| Author | Carvalho, Alcione Silva de | |
| Author | Salomão, Kelly | |
| Author | Castro, Solange Lisboa de | |
| Author | Conde, Taline Ramos | |
| Author | Zamith, Helena Pereira da Silva | |
| Author | Caffarena, Ernesto Raúl | |
| Author | Half, Belinda Suzette | |
| Author | Wilkinson, Shane Robert | |
| Author | Boechat, Núbia | |
| Access date | 2015-04-17T17:04:27Z | |
| Available date | 2015-04-17T17:04:27Z | |
| Document date | 2014 | |
| Citation | CARVALHO, Alcione Silva et al. Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme. Mem Inst Oswaldo Cruz, v.109, n.3, p.315-323, maio 2014. | pt_BR |
| ISSN | 0074-0276 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/10052 | |
| Language | eng | pt_BR |
| Publisher | Fundação Oswaldo Cruz | pt_BR |
| Rights | open access | |
| Title | Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme | pt_BR |
| Type | Article | |
| DOI | 10.1590/0074-0276140497 | pt_BR |
| Abstract | Megazol (7) is a 5-nitroimidazole that is highly active against Trypanosoma cruzi and Trypanosoma brucei, as well as drug-resistant forms of trypanosomiasis. Compound 7 is not used clinically due to its mutagenic and genotoxic properties, but has been largely used as a lead compound. Here, we compared the activity of 7 with its 4H-1,2,4-triazole bioisostere (8) in bloodstream forms of T. brucei and T. cruzi and evaluated their activation by T. brucei type I nitroreductase (TbNTR) enzyme. We also analysed the cytotoxic and genotoxic effects of these compounds in whole human blood using Comet and fluorescein diacetate/ethidium bromide assays. Although the only difference between 7 and 8 is the substitution of sulphur (in the thiadiazole in 7) for nitrogen (in the triazole in 8), the results indicated that 8 had poorer antiparasitic activity than 7 and was not genotoxic, whereas 7 presented this effect. The determination of Vmax indicated that although 8 was metabolised more rapidly than 7, it bounds to the TbNTR with better affinity, resulting in equivalent kcat/KM values. Docking assays of 7 and 8 performed within the active site of a homology model of the TbNTR indicating that 8 had greater affinity than 7. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Departamento de Síntese de Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em Saúde. Departamento de Farmacologia e Toxicologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em Saúde. Departamento de Farmacologia e Toxicologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Programa de Computação Científica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Queen Mary University of London. 5School of Biological and Chemical Sciences. Lonodn, UK. | pt_BR |
| Affilliation | Queen Mary University of London. 5School of Biological and Chemical Sciences. Lonodn, UK. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Departamento de Síntese de Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Megazol | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | Trypanosoma brucei | pt_BR |
| Subject | T. brucei nitroreductase | pt_BR |
| Subject | Genotoxicity | pt_BR |
| DeCS | Trypanosoma brucei brucei | pt_BR |
| DeCS | Testes de Mutagenicidade | pt_BR |
| DeCS | Trypanosoma cruzi | pt_BR |
