Author | Oliveira Filho, Gevanio Bezerra de | |
Author | Cardoso, Marcos Veríssimo de Oliveira | |
Author | Espíndola, José Wanderlan Pontes | |
Author | Ferreira, Luiz Felipe Gomes Rebello | |
Author | Simone, Carlos Alberto de | |
Author | Ferreira, Rafaela Salgado | |
Author | Coelho, Pollyanne Lacerda | |
Author | Meira, Cássio Santana | |
Author | Moreira, Diogo Rodrigo Magalhães | |
Author | Soares, Milena Botelho Pereira | |
Author | Leite, Ana Cristina Lima | |
Access date | 2016-04-14T17:12:17Z | |
Available date | 2016-04-14T17:12:17Z | |
Document date | 2015 | |
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. | pt_BR |
ISSN | 1464-3391 | |
URI | https://www.arca.fiocruz.br/handle/icict/13781 | |
Language | eng | pt_BR |
Publisher | Elsevier | pt_BR |
Rights | open access | pt_BR |
Title | Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.bmc.2015.10.048 | |
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. | 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 | Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil. | pt_BR |
Affilliation | Universidade de São Paulo. Instituto de Física. Departamento de Física e Informática. 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 Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, 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 | Thiosemicarbazones | pt_BR |
Subject | Thiazolidinones | pt_BR |
Subject | Bioisosterism | pt_BR |