Nitrosoimidazoles: highly bactericidal analogues of 5-nitroimidazole drugs

Abstract

It is believed that metronidazole and related 5-nitroimidazoles are activated by reduction of the nitro group and that the active species has a nitrogen functionality of intermediate oxidation state. However, the preparation and isolation of the active forms of the 5-nitroimidazoles used therapeutically have proven elusive. To pursue this problem we have prepared both 1-methyl-4-phenyl-5-nitrosoimidazole (3) and 1-methyl-4-nitroso-5-phenylimidazole (5) from 4(5)-nitroso-5(4)-phenylimidazole (1). We have also prepared the homologous nitroimidazoles. Escherichia coli mutants with defects in DNA repair were found to be sensitive to both 1-methyl-4-phenyl-5-nitroimidazole (4) and metronidazole, but fairly resistant to 1-methyl-4-nitro-5-phenylimidazole (6), a finding in accord with the relative biological activity of 4- and 5-nitroimidazoles examined previously. In contrast, all three nitroso compounds are considerably more bactericidal than their analogous nitro compounds under both aerobic and anaerobic conditions, a finding that provides direct evidence that reduction of the nitro group is responsible for activation of the nitroimidazoles. Further evidence is also consistent with the possibility that the nitrosoimidazoles are themselves biologically active species derived from nitroimidazoles, although a more conservative interpretation is simply that they are more facilely converted to such active species.