title: Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group.
abstract: Nitroimidazoles exhibit high microbicidal activity, but mutagenic, genotoxic and cytotoxic properties have been attributed to the presence of the nitro group. However, we synthesised nitroimidazoles with activity against the trypomastigotes of Trypanosoma cruzi, but that were not genotoxic. Herein, nitroimidazoles (11-19) bearing different substituent groups were investigated for their potential induction of genotoxicity (comet assay) and mutagenicity (Salmonella/Microsome assay) and the correlations of these effects with their trypanocidal effect and with megazol were investigated. The compounds were designed to analyse the role played by the position of the nitro group in the imidazole nucleus (C-4 or C-5) and the presence of oxidisable groups at N-1 as an anion receptor group and the role of a methyl group at C-2. Nitroimidazoles bearing NO2 at C-4 and CH3 at C-2 were not genotoxic compared to those bearing NO 2 at C-5. However, when there was a CH3 at C-2, the position of the NO2 group had no influence on the genotoxic activity. Fluorinated compounds exhibited higher genotoxicity regardless of the presence of CH3 at C-2 or NO2 at C-4 or C-5. However, in compounds 11 (2-CH3; 4-NO2; N-CH2OHCH2Cl) and 12 (2-CH3; 4-NO2; N-CH2OHCH2F), the fluorine atom had no influence on genotoxicity. This study contributes to the future search for new and safer prototypes and provide.
authors.affiliation: Departamento de Síntese de Fármacos, Farmanguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Núbia
authors.initials: N
authors.lastname: Boechat
authors.affiliation: Departamento de Síntese de Fármacos, Farmanguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Alcione S
authors.initials: AS
authors.lastname: Carvalho
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Kelly
authors.initials: K
authors.lastname: Salomão
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Solange L de
authors.initials: SL
authors.lastname: Castro
authors.affiliation: Departamento de Biofísica e Biometria, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Araujo-Lima
authors.affiliation: Departamento de Biofísica e Biometria, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
authors.forename: Francisco V C
authors.initials: FV
authors.lastname: Mello
authors.affiliation: Departamento de Biofísica e Biometria, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
authors.forename: Israel
authors.initials: I
authors.lastname: Felzenszwalb
authors.affiliation: Departamento de Genética e Biologia Molecular, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
authors.forename: Claudia A F
authors.initials: CA
authors.lastname: Aiub
authors.affiliation: Departamento de Farmacologia e Toxicologia, Instituto Nacional de Controle de Qualidade em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Taline Ramos
authors.initials: TR
authors.lastname: Conde
authors.affiliation: Departamento de Farmacologia e Toxicologia, Instituto Nacional de Controle de Qualidade em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Helena P S
authors.initials: HP
authors.lastname: Zamith
authors.affiliation: Organisch-Chemisches Institut, Westfälischen Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Skupin
authors.affiliation: Organisch-Chemisches Institut, Westfälischen Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Haufe
mesh_terms: D000818:Animals; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009152:Mutagenicity Tests; D009593:Nitroimidazoles / Q000737:chemistry* / Q000633:toxicity*; D012475:Salmonella / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D009593:Nitroimidazoles