Voltammetric Behavior of a 4-Nitroimidazole Derivative

Abstract

A new synthesized compound, 1-methyl-4-nitro-2-hydroxymethylimidazole ͑4-MNImOH͒, was electrochemically reduced at the mercury electrode in aqueous, mixed, and aprotic media. In an aqueous medium, only one voltammetric peak was observed because of the four-electron, four-proton reduction of the nitro group to the hydroxylamine derivative in the 2-12 pH range. For the mixed and nonaqueous media, it was possible to observe a reversible couple due to the first one-electron reduction step of the nitro group to the nitro radical anion.The nitro radical anion decays by a disproportionation reaction in mixed media and by dimerization in a nonaqueous medium. Both disproportionation and dimerization rate constants, k 2 , were determined according to Olmstead's approach, obtaining a value of 1460 ± 110 M −1 s −1 in aprotic medium. In mixed media, the values were dependent both on pH and on the nature of the cosolvent.After comparison of 4-MNImOH with the parent compound, 4-nitroimidazole, we concluded that the substitution with 1-methyl and 2-hydroxymethyl produces a more easily reducible nitro compound and a less stable nitro radical anion than the unsubstituted 4-nitroimidazole. According to the electrochemical results, the 4-MNImOH derivative would be more suitable for enzymatic reduction and less toxic to the host than 4-nitroimidazole.In the last decades, nitroimidazoles have been the source of many investigations because of their properties as antibiotics, radiosensitizers, and antiprotozoans. 1-3 The biological activity of nitroimidazoles is dependent on the nitro group reduction process due to the formation of active intermediate species that interact with DNA and cause biochemical damage. The reduction of these compounds can follow two different routes depending on whether the medium is aerobic or anaerobic, 4,5 however, both routes share a common first step, i.e., the one-electron reduction of the nitro group to form the nitro radical anion ͑RNO 2 •− ͒. Consequently, RNO 2 •− is a key intermediate in the biological activity, and the understanding of its behavior is a permanent challenge for these type of compounds.Three types of nitroimidazole derivatives have been currently used, namely, 2-, 4-, and 5-nitrosubstituted derivatives; however, there are still no conclusive results about the incidence of the nitro substitution in their biological activity. A study on the reduction of 2-, 4-and 5-nitroimidazole drugs by hydrogenase 1 in Clostridium pasteurianum 6 revealed that the rate of reduction of the nitroimidazole compounds correlated with their one-electron reduction potential. However, the reduction rates for the drugs did not correlate with the antibacterial activity against Clostridium pasteurianum, suggesting that other factors are also important for determining the antimicrobial potencies of these compounds. Another study on the activity of nitroimidazoles against Trichomonas vaginalis 7 revealed that the potency of this activity follows the order 5-nitroimidazole Ͼ 2-nitroimidazole Ͼ 4-nitroimidazole. How...

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“…In the Figure 2B, the Ep vs. pH plot shows that the peak potential is pH-dependent shifting to more negative potentials when pH increased. From these results we can observe that the obtained Ep values are very similar with the previously reported 21 for other 4-nitroimidazole analogue permitting to conclude that the change in the 2-position substitution did not change the reduction of the 4-nitroimidazole moiety. Furthermore from the comparison of the peak potentials between Hg and GCE we can assume that the reduction of nitroimidazole derivative is favoured on Hg.…”

“…According to the well-known mechanism of 4-nitroimidazole derivatives 20, 21 we can assume that the observed irreversible peak in all the pH range is due to the four-electron, fourproton reduction of the nitroimidazole group to yield the hydroxylamine derivative according to the following overall reaction:…”

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“…Another probable redox pathways for the studied molecules is conversion of the nitro group on the imidazolyl rings to NH 2 , NO, or NHOH. Experimental electrochemical studies on the nitroimidazolyl compounds also indicated the reduction of NO 2 functional group to nitro radical anion, nitroso, hydrohxylamine, and amine (36)(37)(38). Moreover, Metabolism study of 5-nitroimidazole in susceptible and resistant isogenic strains of Bacteroides fragilis by Carlier et al revealed the reduction of NO 2 functional group (39).…”

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“…[28][29][30][31] In the first pathway (Equation (4) and (5)), reversible formation of one-electron nitro radical anion is followed by irreversible three-electron reduction. As the stability of ArNO 2 · is increased by the absence of In the second possible pathway (Equation (6) and (7)), four-electron reduction of NO 2 to NHOH (Equation (6)) and two-electron reduction of NHOH to NH 2 (Equation (7)) takes place.…”