5-Nitroimidazoles. II: Unexpected reactivity of ronidazole and dimetridazole with thiols

Abstract

Ronidazole and dimetridazole, two important veterinary drugs, were found to react readily in the presence of cysteine, under neutral aqueous conditions, leading to the formation of 5-S-cysteinyl-1-methylimidazole-2-methanol carbamate and 5-S-cysteinyl-1,2-dimethylimidazole respectively through nitro displacement. The reaction products were identified by spectroscopic techniques. The rate of reaction was accelerated by increasing the pH of the medium and was accompanied by a slight change in the product distribution. The reaction was also observed, albeit at a slower rate than that of cysteine, with glutathione, another ubiquitous thiol substrate found in biological systems. While this type of nucleophilic reaction has previously been observed for suitably substituted nitrobenzene derivatives, to the best of our knowledge its occurrence with nitro-heteroaromatics has never been reported. The ready reaction of the parent nitro drugs under such mild aqueous conditions suggests that this may be an alternative path for the formation of nonextractable bound residues in tissues.