Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity

Abstract

Nitroaromatic compounds (ArNO2) maintain their importance in relation to industrial processes, environmental pollution, and pharmaceutical application. The manifestation of toxicity/therapeutic action of nitroaromatics may involve their single- or two-electron reduction performed by various flavoenzymes and/or their physiological redox partners, metalloproteins. The pivotal and still incompletely resolved questions in this area are the identification and characterization of the specific enzymes that are involved in the bioreduction of ArNO2 and the establishment of their contribution to cytotoxic/therapeutic action of nitroaromatics. This review addresses the following topics: (i) the intrinsic redox properties of ArNO2, in particular, the energetics of their single- and two-electron reduction in aqueous medium; (ii) the mechanisms and structure-activity relationships of reduction in ArNO2 by flavoenzymes of different groups, dehydrogenases-electrontransferases (NADPH:cytochrome P-450 reductase, ferredoxin:NADP(H) oxidoreductase and their analogs), mammalian NAD(P)H:quinone oxidoreductase, bacterial nitroreductases, and disulfide reductases of different origin (glutathione, trypanothione, and thioredoxin reductases, lipoamide dehydrogenase), and (iii) the relationships between the enzymatic reactivity of compounds and their activity in mammalian cells, bacteria, and parasites.

Synthesis, in vitro Antitrichomonal Activity, and Docking Study of N-[(4-substituted phenyl)-1,3-thiazol-2-yl]-4-substituted Benzenesulfonamides

“…13 C NMR (100 MHz, DMSO-d 6 ) δ 168.8 (C-2´´), 142.2 (C-4´´), 136.7 (C-1´), 132.2 (C-4´), 129.2 (C-4´´´), 129.1 (C-3´, C-5´), 129.0 (C-3´´´, C-5´´´), 128.7 (C-1´´´), 125.9 (C-2´, C-6´), 125.6 (C-2´´´, C-6´´´), 103.5 (C-5´´). MS (EI, 70 eV): 316 [M + ] (100), 285 (2), 251 (4), 175 (30), 134 (22), 77 (16), 18 (5) m/z. [25]: Yield 30 %.…”

Roles of Ferredoxin-NADP+ Oxidoreductase and Flavodoxin in NAD(P)H-Dependent Electron Transfer Systems

“…Cytosolic FAD-containing NAD(P)H-quinone oxidoreductase (NQO1), also known as DT-diaphorase, catalyzes the obligatory two-electron reduction of quinones including benzoquinone and naphthoquinone [ 16 , 17 , 18 , 20 , 93 ]. This enzyme also catalyzes the reduction of nitroaromatic compounds [ 94 ], but its activity is very low, suggesting that the latter substrates are not fitted in an optimal position to receive a hydride from reduced FAD. The most striking feature of NQO1 is its common flavodoxin-like topology within the catalytic domain (residues 1–220) [ 95 ].…”

Exploration of ethylene glycol linked nitrofurantoin derivatives against Leishmania: Synthesis and in vitro activity

“…Nitroreduction can occur in the presence of oxygen (type II) or in the absence of oxygen (type I). [ 15 ] These reactions result in the formation of toxic species such as hydroxylamine, nitroso intermediates, and reactive oxygen/nitrogen (RON) free radicals that can bind to microbial DNA and other biological molecules, and ultimately lead to pathogen death. [ 12 ]…”

“…Nitroreduction can occur in the presence of oxygen (type II) or in the absence of oxygen (type I). [15] These reactions result in the formation of toxic species such as hydroxylamine, nitroso intermediates, and reactive oxygen/nitrogen (RON) free radicals that can bind to microbial DNA and other biological molecules, and ultimately lead to pathogen death. [12] Additionally, cNFs possess a second pharmacophore, the hydrazone moiety (Figure 1 in blue), containing a zwitterionic carbon that stabilises the nitrofuran ring (Figure 1 in red).…”