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PubMedDate not supplied

Comparative physiological disposition of two nitrofuran anti-microbial agents.

The physiological disposition of two nitrofuran derivatives used as antimicrobial agents for the treatment of acute infectious diarrhoea was evaluated in humans and animals. Upon administration of a single oral dose (600 mg) of nifurzide or nifuroxazide, no unchanged parent drug was detected in human blood or urine. In rats given 14C-nifurzide and 14C-nifuroxazide at a dose of 10 mg kg-1, 5 per cent and 17 per cent of the dose of nifurzide and nifuroxazide, respectively, were excreted in urine over a 48-hour period. None of this radioactivity was present as unchanged drug, indicating that renal excretion of both drugs occurs as metabolites. In the faeces 20 per cent of the radioactivity recovered was associated with unchanged nifuroxazide as compared with 100 per cent for nifurzide. Whole body autoradiography using rats showed that after oral administration of 14C-nifurzide and 14C-nifuroxazide, most of the radioactivity remained in the gastrointestinal lumen.

Adult↗
PubMed1981

Genetic analysis of ad-3 mutants induced by AF-2 and two other nitrofurans in Neurospora crassa.

Our previous studies have shown that the nitrofurans AF-2, SQ18506, and FANFT are potent mutagens in Neurospora crassa. The genetic damage produced by these chemicals at the ad-3 region in N crassa has been characterized by a series of genetic tests. The results of these tests indicate that all three agents induce a high frequency of point mutations and probably a low frequency of multilocus deletions. A comparison of the complementation patterns among the AF-2--induced ad-3B mutants and those induced by other chemical agents indicates that the spectra of intragenic alterations induced by AF-2 in N crassa are similar to those induced by monofunctional alkylating agents.

5-Amino-3-((5-nitro-2-furyl)vinyl)-1,2,4-oxadiazol↗
PubMed1979

Detection of the carcinogenic nitrofuran derivative VR-6 as a mutagen in the Salmonella/microsome test.

The carcinogenic nitrofuran, VR-6, was evaluated for mutagenicity in Salmonella typhimurium TA 100 using the plate assay (Ames test). The dose-response curve indicated that S. typhimurium TA 100 is a very sensitive genetic indicator for this chemical class and that basepair substitution appears to be the molecular mechanism with VR-6. The results reported here provide evidence, that VR-6 is a directly acting mutagen for S. typhimurium TA 100 and that the chemical is partially deactivated in the presence of rat liver homogenates. Comparison of the results obtained with this agent in the Ames test with data from a subacute animal study, showed a good agreement in predicting the carcinogenic risk.

Animals↗
PubMed1984

Formation of novel nitrofuran metabolites in xanthine oxidase-catalyzed reduction of methyl 5-nitro-2-furoate.

After methyl 5-nitro-2-furoate was incubated with milk xanthine oxidase, three reduction products were isolated from the incubation mixture. Among them, two reduction products were new types of nitrofuran metabolites, i.e., metabolites 1 and 2 were identified as the dihydroxyhydrazine derivative (1,2-dihydroxy-1,2-di(5-methoxycarbonyl-2-furyl)hydrazine) and the hydroxylaminofuran derivative (methyl 5-hydroxylamino-2-furoate), respectively. Metabolite 3 was also identified as the aminofuran derivative (methyl 5-amino-2-furoate) by comparison with a synthetic sample.

Animals↗
PubMed1981

An electron spin resonance investigation and molecular orbital calculation of the anion radical intermediate in the enzymatic cis-trans isomerization of furylfuramide, a nitrofuran derivative of ethylene.

The enzymatic cis-trans isomerization of nitrofuran derivatives has been proposed to occur via the formation of a radical anion intermediate. ESR investigations, in conjunction with intermediate neglect of differential overlap (INDO) molecular orbital calculations, support this concept by demonstrating the enzymatic generation of cis and trans radical anions of 3-(5-nitro-2-furyl)-2-(2-furyl) acrylamide. The INDO calculations further indicate that the rotational barrier between the cis and trans anion radicals of this compound is only 5--10 kcal/mol, whereas a 70 kcal/mol barrier exists for the parent geometric isomers. Hyperfine splitting constants for the cis-trans conformers have been assigned on the basis of INDO calculations. Surprisingly, only the nitrogen hyperfine splitting of the nitro group is distinguishably different in the two conformers, a result which is not inconsistent with the INDO calculations.

Animals↗
PubMed1984

No detectable reaction of the anion radical metabolite of nitrofurans with reduced glutathione or macro-molecules.

The initial metabolite formed by most mammalian nitroreductases is the nitro anion free radical. We, as well as others, have proposed that nitroheterocyclic anion radicals covalently bind to protein, DNA, or thiol compounds such as reduced glutathione (GSH). Our results indicate that even at 100 mM GSH does not affect the steady-state concentration of the nitro anion free radical of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA) in rat hepatic microsomal or xanthine oxidase incubations. The steady-state ESR amplitude of the anion radical is also unchanged by the addition of BSA or DNA. Similar results are obtained with nitrofurazone and nitrofurantoin. The reactive chemical species which binds to tissue macromolecules and GSH upon the reduction of nitrofurans remains unknown, but the anion free radical metabolite can be excluded from consideration.

Anions↗
PubMed1987

Nitrofuran inhibition of microsomal lipid peroxidation.

Two nitrofuran compounds, nifurtimox and nitrofurantoin, inhibited in a concentration-dependent manner the NADPH-, iron-induced lipid peroxidation in rat liver microsomes, as shown by the decreased rate of MDA accumulation. Other nitro compounds (benznidazole and chloramphenicol) were relatively inactive. Nifurtimox inhibition affected polyenoic fatty acids and cytochrome P-450 degradation that follows lipid peroxidation. The ascorbate- or tert-butyl hydroperoxide-dependent lipid peroxidations were much less inhibited than the NADPH-dependent one. Nifurtimox and nitrofurantoin, but not benznidazole and chloramphenicol, strongly stimulated the microsomal NADPH-oxidase activity, thus supporting electron diversion, as the main cause of the inhibition of peroxidation initiation.

Animals↗
PubMed1977

Mutagenicity of nitrovin--a nitrofuran feed additive.

Nitrovin, a nitrofuran feed additive, is shown to be directly mutagenic in Salmonella typhimurium TA 98 and TA 100 between 0.1 and 2.5 microgram per plate (0.09--2.3 micrometer). Addition of a rat-liver homogenate reduces the mutation rates. Nitrovin inhibits growth of the same bacteria in suspension cultures at concentrations above 0.09 micrometer.

Animal Feed↗
PubMed1995

5-Nitrofuran derivatives of fatty acid hydrazides induce differentiation in human myeloid leukaemic cell lines.

Compounds formed by 5-nitrofuran with hydrazides of formic, acetic and propionic acids, hereafter respectively known as SBF, SBA and SBP have been used to evaluate the differentiation-inducing properties on two established myeloid leukaemic cell lines ML-2 and EOL-1. SBP is found to be the most effective as an antineoplastic agent amongst the three. Induction of differentiation observed are in the order SBP > SBA > SBF, as assessed by morphology, NBT-reducing activity and surface marker antigens of the treated cells. Induction of differentiation of ML-2 and EOL-1 cells by the most effective compound, SBP (3 microM), is accompanied by perturbation of the cell cycle, with most of the cells accumulating in the G0-G1, phase. Inhibition of DNA synthesis occurs while protein and RNA synthesis remain practically unchanged.

Acetates↗
PubMed2005

Quantitative determination of four nitrofuran metabolites in meat by isotope dilution liquid chromatography-electrospray ionisation-tandem mass spectrometry.

A confirmatory method based on isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the low-level determination of residues of four nitrofuran veterinary drugs in meat, e.g., furazolidone, furaltadone, nitrofurantoin, and nitrofurazone. The procedure entails an acid-catalysed release of protein-bound metabolites, followed by their in situ conversion into the 2-nitrobenzaldehyde (NBA) imine-type derivatives. Liquid-liquid extraction and clean-up on a polymeric solid phase extraction cartridge are then performed before LC-MS/MS analysis by positive electrospray ionisation (ESI) applying multiple reaction monitoring of three transition reactions for each compound. Reliable quantitation is obtained by using one deuterated analogue per analyte (d4-NBA derivative) as internal standard (IS). Validation of the method in chicken meat was conducted following the European Union (EU) criteria for the analysis of veterinary drug residues in foods. The decision limits (CCalpha) were 0.11-0.21 microg/kg, and the detection capabilities (CCbeta) 0.19-0.36 microg/kg, thus below the minimum required performance limit (MRPL) set at 1 microg/kg by the EU. The method is robust and suitable for routine quality control operations, and more than 200 sample injections were performed without excessive pollution of the mass spectrometer or loss of LC column performance.

Chromatography, Liquid↗
PubMed2005

Novel bidentate complexes of Cu(II) derived from 5-nitrofuran-2-carboxaldehyde thiosemicarbazones with antiamoebic activity against E. histolytica.

The novel analogues of 5-nitrofuran-2-carboxaldehyde thiosemicarbazones 1-10 were synthesized and their copper(II) complexes 1a-10a were obtained by means of coordination with cupric chloride. All these compounds have been characterized by elemental analysis, IR, electronic spectra and thermogravimetric patterns while ligands have also been characterized by 1H NMR spectral studies. These copper complexes are bidentate and possess octahedral geometry around Cu(II) ion. Their antiamoebic activities were carried out to ascertain their effectiveness in comparison to their corresponding thiosemicarbazones. A number of these complexes possess noteworthy potencies towards HK-9 strain of Entamoeba histolytica in vitro. The complexes 2a-7a, 9a and 10a showed less IC50 value than metronidazole, the drug of choice for amoebiasis. Moreover, complexes 2a and 9a have shown the most promising antiamoebic activities (IC50 = 0.38 microM of 2a and IC50 = 0.34 microM of 9a versus IC50 = 1.81 microM of metronidazole). These results indicate that the metallated thiosemicarbazone may be lead molecule to inhibit growth of E. histolytica.

Animals↗
PubMed2005

Conformational analyses and docking studies of a series of 5-nitrofuran- and 5-nitrothiophen-semicarbazone derivatives in three possible binding sites of trypanothione and glutathione reductases.

To explore three possible binding sites of trypanothione and glutathione reductase, namely, the active, the dimer interface and the coenzyme NADPH binding site, a series of eight compounds, nitrofurans and nitrothiophenes derivatives, were docked, using their crystallographic and modeled conformations. Docking results showed that, for both families and both enzymes, compounds are more likely to bind in the interface site, even though there is some probability of binding in the active site. These studies are in agreement with experimental data, which suggest that these class of compounds can act either as uncompetitive or mixed type inhibitors, and also with the finding that there is an alpha-helix which connects the active with the interface site, thus allowing charge transference between them.

Binding Sites↗
PubMed2003

Trypanosoma cruzi: effect and mode of action of nitroimidazole and nitrofuran derivatives.

With the aim of determining the actual target(s) of nitro-group bearing compounds considered as possible leads for the development of drugs against Chagas' disease, we studied in parallel nitrofurans and nitroimidazoles. We investigated nine representative compounds for the following properties: efficacy on different Trypanosoma cruzi strains, redox cyclers, inhibition of respiration, production of corresponding nitroso derivatives and intracellular thiol scavengers. Our results indicate that nifurtimox and related compounds act as redox cyclers, whereas the most active in the series, the 5-nitroimidazole megazol essentially acts as thiol scavenger particularly for trypanothione, the cofactor for trypanothione reductase, an essential enzyme in the detoxification process.

Animals↗
PubMed2001

Determination of the metabolites of nitrofuran antibiotics in animal tissue by high-performance liquid chromatography-tandem mass spectrometry.

A LC-MS-MS method is presented to analyse simultaneously the metabolites of four nitrofuran antibacterial agents, furazolidone, furaltadone, nitrofurazone and nitrofurantoin in animal muscle tissue. Sample clean-up and analyte enrichment was performed by solid-phase extraction (SPE) with a polystyrene sorbent following combined hydrolysis of the protein-bound drug metabolites and derivatisation of the homogenised tissue with 2-nitrobenzaldehyde. Limits of detection of 0.5-5 ng g(-1) tissue and limits of determination of 2.5-10 ng g(-1) tissue were achieved using electrospray ionisation in positive mode. Analyte identification and quantification was performed according to EU guidelines, using multiple reaction monitoring (MRM) with one precursor ion and two product ions as identifiers. The use of an internal standard in combination with the simplified sample preparation led to a sensitive and reliable analysis method. The yield of the derivatisation reaction was between 66 and 74% and the recovery of SPE reached 92-105% for all values between 10 and 500 ng g(-1). The developed analytical protocol has been applied to contaminated tissue samples of furazolidone- and furaltadone-treated pigs and allowed unequivocal identification and quantification of the metabolites.

Animals↗
PubMed1993

Mechanistic interpretation of the genotoxicity of nitrofurans (antibacterial agents) using quantitative structure-activity relationships and comparative molecular field analysis.

Quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) have been applied to elucidate the mechanisms of genotoxicity (SOSIP) of nitrofuran derivatives on Escherichia coli PQ37. The following equation was developed: log SOSIP = -33.1qc2 + 1.00 log P - 1.50Isat - 1.19MR - 0.76I5,6 - 3.76; n = 40, r = 0.900, s = 0.475. The QSAR model clearly reveals three important factors, namely, electronic (qc2), hydrophobic (log P) and steric (MR, Isat, I5,6) contributing toward the genotoxic activity of this class of compounds. qc2, the charge on the c2 atom attached to the NO2 group, supports a furan ring opening mechanism in explaining the genotoxicity. The finding of the coefficient of 1 with log P conforms to our previous findings with several different classes of mutagens acting on different systems. CoMFA analysis clearly demonstrates its potential in unraveling the steric features of the molecules through contour maps. The CoMFA cross-validated model also supports the importance of the electronic factor. It could not reveal any hydrophobic influence because the interaction energies of the CH3 and H2O probes are collinear. QSAR (classical) and CoMFA, if used judiciously, may complement each other and enhance the applicability of SAR in drug design.

Escherichia coli↗
PubMed1975

Synthesis and antibacterial properties of methylsulfinyl and methylsulfonyl analongs of some nitrofurans.

The sulfoxides 5-methylsulfinyl-2-furaldehyde semicarbazone (2) and 1-[(5-methylsulfinyl-2-fufurylidene)amino]hydantoin (3) as well as the sulfones 1-[(5-methylsulfonyl-2-furfurylidene)animo]hydantoin (1) and 1-(5-methylsulfonly-2-furyl)-2-(6-amino-3-p-ridazyl)ethylene hydrochloride (4) have been prepared and tested for antibacterial activity against a number of gram-negative and gram-positive organisms. The compounds are much less active than the corresponding 5-nitrofuran derivatives, possibly because their reduction potentials are too negative for them to interfere with reductive enzyme systems within the bacteria.

Anti-Bacterial Agents↗