Nitroimidazoles Subject

Methyl-substituted nitrodiazoles (nitropyrazoles and nitroimidazoles) in which the substituents occupy adjacent positions in the cycle are subject to several ortho effects [1283, 1284], The latest are useful in structure determination and isomer recognition of compounds. These effects are attributed to interaction of the substituents only. As a result, in some cases loss of OH and H20 [1283], and CHO and CH20 [1284] is observed. The way by which loss of H20 in 3(5)-nitro-4-meth-ylpyrazole occurs is shown in Scheme 3.52 [1283] ... 

When nitroimidazoles and -benzimidazoles are subjected to electrochemical reduction, the initially formed unstable radical anions subsequently decompose with elimination of hydrogen. Thus, in acetonitrile, 2-substituted 5(6)-nitrobenzimidazoles generate hydrogen as a result of bimolecular reaction of two primary radical anions <85CHE688>. 

Imidazoles with a ring iV-hydrogen are subject to tautomerism, which becomes evident in unsymmetri-cally substituted compounds such as the methylimidazole shown. This special feature of imidazole chemistry means that to write simply 4-methylimidazole would be misleading, for this molecule is in rapid tautomeric equilibrium with 5-methylimidazole. All such tautomeric pairs are inseparable and the convention used to cover this phenomenon is to write 4(5)-methylimidazole . In some pairs, one tantomer predominates, for example 4(5)-nitroimidazole favours the 4-nitro-tautomer by 400 1. 

Metronidazole, at least in part, is subject to reductive metabolism by rat liver microsomes and it is believed that short-lived highly reactive metabolites may be responsible for the genotoxic effects, a phenomenon that might then be extended to other nitroimidazoles. Unfortunately, like the nitrofurans (see Chapter 8), these studies have proved inconclusive. Although the nitroimidazoles are reactive, or are converted to reactive metabolites which then bind covalently to cellular macromolecules, it has not been possible to prove that the bound residues cannot be released as potentially toxic materials following... 

---