An investigation into the mechanism of action of nitroimidazole antibiotics

The three most likely intermediates in the mechanism of action of 5-nitroimidazole antibiotics (the radical anions of nitroimidazoles, imidazol-5-yl radicals and 5-nitroso imidazoles) have been studied. A range of 5-nitroimidazoles have been synthesised and analysed by electron spin resonance spectroscopy, (e.s.r.) and the electron spin density of their radical anions has been determined. Under reducing conditions known to proceed by a radical mechanism, a number of 5-nitroimidazoles did not undergo intramolecular cyclisation, [e.g. 1-(but-3-en-1- yl)-2-methyl-5-nitroimidazolel, form stable covalent adducts with nucleotide bases, or dissociate to nitrite anions and the corresponding imidazol-5-yl radicals. This disproves the putative explanation for the generation of nitrite anions in the antimicrobial mode of action of 5- ni troimidazoles. A mechanism has been proposed to explain the release of nitrite in the mechanism of action of 5-nitroimidazoles [continued]…