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

Bibliographic Details
Main Author: Carvalho, Alcione Silva de
Publication Date: 2014
Other Authors: Salomão, Kelly, Castro, Solange Lisboa de, Conde, Taline Ramos, Zamith, Helena Pereira da Silva, Caffarena, Ernesto Raul, Half, Belinda Suzette, Wilkinson, Shane Robert, Boechat, Nubia
Format: Article
Language: eng
Source: Repositório Institucional da FIOCRUZ (ARCA)
DOI: 10.1590/0074-0276140497
Download full: https://arca.fiocruz.br/handle/icict/10052
Summary: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Departamento de Síntese de Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil.
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spelling Carvalho, Alcione Silva deSalomão, KellyCastro, Solange Lisboa deConde, Taline RamosZamith, Helena Pereira da SilvaCaffarena, Ernesto RaulHalf, Belinda SuzetteWilkinson, Shane RobertBoechat, Nubia2015-04-17T17:04:27Z2015-04-17T17:04:27Z2014CARVALHO, 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 2014.0074-0276https://arca.fiocruz.br/handle/icict/1005210.1590/0074-0276140497engFundação Oswaldo CruzMegazol 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 enzymeinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação 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, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, BrasilFundação 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.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.MegazolTrypanosoma cruziTrypanosoma bruceiT. brucei nitroreductaseGenotoxicityTrypanosoma brucei bruceiTestes de MutagenicidadeTrypanosoma cruziinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txttext/plain1914https://arca.fiocruz.br/bitstreams/59783a92-ff7c-441f-976b-98ce291584da/download7d48279ffeed55da8dfe2f8e81f3b81fMD51falseAnonymousREADORIGINALalcione_carvalhoetal_IOC_2014.pdfapplication/pdf807715https://arca.fiocruz.br/bitstreams/051eaacf-7aac-40e0-bdba-1f765521d929/download232ad621b81346a9c62880649813630cMD52trueAnonymousREADTEXTalcione_carvalhoetal_IOC_2014.pdf.txtalcione_carvalhoetal_IOC_2014.pdf.txtExtracted texttext/plain47469https://arca.fiocruz.br/bitstreams/af1298b7-2c39-4ae1-bf68-c209fc0f77c2/downloadd76074f859886a87abc245e33953e0c8MD55falseAnonymousREADTHUMBNAILalcione_carvalhoetal_IOC_2014.pdf.jpgalcione_carvalhoetal_IOC_2014.pdf.jpgGenerated Thumbnailimage/jpeg6003https://arca.fiocruz.br/bitstreams/15e39181-6fe3-4c15-9844-682ccfb7da5c/download31c25739cdf6ba0d2f4cdd9ab1cc99bdMD56falseAnonymousREADicict/100522025-07-30 01:39:49.779open.accessoai:arca.fiocruz.br:icict/10052https://arca.fiocruz.brRepositório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352025-07-30T04:39:49Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)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
dc.title.none.fl_str_mv 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
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
spellingShingle 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
Carvalho, Alcione Silva de
Megazol
Trypanosoma cruzi
Trypanosoma brucei
T. brucei nitroreductase
Genotoxicity
Trypanosoma brucei brucei
Testes de Mutagenicidade
Trypanosoma cruzi
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
author Carvalho, Alcione Silva de
author_facet Carvalho, Alcione Silva de
Salomão, Kelly
Castro, Solange Lisboa de
Conde, Taline Ramos
Zamith, Helena Pereira da Silva
Caffarena, Ernesto Raul
Half, Belinda Suzette
Wilkinson, Shane Robert
Boechat, Nubia
author_role author
author2 Salomão, Kelly
Castro, Solange Lisboa de
Conde, Taline Ramos
Zamith, Helena Pereira da Silva
Caffarena, Ernesto Raul
Half, Belinda Suzette
Wilkinson, Shane Robert
Boechat, Nubia
author2_role author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Carvalho, Alcione Silva de
Salomão, Kelly
Castro, Solange Lisboa de
Conde, Taline Ramos
Zamith, Helena Pereira da Silva
Caffarena, Ernesto Raul
Half, Belinda Suzette
Wilkinson, Shane Robert
Boechat, Nubia
dc.subject.en.none.fl_str_mv Megazol
Trypanosoma cruzi
Trypanosoma brucei
T. brucei nitroreductase
Genotoxicity
topic Megazol
Trypanosoma cruzi
Trypanosoma brucei
T. brucei nitroreductase
Genotoxicity
Trypanosoma brucei brucei
Testes de Mutagenicidade
Trypanosoma cruzi
dc.subject.decs.none.fl_str_mv Trypanosoma brucei brucei
Testes de Mutagenicidade
Trypanosoma cruzi
description Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Departamento de Síntese de Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil.
publishDate 2014
dc.date.issued.fl_str_mv 2014
dc.date.accessioned.fl_str_mv 2015-04-17T17:04:27Z
dc.date.available.fl_str_mv 2015-04-17T17:04:27Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv 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.
dc.identifier.uri.fl_str_mv https://arca.fiocruz.br/handle/icict/10052
dc.identifier.issn.none.fl_str_mv 0074-0276
dc.identifier.doi.none.fl_str_mv 10.1590/0074-0276140497
identifier_str_mv 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.
0074-0276
10.1590/0074-0276140497
url https://arca.fiocruz.br/handle/icict/10052
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Fundação Oswaldo Cruz
publisher.none.fl_str_mv Fundação Oswaldo Cruz
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
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