Radicals of Nitroimidazole Derivatives: pH Dependence of Rates of Formation and Decay Related to Acid-base Equilibria

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Abstract
Three analogous 5-nitroimidazoles, having radiosensitizing and cyotoxic properties, have been studied by pulse-radiolysis in N2O-saturated aqueous formate solutions. Rates of formation of the radicals Im are found to have little pH dependence. Decay of the radicals always follows second-order kinetics. The observed rates of decay decrease by three to four orders of magnitude over the pH range 0–12. A pK at 2·3 has been observed kinetically for metronidazole. The pK assigned to the radical couple (ImH)NO2H·/(ImH)- , or alternatively (ImH+2)- /(ImH)- , varies from 4·7 to 6·1, depending on the substituents on the imidazole ring. Intrinsic second-order rate constants for decay of the acidic form of the radical, of the anionic form and of the mixed reactions were determined. While the anionic radical reacts slowly with itself, both the acidic radical self-reaction and the mixed reaction proceed at fast rates. The implications of these chemical properties to the mechanisms of radiosensitization and cytoxicity of the nitroaryl compounds are briefly discussed.