3- Nitrofurans, reduction

Aminofurans cannot be prepared by reduction of 2-nitrofurans or by hydrolysis of 2-acetamidofurans. The latter are prepared by the reduction of 2-nitrofurans in the presence of acetic anhydride. Benzofuranone (161) and not 2-aminobenzofuran is obtained from tin and hydrochloric acid reduction of 2-nitrobenzo[h]furan (160). 

Type 1 are 02-insensitive six-electron reductases that catalyze the sequential reduction of nitroarenes to nitroso, hydroxylamino, and amino arenes. They are encoded in E. coli by NfsA for the major enzyme and NfsB for the minor (Rau and Stolz 2003), and are also important in establishing resistance to nitrofuran drugs (Koziarz et al. 1998). 

Nitrotoluenes including 2,4,6-trinitrotoluene (TNT) are important components of explosives and several nitroarenes including the antibacterial nitrofurans have established mntagenicity (Purohit and Basu 2000). Substantial effort has been directed to the degradation of nitroarenes, and to their reduction to amines. Although nitroarene reductases, noted in Chapter 3, Part 3, are distribnted in a range of biota, the products may not necessarily represent intermediates in the degradation... 

Interestingly, the photoreaction of indene with nitroarenes gives good yields of coupling products as shown in equation 62 (66% from 2-nitrothiophene and 52% from 2-nitrofurane). Nitrobenzene gives the reduction product. Strangely there is no reaction for p-nitrotoluene with indene. 

A number of 5-nitro-2-furaldehyde derivatives, called nitrofurans, are used in the treatment and/or prophylaxis of microbial infections, primarily in the urinary tract. Recent evidence suggests that the reduction of the 5-nitro group to the nitro anion results in bacterial toxicity. Intermediate metabolites modify various bacterial macromolecules that affect a variety of biochemical processes (e.g., DNA and RNA synthesis, protein synthesis) this observation may explain the lack of resistance development to these drugs. Evidence also indicates that the nitro anion undergoes recycling with the production of superoxide and other toxic oxygen compounds. It is presumed that the nitrofurans are selectively toxic to microbial cells because in humans, the slower reduction by mammalian cells prevents high serum concentrations. 

Moreno SN, Mason RP, Docampo R (1984) Distinct reduction of nitrofurans and metronidazole to free radical metabolites by Tritrichomonas foetus hydrogenosomal and cytosolic enzymes. J Biol Chem 259 8252-8259... 

On the other hand, the type of the packaging material did not exert any effect on tire residue levels at a storage temperature of 20 C. At 4 C, nitrofuran residues remained stable when the egg samples were stored in glass or polypropylene tubes, but a loss of 60-70% was observed when a laminated foil was used. At 20 C, all four nitrofurans exhibited marked residue reduction, the losses being 30-50% for glass tubes, 40-60% for polypropylene tubes, and 100% for laminated foil. 

The enteric bacterium Enterobacter cloacae produces a nitroreductase that reduces nitrofurans, nitroimidazoles, nitrobenzene derivatives, and quinones (Bryant DeLuca, 1991). This oxygen-insensitive enzyme has been purified and is known to require FMN to transfer reducing equivalents from NAD(P)H to the nitroaromatic compounds, TNT being the preferred substrate. Aerobically, this enzyme reduces nitrofurazone through the hydroxylamine intermediate, which then tautomerizes to yield an oxime end-product. Anaerobically, however, the reduction proceeds to the fully reduced amine adduct. When E. cloacae was grown in the presence of TNT, the nitroreductase activity increased five- to tenfold. 

Few simple amines are known in either the furan or the benzo[Z>]furan series. Simple nitrofurans on attempted reduction by mild chemical methods suffer what is probably a deaminative degradation. Similarly, attempted reduction of 2-nitrobenzo[6]furan affords not the amine but the product of its hydrolysis, benzofuran-2(3/f )-one. 

Electron spin resonance (ESR) spectroscopy reveals that an increase in the electron-donating ability of substituents in the 2-position of the furan ring produces an increase in the spin density at the 3-position and a decrease at the 4-position the coupling constants in the ESR spectra of anion radicals generated by electrochemical reduction of 2-substituted 5-nitrofurans equate to o values.295... 

Both 2- and 3-nitrothiophenes are reduced by tin and hydrochloric acid to the corresponding aminothiophenes. Reduction of 2,5-dibromo-3,4-dinitrothiophene gives 3,4-diaminothiophene as a stable crystalline solid. 2-Acetamido-furans are prepared by the reduction of 2-nitrofurans in the presence of acetic anhydride. 2-Substituted 5-nitrofurans can be reduced to the S-aminofurans by an electrochemical method. Although catalytic reduction gives 2-aminofurans only in low yields, they can be trapped using ethyl ethoxymethylenecyanoacetate or ethoxymethylenemalononitrile. Benzofuranone 412 and not 2-aminobenzofuran is obtained from tin and hydrochloric acid treatment of 2-nitrobenzo[ ] furan 411. 

Polarographic reduction of a nitro group at the 2-position showed96 that 2-nitrofuran was the easiest to reduce, while 2-nitrothiophene and 2-nitroselenophene required 20-30 mV, and nitrobenzene 40 mV higher potential. The reduction potentials of the five-membered heterocyclic isologs may increase with a decrease in electron shifts produced by the lone-pair of the heteroatom in the series 0 > S > Se. Hence, in its polarographic behavior 2-nitroselenophene is closer to nitrobenzene than to nitrofuran. 

In addition to the ESR work noted previously, Soviet groups have investigated the polarographic properties of nitrofurans, elucidating the mechanisms by which anion-radicals are formed, and their reactions, (e.g., acid-base equilibria and those which destroy the radicals), and the relationships of these properties to medium effects, ESR phenomena, and substituent character. Kemula and Zawadowska have reported a cyclic chronovoltammetric investigation of the reduction mechanism of 2-nitrofuran and various derivatives. 

All the evidence reviewed above points to an interesting possibility that the primary action of metronidazole and nitrofurans in T. vaginalis may be the inhibition of synthesis of proteins. Whether reduction of the nitro group is the prerequisite for this activity remains to be seen. 

A number of studies in this area have been prompted by interest in the antibacterial activity of hydrazone derivatives of 5-nitrofurfuraldehyde having the general structure 33 (R1 = CH = N-NR2, R3 = R4 = H). The antibacterial activity, and associated carcinogenic and mutagenic activities, of these 2-nitrofurans are related to reduction of the nitro group, which has led to chemical studies of the reductive process (Table 5). Early work on the reduction of 2-nitrofurans has previously been reviewed (74H391). 

The parent 2-aminofuran 103 is extremely unstable but when generated in situ, by catalytic reduction of 2-nitrofuran, and immediately reacted with the electrophiles ethoxymethylene malononitrile (EMMN) and ethyl ethoxymethylenecyanoacetate (EMCA) the 5-substitution products 104 were formed in low yield (Eq. (16)) (93JHC113). If the 5-position is blocked as in the case of the 5-methyl derivative 105, or 2-aminobenzo[Z>]furan, then substitution occurs at position 3, e.g. 106 (Eq. (17)) (93JHC113). 

Little has been reported on the reduction of 3-nitrofurans to the amines. An early report (34MI13) described the reduction of the derivative 186 to ethyl 2-acetamido-3-amino-5-furoate 187 in 10% yield using Pt02/H2 in ethanol (Eq. (31)). Reduction of a 2-alkenyl derivative using H2 and Raney nickel has been described more recently but the product was not characterised (98H1431). 

The reduction of nitrofurans leading to the generation of ROS takes place... 

Olea-Azar, C., Rigol, C., Mendizabal, F., MoreUo, A., Maya, J.D., Moncada, C., Cabrera, E., Di Maio, R., Gonzalez, M., and Cerecetto, H. (2003). ESR spin trapping studies of free radicals generated from nitrofuran derivative analogues of nifurtimox by electrochemical and Trypanosoma cruzi reduction. Free Radic Res 37, 993-1001. 

Medicinal chemists have tended to avoid the aromatic nitro group as a structural component of potential drugs because of the well-known ability of compounds such as trinitrotoluene (TNT), used in munitions, to cause a high incidence of methemoglobinemia following skin absorption. The mechanism involved is presumably in vivo reduction to nitroso and phenyl-hydroxylamine intermediates. However, many nonbenzenoid nitro compounds have been utilized in clinical practice since the introduction of the nitrofuran drugs in 1944. 

The nitroaromatic compounds such as the nitrofurans are known to be activated by a bacterial nitroreductase system in susceptible microorganisms. Intermediate, highly reactive species such as free radicals produced during the reduction process are likely responsible for damage to DNA strands that lead to bacterial and protozoal cell death. Thus a reduced nitroaryl anion radical could be oxidized by 02 to produce superoxide anions (Eq. 7.3). Under the influence of superoxide dismutase (SOD) (Chapter 4) hydrogen peroxide can be produced (Eq. 7.4), which, in turn, interacts with additional superoxide anion radical, producing ionizing toxic hydroxyl radicals (Eq. 7.5). 

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