicarbazones
Thiazolidinones
Bioisosterism
Issue Date: 2015
Publisher: Elsevier
Citation: OLIVEIRA FILHO, G. B. et al. Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi. Bioorganic & Medicinal Chemistry, v. 23, n. 23, p. 7478-7486, 2015.
DOI: dx.doi.org/10.1016/j.bmc.2015.10.048
ISSN: 1464-3391
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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