Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group

Nitroimidazoles exhibit high microbicidal activity, but mutagenic, genotoxic andcytotoxic properties have been attributed to the presence of the nitro group.However, we synthesised nitroimidazoles with activity against the trypomastigotes ofTrypanosoma cruzi, but that were not genotoxic. Herein,nitroimidazoles (11-19) bearing different substituent groups were investigated fortheir potential induction of genotoxicity (comet assay) and mutagenicity(Salmonella/Microsome assay) and the correlations of theseeffects with their trypanocidal effect and with megazol were investigated. Thecompounds were designed to analyse the role played by the position of the nitro groupin the imidazole nucleus (C-4 or C-5) and the presence of oxidisablegroups 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 tothose bearing NO₂ at C-5. However, when there was a CH3at 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 CH3at 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 ongenotoxicity. This study contributes to the future search for new and saferprototypes and provide.