Radiation-induced reduction of nitroimidazole derivatives in aqueous solution

The radiation-induced reduction of N1-alkyl substituted 2- and 5-nitroimidazoles in aqueous solution containing sodium formate or 2-propanol was studied at pH 7.0 +/- 0.1 under deaerated conditions. Irrespective of 2- or 5-nitroimidazole, N1-unsubstituted nitroimidazoles (2-nitro-(1a), 4(5)-nitro-(2a), 2-methyl-4(5)-nitro (3a), and 4(5)-methyl-5(4)-nitro- (4a) imidazoles) were reduced stepwise to consume 6 electrons per molecule, whereas N1-alkyl substituted nitroimidazoles (1-methyl-2-nitro (5a) and 1-methyl-5-nitro (6a) imidazoles, misonidazole (7a), and metronidazole (8a] reacted with consumption of 4 electrons. In accord with the stoichiometry for the reduction of N1-unsubstituted nitroimidazoles, the formation of the amino derivatives of (1a)-(4a) was shown by HPLC or colour identification tests. 4-Electron-reduction products of N1-alkyl substituted 2-nitroimidazoles (5a) and (7a) were characterized by 13C and 1H n.m.r. and FDMS measurements, indicating that the hydroxyamino derivative of (5a) as a 4-electron-reduction product isomerizes to an oxime form. The formation of an analogous oxime-type product was also suggested for (7a) together with a product bearing the partially cleaved imidizole ring. The HPLC analysis showed that 4-electron-reduction products of N1-alkyl substituted 5-nitroimidazoles (6a) and (8a) are unstable relative to those of the corresponding 2-nitroimidazoles (5a) and (7a).