Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/10052
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
Authors: Carvalho, Alcione Silva de
Salomão, Kelly
Castro, Solange Lisboa de
Conde, Taline Ramos
Zamith, Helena Pereira da Silva
Caffarena, Ernesto Raúl
Half, Belinda Suzette
Wilkinson, Shane Robert
Boechat, Núbia
Affilliation: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Departamento de Síntese de Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em Saúde. Departamento de Farmacologia e Toxicologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em Saúde. Departamento de Farmacologia e Toxicologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Programa de Computação Científica. Rio de Janeiro, RJ, Brasil.
Queen Mary University of London. 5School of Biological and Chemical Sciences. Lonodn, UK.
Queen Mary University of London. 5School of Biological and Chemical Sciences. Lonodn, UK.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Departamento de Síntese de Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil.
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.
Keywords: Megazol
Trypanosoma cruzi
Trypanosoma brucei
T. brucei nitroreductase
Genotoxicity
DeCS: Trypanosoma brucei brucei
Testes de Mutagenicidade
Trypanosoma cruzi
Issue Date: 2014
Publisher: Fundação Oswaldo Cruz
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.
DOI: 10.1590/0074-0276140497
ISSN: 0074-0276
Copyright: open access
Appears in Collections:INCQS - Artigos de Periódicos
IOC - Artigos de Periódicos

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