Abstract
Nitroaromatic antibiotics show activity against anaerobic bacteria and parasites, finding use in the treatment of Heliobacter pylori infections, tuberculosis, trichomoniasis, human African trypanosomiasis, Chagas disease and leishmaniasis. Despite this activity and a clear need for the development of new treatments for these conditions, the associated toxicity and lack of clear mechanisms of action have limited their therapeutic development. Nitroaromatic antibiotics require reductive bioactivation for activity and this reductive metabolism can convert the nitro group to nitric oxide (NO) or a related reactive nitrogen species (RNS). As nitric oxide plays important roles in the defensive immune response to bacterial infection through both signaling and redox-mediated pathways, defining controlled NO generation pathways from these antibiotics would allow the design of new therapeutics. This review focuses on the release of nitrogen oxide species from various nitroaromatic antibiotics to portend the increased ability for these compounds to positively impact infectious disease treatment.
Highlights
1.1.IntroductionNitroaromatic compounds contain or nitro moregroups nitro directly groups bonded directlytobonded to Nitroaromatic compounds contain one orone more an aromatic group (Figure 1) [1]. aromatic groupNitrogen Oxide Sources
This review focuses on the release of nitrogen oxide species fr pathways, defining controlled nitric oxide (NO) generation pathways from these antibiotics would allow the various nitroaromatic antibiotics to portend the increased ability for these compounds to positiv design of new therapeutics
Dependence that lead to a plausible mechanistic proposal of direct thiol addition to the nitroimidazole forming a Meisenheimer-type complex that liberates nitrous acid while restoring aromaticity [43]. These results clearly show direct nitrogen oxide release from metronidazole in the form of NO2− and define a substitution mechanism that does not these nitroaromatic antibiotics
Summary
Nitroaromatic compounds contain or nitro moregroups nitro directly groups bonded directlytobonded to Nitroaromatic compounds contain one orone more an aromatic group The uncoupling of NADPH-derived reducing equivalents from normal nitroso species or react with oxygen to give the nitroaromatic compound and the reactive metabolism or the formation of reactive radical, nitroso or hydroxylamine intermediates, superoxide anion (Scheme 1). The uncoupling of NADPH-derived reducing equivalents which can react with other biomolecules, provides a potential mechanism for nitroaromatic from normal metabolism or the of formation of reactive nitroso or hydroxylamine antibiotics activity. Nitro group reductive metabolism with nitrogen oxide release defines nitroaromatic antibiotics as prodrugs increasing the likelihood of identifying active non-toxic lead compounds [1,4]. Nitronate anion hydrolysis would yield HNO (Nef reaction) and a lactam-like derivative (Scheme 2, Path A) These reactions produce nitrogen oxides from nitro aromatic compounds through direct nucleophilic addition without a nitro group reduction. Other reviews focus on nitroaromatic antibiotic drug developm or clinical treatment of TB and other infectious diseases [3,30,31]
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