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...

Inhibitors of the ubiquitin-proteasome system improve hemodynamic parameters and decrease the infarct size after ischemia reperfusion. The molecular basis of this protection is not fully understood since most available data report inhibition of the 26 proteasome after ischemia reperfusion. The decrease in cellular ATP levels during ischemia leads to the dissociation of the 26S proteasome into the 19S regulatory complex and the 20S catalytic core, which results in protein degradation independently of ubiquitination. There is scarce information on the activity of the 20S proteasome during cardiac ischemia. Accordingly, the aim of this work was to determine the effects of 30 minutes of ischemia, or 30 min of ischemia followed by 60 minutes of reperfusion on the three main peptidase activities of the 20S proteasome in Langendorff perfused rat hearts. We found that 30 min of ischemia produced a significant increase in the chymotrypsin-like activity of the proteasome, without changes in its caspase-like or trypsin-like activities. In contrast, all three activities were decreased upon reperfusion. Ixazomib, perfused before ischemia at a concentration that reduced the chymotrypsin-like activity to 50% of the control values, without affecting the other proteasomal activities, improved the hemodynamic parameters upon reperfusion and decreased the infarct size. Ixazomib also prevented the 50% reduction in RyR2 content observed after ischemia. The protection was lost, however, when simultaneous inhibition of chymotrypsin-like and caspase-like activities of the proteasome was achieved at higher concentration of ixazomib. Our results suggest that selective inhibition of chymotrypsin-like activity of the proteasome during ischemia preserves key proteins for cardiomyocyte function and exerts a positive impact on cardiac performance after reperfusion.

The electrochemical reduction of 1-methyl-4-nitro-2-carboxyimidazole (RNnormalO2COOH) in a nonaqueous medium produced two reduction signals, which were influenced by the dissociation of the compound. The first reduction signal was caused by the reduction of the acidic species, and the second signal was a quasi-reversible couple caused by the reduction of the conjugate base to the radical dianion. According to the theory developed by Nicholson for the study of the electrode reaction kinetics, we have obtained the heterogeneous rate constant, k0=(9.74±0.052)×10−3cmnormals−1 , for the reduction of the conjugate base to the radical dianion. The voltammetric behavior of RNnormalO2COOH and its comparison with the behavior of another related compound such as 1-methyl-4-nitro-2-hydroxymethylimidazole is a good example to show the applicability of the general theory about the mechanism of self-protonation reactions in organic electrochemical processes to the specific case of nitroimidazole derivatives. According to the presented results, the presence of acidic hydrogen as a substituent in the nitroimidazole moiety would permit the modulation of the nitro radical anion stability, thus affecting its potential biological activity.