Products of the Reductions of 2-Nitroimidazoles

Article abstract of DOI:10.1021/ja00248a028

Reductions under neutral conditions of misonidazole (1-(2'-hydroxy-3'-methoxypropyl)-2-nitroimidazole) and 1-methyl-2-nitroimidazole have been studied with radiation chemical, electrochemical, and chemical (zinc/ammonium chloride) techniques.Major products accounting for 70-80percent of the reduction mixture have been identified as the cis:trans isomers of 4 (1-substituted 2-amino-4,5-dihydro-4,5-dihydroxyimidazolium ions).These have been independently synthesized by the reaction of glyoxal and the appropriate guanidinium ion.Their presence after nitroreduction has been established by 1H NMR and by spectroscopic analysis in which 4 is converted into glyoxal bis-oxime.The ability of misonidazole reduction mixtures to form glyoxal derivatives has been noted previously, even in vivo; the presence of the cyclic 4 accounts for this.The four-electron-reduced product, a 2-(hydroxylamino)imidazole, is the precursor of 4.The hydroxylamine is unstable at pH 7, but it can be observed in acid where decomposition also gives 4 but in a much slower reaction.Nitroreduction or hydroxylamine decomposition in pH 7 phosphate gives two additional products which have been identified on the basis of their 1H NMR spectra as cis:trans isomers of monophosphate esters of 4.The reaction leading to these may model the DNA binding which is observed with reduced misonidazole.Azomycin (2-nitroimidazole) has been investigated by the radiation chemical technique.At pH 7 the isomers of 4 are formed, but they are minor products.The major product (70percent) is 2-aminoimidazole.