Interaction Of Metronidazole Research Articles

Metronidazole, acyclovir and tetrahydrobiopterin may be promising to treat COVID-19 patients, through interaction with interleukin-12

COVID-19 patients have shown overexpressed serum levels of several pro-inflammatory cytokines, leading to a high mortality rate due to numerous complications. Also, previous studies demonstrated that the metronidazole (MTZ) administration reduced pro-inflammatory cytokines and improved the treatment outcomes for inflammatory disorders. However, the effect and mechanism of action of MTZ on cytokines have not been studied yet. Thus, the current study aimed to identify anti-cytokine therapeutics for the treatment of COVID-19 patients with cytokine storm. The interaction of MTZ with key cytokines was investigated using molecular docking studies. MTZ-analogues, and its structurally similar FDA-approved drugs were also virtually screened against interleukin-12 (IL-12). Moreover, their mechanism of inhibition regarding IL-12 binding to IL-12 receptor was investigated by measuring the change in volume and area. IL-12–metronidazole complex is found to be more stable than all other cytokines under study. Our study also revealed that the active sites of IL-12 are inhibited from binding to its target, IL-12 receptor, by modifying the position of the methyl and hydroxyl functional groups in MTZ. Three MTZ analogues, metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5-nitroimidazol-2-yl]-N-methylmethanimine-oxide, and two FDA-approved drugs acyclovir (ACV), and tetrahydrobiopterin (THB) were also found to prevent binding of IL-12 to IL-12 receptor similar to MTZ by changing the surface and volume of IL-12 upon IL-12-drug/ligand complex formation. According to the RMSD results, after 100 ns MD simulations of human IL-12-MTZ/ACV/THB drug complexes, it was also observed that each complex was swinging within a few Å compared to their corresponding docking poses, indicating that the docking poses were reliable. The current study demonstrates that three FDA-approved drugs, namely, metronidazole, acyclovir and tetrahydrobiopterin, are potential repurposable treatment options for overexpressed serum cytokines found in COVID-19 patients. Similar approach is also useful to develop therapeutics against other human disorders.

Potential application of Al and Si doped carbon nanotubes for metronidazole detection: A theoretical study

The interaction of metronidazole (MNZ) drug with pristine, Al and Si doped single-walled carbon nanotubes (SWCNTs) was explored utilizing density functional theory (DFT) method. The calculations revealed that MNZ prefers to be adsorbed on the pristine CNT via its 5-membered ring with an Eadsorption value of −17.88 kcal.mol−1. The HOMO-LUMO energy gap (Eg) of pristine CNT increases by about 60.9% upon adsorption of MNZ. MNZ molecule prefers to be adsorbed on the Al- and Si doped CNT via its NO2 group with a binding energy of about −43.94 and −49.25 kcal mol−1, respectively. The electronic properties of SiCNT are more sensitive to MNZ adsorption than those of AlCNT but not pristine CNT. The recovery time of MNZ from the CNT, AlCNT and SiCNT nanostructures is calculated to be about 1.24 × 10−3, 1.51 × 1016, and 1.17 × 1020 s, respectively, indicating AlCNT and SiCNT suffer from a very long recovery time compared to pristine nanotube.

A new enhanced chemiluminescence reaction based on polymer dots for the determination of metronidazole

Polymer dots (PDs) with non-conjugated functional groups are attracting nanomaterials due to their ease of synthesis, the biocompatibility of precursors, and low toxicity. In this work, PDs with non-conjugated groups were synthesized with a simple and straightforward method by Schiff base reaction. Then their possible application in the chemiluminescence (CL) reactions was explored. Results were shown that PDs increased the CL intensity of the NaIO4-fluorescein system about 15 times. Regarding the CL mechanism, we proved that the emitting species is fluorescein, which can be excited by the energy transfer from the excited-state PDs. It was observed that CL emission is promoted by the interaction of metronidazole (MND) with the PDs. Therefore, we designed a novel and sensitive assay for MND based on its enhancing effect on NaIO4-fluorescein-PDs CL system. The introduced assay showed a linear response in the range of 5.0–300 nM with a detection limit of 1.5 nM. The method was used for the determination of MND in spiked plasma samples.

Borophene as an electronic sensor for metronidazole drug: A computational study

The electronic sensitivity and reactivity of a B36 borophene are scrutinized toward the metronidazole (ML) drug using density functional theory calculations. The drug is mainly adsorbed via its –NO2 group on the edge of the B36 borophene. In the gas phase, the adsorption energy and Gibbs free energy change are about −22.1 and −19.3 kcal/mol, respectively. Because of a large HOMO destabilization upon the ML adsorption, the HOMO-LUMO gap (Eg) of B36 meaningfully decreases from 1.84 to 0.75 eV. It increases the electrical conductivity which creates an electrical signal. The signal is connected to the ML presence, indicating that the borophene may be a proper sensor for the ML detection. A short recovery time of 1.53 s is estimated for the ML desorption from the B36 surface. Unlike the Eg, the Fermi level and work function of B36 are not altered sensibly by the ML drug adsorption. The interaction of ML with the B36 sheet weakens in the water solvent.

The effect of metronidazole on the cell cycle and DNA in metronidazole-susceptible and -resistant Giardia cell lines

Metronidazole (MTZ) is used as the drug of choice to treat Giardia infections. It is believed that the prodrug is transformed intracellularly into toxic intermediates that interact with cellular components, leading to cell death. The present study aimed to describe the effects of MTZ treatment on DNA and cell cycle progression in MTZ-sensitive and in vitro-derived MTZ-resistant cell lines. Detection of the phosphorylated form of histone H2A in cell nuclei together with electrophoresis of genomic DNA, flow cytometry analysis and incubation of cells with other drugs (albendazole or neomycin) demonstrated that DNA damage in MTZ-treated cells is clearly conditioned by the presence of this drug. The flow cytometry analysis and a BrdU labeling assay showed that the sublethal drug concentration affects the replication phase of the cell cycle. Cells incubated with lethal drug concentration exhibit unchanged DNA profile, only about 50% of cells are positive for γH2A and lose an ability to attach to a surface after few hours of incubation. It is likely that the early reaction of cells to lethal concentration of MTZ is not primarily initiated by the reaction to DNA damage but rather by the immediate interaction of MTZ with biomolecules where activated MTZ is generated. Interestingly, in MTZ-resistant lines incubated in the presence of the drug, about 40% of cells remain permanently positive for γH2A without any effects on the cell cycle progression suggesting that DNA damage caused by MTZ treatment persists in these cells. Accelerated mutagenesis caused by MTZ-induced DNA damage may therefore be a new factor contributing to the development of natural resistance.

<i>In vitro</i> Interaction of Metronidazole and Mebendazole with Copper (II) and Chromium (III) in Aqueous Media

The interaction of metronidazole, an antiprotozoal agent and mebendazole, an important anthelmentic agent with Cu (II) and Cr(III) ions have been studied in aqueous systems at a fixed temperature of 37±0.5°C and at different pH values. It has been found that metronidazole and mebendazole form stable 1:1 complexes with Cu(II), but a less stable complex with Cr(III) ion. The studies were performed by electroanalytical and spectrophotometric methods. Spectral studies helped to detect initial complexation between the species. Conductometric titration indicated the nature of interaction and the stoichiometries of complexation. The conductometric study also indicated the formation of complexes of various molar ratios viz 1:2, 4:1, 3:1, 1:2, 1:3 and 1:4. etc. along with 1:1 complexes at various pH conditions. Similar types of complexation were observed by Job’s plots at various pH values. The Ardon’s spectroscopic method confirmed the 1:1 complexation and the values of stability constant were calculated using Ardon’s plot. Complexation at molar ratios 1:3 and 1:4 can not be ruled out. Keywords: Metronidazole; Mebendazole; Cu(II); Cr(III); Ardon’s plot; Complexation. © 2012 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved. doi: http://dx.doi.org/10.3329/jsr.v4i1.7599J. Sci. Res. 4 (1), 173-181 (2012)

Metronidazole-induced myocardial depression: chemical and pharmacological studies on the role of calcium in-vitro.

The interaction of metronidazole with calcium to form a water-soluble complex has been studied by titration with ethylenediaminetetraacetate (EDTA), direct current and pulse polarographic reduction steps of the nitro-group at pH 5 and 7, and by ultraviolet absorption. Stoichiometric calculations, X-ray powder diffraction pattern of the synthesized metronidazole-calcium complex, and molecular ion peak at m/z 381 in the mass spectrum of this product, showed that a 2:1 complex is formed. The interaction of metronidazole with calcium on myocardial contractile performance of guinea-pig electrically-driven isolated left atria in physiological solution was also examined. Metronidazole induced a sustained, concentration-dependent depression of the tension that was reversed by changing the bathing fluid to physiological solution, and/or by adding excess calcium ion. The drug-induced negative inotropic response was antagonized competitively by increasing calcium ion in the bath, whereas noradrenaline antagonized metronidazole-induced negative inotropic responses non-competitively. Addition of the metronidazole-calcium complex to the bath did not affect normal myocardial contractile performance. The results show that metronidazole produces a direct negative inotropic effect on isolated atrial muscles by interfering with Ca2+, and by preventing Ca2+ function in the events leading to contractile activity of atrial muscles.

Effect of temperature on the metronidazole–BSA interaction: Multi-spectroscopic method

The interaction between metronidazole and bovine serum albumin (BSA) was investigated using fluorescence spectroscopy (FS) and resonance light scattering spectroscopy (RLS). The apparent binding constants ( K a) between metronidazole and BSA were 3.42 × 10 4 (20 °C), 5.78 × 10 4 (30 °C) and 8.23 × 10 4 L mol −1 (40 °C), and the binding sites values ( n) were 1.48 ± 0.03. The experimental results showed that the metronidazole could be inserted into the BSA, quenching the inner fluorescence by forming the metronidazole–BSA complex. The addition of increasing metronidazole to BSA solution leads to the gradual enhancement in RLS intensity, exhibiting the formation of the aggregate in solution. It was found that both static quenching and non-radiation energy transfer were the main reasons for the fluorescence quenching. The entropy change and enthalpy change were positive, which indicated that the interaction of metronidazole and BSA was driven mainly by hydrophobic forces. The process of binding was a spontaneous process in which Gibbs free energy change was negative.

Study on the Interaction of Metronidazole with Bovine Serum Albumin by Using Fluorescence and Resonance Ralyeigh Light Scattering Spectrum

Study on the Interaction of Metronidazole with Bovine Serum Albumin by Using Fluorescence and Resonance Ralyeigh Light Scattering Spectrum

Coupling microdialysis with flow-injection chemiluminescence detection for a protein–drug interaction study

The interaction of metronidazole (MTZ) and human serum albumin (HSA) was studied using the coupling system of on-line microdialysis sampling with flow-injection chemiluminescence detection (FI-MD-CL). The interested drug and HSA were mixed in different molar ratios in 0.067 mol L −1 phosphate buffer (pH 7.4) and incubated at 37 °C in a water-bath. Then the microdialysis probe was put into the MTZ–HSA mixed solution and sampled at a perfusion rate of 5 μL min −1. The microdialysates was determined using flow-injection chemiluminescence. In vitro recovery ( R) of MTZ under experimental conditions was approximately 25.2% with a R.S.D. of about 3.2%. The values estimated for the binding constant ( K) and the number of the binding sites ( n) were found to be 1.50 × 10 3 L mol −1 and 1.89, respectively. The values of nK obtained using Scatchard analysis and Klotz plot were found to be quite similar. The method provided a reliable and simple technique for the study of drug–protein interaction.

Interaction of metronidazole with amino acids and their thermodynamics

Interactions of the drug metronidazole with amino acids viz. tryptophan, tyrosine, phenylalanine and alanine have been studied and the thermodynamic parameters calculated. The drug has been found to interact with amino acids in water. The interaction may not be simple charge-transfer interactions; other interactions like hydrogen bonding, hydrophobic interaction and dipole-dipole interaction are equally possible. The stability of the complexes indicates fairly stable complex formation.

Metronidazole twin ester prodrugs: synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity

A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as R mvalues, were determined using reversed-phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20 % rat liver homogenate) at 37 °C using HPLC. In all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction ( k 1 and k 2) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH ( t 1/2 ~ 25–72 h) and also at the physiological pH ( t 1/2 ~ 13–40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma ( t 1/2 ~ 10–150 min) and in rat liver homogenate ( t 1/2 ~ 4–55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids ( t 1/2 ~ 3–9 h and 1–11 h respectively). In vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazole for oral drug delivery.

In vitro activity of metronidazole alone and in combination with clotrimazole against clinical isolates of Trichomonas vaginalis.

Trichomonas vaginalis vaginitis is generally treated with oral metronidazole. Widespread use of this drug has led, however, to selection of resistant strains. Topical therapy seems appropriate whenever systemic high dosage schedule cannot be adopted in order to overcome resistance. This study was designed to assess the activity of metronidazole alone and in combination with clotrimazole, an imidazole derivative for topical use, against T. vaginalis. Tests were performed employing the antitrichomonas activity of a fixed ratio of metronidazole with clotrimazole (5:1) which has been recently suggested for topical therapy and the checkerboard technique. All tests were carried out under aerobic conditions to maximize T. vaginalis resistance traits. Minimum inhibitory concentrations (MICs) of metronidazole for the 12 strains studied were in the range reported in the literature (0.5-32 micrograms/ml). The interaction of metronidazole with clotrimazole as assessed by the checkerboard technique gave an indifferent outcome with all the strains assayed (FIC = 1-2). The fixed concentration of drugs, however, produced synergism (FIC = 0.5) in 5 of 12 isolates. Spontaneous resistant strains were not selected from T. vaginalis exposed to sub-lethal levels of the drugs or by culturing a large inoculum in the presence of 1, 2, 4 and 8 times the MICs of metronidazole alone or in combination with clotrimazole. These results confirm and extend previous reports highlighting the good in vitro efficacy of the association of metronidazole plus clotrimazole against T. vaginalis.

Interaction of metronidazole with escherichia coli deoxyribonucleic acid

To define the characteristics of the reported binding of metronidazole to DNA, we isolated the DNA from hypoxic incubation mixtures that contained both [ 14C]metronidazole and metronidazolesusceptible strains of Escherichia coli. Thus, either [2- 14C] metronidazole or [1',2'- 14C] metronidazole was incubated with either wild-type E. coli (strain AB1157) or a DNA repair mutant (strain SR58) that is highly susceptible to metronidazole. Approximately 0.02% of the radiolabel in the metronidazole was found to be associated with DNA isolated from both strains of bacteria, a percentage similar to that found to be associated with DNA from mammalian sources in a variety of in vitro and in vivo experiments performed by other investigators. The bound radioactivity was not diminished, however, when a great excess of non-radiolabeled metronidazole was included in the incubation mixture, indicating that the binding we observed was probably due to impurities in the radiolabeled metronidazole. We also examined the binding to DNA of a possible surrogate for the partially reduced form of metronidazole, l-methyl-4-phenyl-5-nitrosoimidazole (5NO), that has been described previously. The binding of the tritiated form of 5NO to DNA was also found to be undiminished by the addition of carrier 5NO (a finding which does not refute the hypothesis that 5NO may serve as a surrogate for the study of the active form of metronidazole). These studies do not exclude the binding to DNA of either metronidazole or a possible surrogate of its active functionality, but they indicate that if such binding occurs, it must be limited to very few sites on DNA and hence will be difficult to characterize.

Interaction of metronidazole with antibiotics containing the 2-aminothiazole moiety.

The mechanism of possible incompatibility between commercially available metronidazole parenteral solutions and the injectable aztreonam leading to the development of pink color in their intravenous admixtures was studied. It was demonstrated that nitrite ions may be produced in metronidazole solutions at the time of preparation or during storage by the effects of temperature and light. Under acidic pH conditions of admixtures the aminothiazole moiety of aztreonam was diazotized by the nitrite ion contributed by metronidazole solutions. The diazotized molecule, in turn, reacted with another aztreonam molecule by diazo-coupling. The resultant pink-colored product was isolated by chromatography and its structure was determined by mass spectral and NMR analyses. Other beta-lactam antibiotics containing the 2-aminothiazole moiety also react in acidic media in a similar manner.

The interaction of metronidazole with electron carriers of the Azotobacter vinelandii respiratory particle fraction

The interaction of metronidazole with electron carriers of the Azotobacter vinelandii respiratory particle fraction

Interaction of metronidazole with phenobarbital, cimetidine, prednisone, and sulfasalazine in Crohn's disease.

The influence of prednisone(PR), sulfasalazine(SZ), cimetidine(CM), and phenobarbital(PB) on the pharmacokinetics of metronidazole was investigated in six Crohn's patients. Metronidazole was first administered alone (250 mg bid, po) and then with prednisone (10 mg bid, po), sulfasalazine (1 g bid, po), cimetidine (600 mg bid) or phenobarbital (60 mg bid, po). Each regimen was followed for 6 days and sampling of blood and urine was carried out on the 7th day after the first dose of each regimen. Plasma and urine samples were analysed for the drug and its two principal metabolites, hydroxymetronidazole and metronidazole-1-acetic acid, by HPLC. When given alone, metronidazole had a mean volume of distribution of 0.667 +/- 0.15 lkg-1, a half-life of 9.7 +/- 3.1 h and an oral clearance of 0.852 +/- 0.23 (ml-1 min) kg-1. The disposition kinetics of metronidazole and its metabolites was not altered by CM and SZ. Induction of metabolism of metronidazole by PR was made manifest in significant increases in oral clearance of the former and urinary excretion of the hydroxy metabolite, and significant decrease in AUC of the parent compound. PB also induced the metabolism of metronidazole. This induction was reflected in significant increases in the oral clearance of metronidazole and AUC of the hydroxy metabolite as well as significant decreases in AUC, half-life, and urinary excretion of the parent drug.

Interaction of metronidazole with DNA repair mutants of Escherichia coli.

It has been proposed that one of metronidazole's partially reduced intermediates interacts either with DNA to exert a bactericidal effect or with water to form acetamide. To test this hypothesis we have examined the effect of metronidazole on several mutants of Escherichia coli that are defective in DNA repair. UV-susceptible RecA- and UvrB- point mutants have an increased susceptibility to metronidazole as manifested by both a decreased minimal inhibitory concentration and a greater bactericidal response to metronidazole in resting cultures. By these criteria, however, we find that UvrB- deletion mutants, which lack the ability to reduce nitrate and chlorate, are no more susceptible to metronidazole than is the wild type. We find, however, that these deletion mutants also lack the ability to reduce metronidazole and thus possibly to form its reactive species. When metronidazole's bactericidal effect is expressed in terms of the concurrent accumulation of acetamide derived from metronidazole, then all RecA- and UvrB- mutants are killed more efficiently than their wild types. The data are consistent, therefore, with metronidazole's lethal effect being mediated by a partially reduced intermediate on the metabolic pathway between metronidazole and acetamide. Defects in other aspects of the DNA repair system do not confer this increased susceptibility to the proposed intermediate. A Tag- mutant, for example, which is defective in 3-methyl-adenine-DNA glycosylase, does not have this increased susceptibility to the presumed precursor of acetamide. Thus, these results provide further support for the hypothesis that the bactericidal effect of metronidazole is mediated by a partially reduced intermediate in the metabolic conversion of metronidazole to acetamide and suggest that this intermediate interacts with DNA to produce a lesion similar to that caused by UV light.

Interaction of metronidazole with resistant and susceptible Bacteroides fragilis.

The kinetics of the lethal action of metronidazole and the formation of acetamide have been studied in a strain of Bacteroides fragilis which is relatively resistant to metronidazole. As with a susceptible strain of B. fragilis, the data are consistent with a model in which a labile intermediate in metronidazole metabolism interacts either with water to form acetamide or with a bacterium to cause its death. Although the relatively resistant strain grows more slowly than the susceptible one and is killed less rapidly by metronidazole, the resistant strain displays the same relationship between the lethal action of metronidazole and metronidazole metabolism to acetamide. The relatively resistant strain, like the susceptible one, has an enhanced lethal response to metronidazole in the presence of a strain of Escherichia coli. The results suggest that the proposed labile reactive intermediate of metronidazole forms more slowly in the resistant strains.

Absence of strand breaks in deoxyribonucleic acid treated with metronidazole.

The deoxyribonucleic acid (DNA)-degrading potential of metronidazole was evaluated in vitro by three techniques: determination of melting curve, measurement of viscosity, and centrifugation in neutral or alkaline sucrose gradients. Studies were performed on calf thymus DNA and on (3)H-labeled or unlabeled pneumococcal and T7 phage DNA after treatment with metronidazole alone or metronidazole reduced by sodium dithionite in the presence of DNA. This latter process is known to elicit covalent binding of metronidazole to DNA. Reduced or unreduced metronidazole had no effect on the melting properties, viscosity, or sedimentation velocity of the nucleic acids studied. Sodium dithionite alone, however, caused a 25% decrease in the intrinsic viscosity of pneumococcal DNA, and decreased the sedimentation velocity of pneumococcal and T7 phage DNA in both neutral and alkaline sucrose gradients. These data suggest that degradation of DNA is not important in the interaction of metronidazole with nucleic acids, an interaction assumed relevant to the cytotoxic, radiosensitizing, and mutagenic activities of this compound.