The development of 5-nitroimidazoles for the treatment and prophylaxis of anaerobic bacterial infections

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Abstract
The nitroimidazoles have a wide range of biological properties that provide an increasing number of therapeutic applications. Some properties are common to all nitroimidazoles whereas others are characteristic only of certain compounds. Considerable insight may be gained into the mechanism of action of the nitroimidazoles by seeking correlations between their chemical and biological properties. Thus the reduction potential of the nitro group of a nitroimidazole tends to correlate with its relative potency as a mutagen, cytotoxin, or radiation sensitizer. The apparent obligatory rule of nitro group reduction for biological activity explains why 5-nitroimidazoles such as tinidazole and metronidazole exhibit selective toxicity for anaerobic micro-organisms. Such organisms would be expected to carry out more readily the reduction that is necessary to activate the nitroimidazole. Furthermore, anoxic conditions favour nitroimidazole activity because oxygen interferes with nitro group reduction and thus the formation of the postulated reactive form of the nitroimidazole. By changing the chemical substituents at the 1-and 2-positions of a 5-nitroimidazole one may alter both its microbiocidal activity spectrum and its human pharmacokinetic properties. The result may be a drug that improves the treatment of trichomoniasis, amoebiasis, or giardiasis, or the treatment or prophylaxis of anaerobic bacterial infections. Alternatively, structural modifications of the 5-nitroimidazoles may yield drugs with activity against a broader range of protozoal and bacterial infections.

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