Nitro radical anion formation from nitrofuryl substituted 1,4-dihydropyridine derivatives in mixed and non-aqueous media.

Three new nitrofuryl substituted 1,4-dihydropyridine derivatives were electrochemically tested in the scope of newly found compounds useful as chemotherapeutic alternative to the Chagas' disease. All the compounds were capable to produce nitro radical anions sufficiently stabilized in the time window of the cyclic voltammetric experiment. In order to quantify the stability of the nitro radical anion we have calculated the decay constant, k2. Furthermore, from the voltammetric results, some parameters of biological significance as E7(1) (indicative of in vivo nitro radical anion formation) and KO2 (thermodynamic indicator of oxygen redox cycling) have been calculated. From the comparison of E7(1), KO2 and k2 values between the studied nitrofuryl 1,4-DHP derivatives and well-known current drugs an auspicious activity for one of the studied compounds i.e. FDHP2, can be expected.

1,4-dihydropyridines: reactivity of nitrosoaryl and nitroaryl derivatives with alkylperoxyl radicals and ABTS radical cation.

In the present paper, a direct quenching of radical species by a number of synthesized nitrosoaryl 1,4-dihydropyridines and their parent nitroaryl 1,4-dihydropyridines was determined in aqueous media at pH 7.4. These two series of compounds were compared with the C-4 unsubstituted 1,4-dihydropyridines derivatives and the corresponding C-4 aryl substituted 1,4-dihydropyridines derivatives. Kinetic rate constants were assessed by UV-Vis spectroscopy. Nitrosoaryl derivatives were more reactive than the parent nitroaryl 1,4-dihydropyridines. Our results strongly support the assumption that the reactivity between the synthesized 1,4-dihydropyridines derivatives with alkylperoxyl radicals involves electron transfer reactions, which is documented by the presence of pyridine as final product of reaction and the complete oxidation of the nitroso group to give rise the nitro group in the case of the nitrosoaryl 1,4-dihydropyridines derivatives.

Electrochemical, UV--visible and EPR studies on nitrofurantoin: nitro radical anion generation and its interaction with glutathione.

This paper deals with the reactivity of the nitro radical anion electrochemically generated from nitrofurantoin with glutathione. Cyclic voltammetry (CV) and controlled potential electrolysis were used to generate the nitro radical anion in situ and in bulk solution, respectively and cyclic voltammetry, UV--Visible and EPR spectroscopy were used to characterize the electrochemically formed radical and to study its interaction with GSH. By cyclic voltammetry on a hanging mercury drop electrode, the formation of the nitro radical anion was possible in mixed media (0.015M aqueous citrate/DMF, 40/60, pH 9) and in aprotic media. A second order decay of the radicals was determined, with a k2 value of 201 and 111 M(-1) s(-1), respectively. Controlled potential electrolysis generated the radical and its detection by cyclic voltammetry, UV--Visible and EPR spectroscopy was possible. When glutathione (GSH) was added to the solution, an unambiguous decay in the signals corresponding to a nitro radical anion were observed and using a spin trapping technique, a thiyl radical was detected. Electrochemical and spectroscopic data indicated that it is possible to generate the nitro radical anion from nitrofurantoin in solution and that GSH scavenged this reactive species, in contrast with other authors, which previously reported no interaction between them.

A nitro radical anion formation from nifedipine: an electrochemical approach.

The cyclic voltammetric behaviour of nifedipine was studied. The addition of three aprotic solvents to nifedipine in an aqueous citrate buffer system was examined. Qualitatively they result in separation of the initial irreversible 4 electron reduction into two stages, the NO2/RNO2.- and RNO2.-, 4H/RNHOH, H2O couples, respectively. Particular attention was directed to the 1-electron RNO2/RNO2.- couple as measured by the cyclic voltammetric mode in mixed media. Analysis of the cyclic voltammetric response as a function of scan rate and non-aqueous solvent content yields information on the stability of the radical anion. The chemical forward reaction of the radical anion follows a second order kinetics with a stability constant of 1.1 x 10(-3) l mol-1 s-1 and a half-life time of 0.09 s for 1 mM of nifedipine in aqueous citrate buffer, pH 7.4/DMF; 50:50.

Reactivity of the one-electron reduction product from nifedipine with relevant biological targets.

The reactivity of the electrochemically generated nitro radical anion from nifedipine, a nitro aryl 1,4-dihydropyridine derivative, with relevant endobiotics and thiol-containing xenobiotics, was quantitatively assessed by cyclic voltammetry. The method was based on the decrease in the return-to-forward peak current ratio after the addition of compounds. A quantitative procedure to calculate the respective interaction constants between the radicals and the xeno/endobiotics is also provided. In the optimal selected conditions, i.e. mixed media (0.015 M aqueous citrate/DMF: 40/60, 0.3 M KCl, 0.1 TBAI) at pH 9.0 the following order of reactivity was obtained: glutathione > uracil > adenine and cysteamine > N-acetylcysteine > captopril > penicillamine. In all cases, the interaction rate constants for these derivatives were greater than the natural decay constant of the radical. Studies on the reactivity at pH 7.4 were also conducted. Results from these experiments indicate a significant reactivity between the radical and the endo/xenobiotics. The increase in the stability of the radical anion by increasing the pH of the mixed media resulted in a decreased reaction with the endo/xenobiotics tested. Computerized simulation with DIGISIM 2.0 of the proposed mechanisms fitted very well with the experimental results for both the natural decay of the radical and its reaction with the tested compounds.

Electrochemical generation and reactivity of free radical redox intermediates from ortho- and meta-nitro substituted 1,4-dihydropyridines.

This paper reports a comprehensive study by cyclic voltammetry on the electrochemical characteristics and the reactivity of the one-electron reduction product from a series of nitro aryl 1,4-dihydropyridines in mixed and aprotic media. In addition, the effects of 1,4-DHP on the oxygen consumption of T. cruzi epimastigotes are reported. One-electron reduction products from 1,4-DHP derivatives significantly reacted with both thiol compounds and the nuclei acid bases, adenine and uracil. This reactivity was significantly higher than the natural decay of the radicals in mixed media. Based on these results the following tentative order of reactivity towards the xeno/endobiotics is as follows: cysteamine > glutathione > adenineuracil. Both the stability and the reactivity of the nitro radical anions electrochemically generated from 1,4-DHP showed a linear dependence with pH. The sensitivity to pH of the radicals derived from o-nitro substituted derivatives was significantly higher than m-nitro substituted derivatives. On the other hand, in all cases an increase of pH produced a significant decrease in the interaction rate constant. Interaction studies carried out in aprotic media did not show any reactivity of the radicals towards both thiol compounds and the nuclei acid bases, adenine and uracil. Therefore, we concluded that the interaction process requires certain proton activity in the media. All the tested 1,4-dihydropyridines inhibited the oxygen consumption by T. cruzi epimastigotes, Tulahuén strain. The drugs with higher electron-affinity produced greater inhibition than those with lower electron-affinity (i.e. nicardipine vs nifedipine).

Redox behaviour of nifuroxazide: generation of the one-electron reduction product.

The electrochemical properties of nifuroxazide have been investigated in aqueous and aqueous-DMF mixed solvents. In aqueous media, a single, irreversible four-electron reduction occurs to give the hydroxylamine derivative. In mixed media, a reversible one-electron reduction to form a nitro radical anion takes place. Cyclic voltammetric studies show that the anion radical product is stable, although the nitro radical anion intermediate shows a tendency to undergo further chemical reactions. A comparison with the voltammetric behaviour of other nitrofurans such as nifurtimox, nitrofurazone and furazolidone is made. The electrochemically-obtained parameters are correlated with the in vivo studies of oxygen consumption on Trypanosoma cruzi cell suspensions.

Antioxidant activity of gallates: an electrochemical study in aqueous media.

The electron-donating ability of gallates, which are food and pharmaceutical antioxidants, is quantitatively assessed on the basis of their electrochemical characteristics. Gallic acid and the propyl, i-propyl, butyl, i-butyl, pentyl and i-pentyl gallate derivatives were electrochemically oxidized on the glassy carbon electrode by using differential pulse voltammetry, cyclic voltammetry and hydrodynamic voltammetry on the rotating disk electrode. All the compounds under study were easily oxidized in acidic and neutral solutions. Electrochemical oxidation occurs via two electron-transfer steps; however good resolution for the second wave was obtained only by using hydrodynamic conditions. The oxidation process results to be irreversible, diffusion controlled and pH-dependent. The introduction of the alkyl groups seems to affect the intensities of the semiquinone gallate radicals as can be ascribed from the observed differences in i(II)d/i(I)d ratio obtained from hydrodynamic voltammetric experiments for the different derivatives. We have found that the intensity of the gallate radicals follows the sequence GA > or = i-PG > PG > i-BG > BG > i-PeG > PeG. From the pH-dependence of the peak current it is possible to affirm that pH 2 is the better condition for the oxidative activity showing that the antioxidant behaviour of these compounds are important in the stomach acid.

Polarographic analysis of cephalexin.

Cephalexin was found to be polarographically reducible after hydrolysis in an acidic medium, producing two polarographic waves. Both waves were diffusion controlled. The concentration-diffusion plot method was used for the analysis of cephalexin in capsules.

Polarographic study of nifurtimox.

Nifurtimox is polarographically reducible over the whole pH range, the nitro group being reduced to the hydroxylamine group in a 4e process and subsequently the amine being formed in a 2e process at a pH value below 4. The C = N-N linkage is reduced by a mechanism involving reductive fission of the N-N bond. The differential pulse polarographic peaks for the reduction of the nitro group to the hydroxylamine group at pH 6 were used in developing a new polarographic method for the determination of nifurtimox in pharmaceutical forms.

Photodecomposition of a new 1,4-dihydropyridine: furnidipine.

The photodecomposition of new 1,4-dihydropyridine, furnidipine (CRE-319); [2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-tetrahydrofurfuryl 5-methyl diester) was studied by voltammetric, UV-vis spectrophotometric, and HPLC technique with three different light conditions (artificial daylight, UV light, and room daylight). The artificial daylight photodecomposition of furnidipine follows 0.5-order kinetics as assessed by the above-mentioned techniques. Furthermore, the daylight photoderivative was isolated and identified by NMR and IR as 2,6-dimethyl-4-(2-nitros-ophenyl)pyridine-3,5-dicarboxylic acid 3-tetrahydrofurfuryl 5-methyl diester. Quantitative kinetic data for the UV photodecomposition of furnidipine cannot be obtained due to both the high rate of degradation (< 1 min) and intermediate reactions. However, polarographic, spectroscopic, and chromatographic evidence permits us to identify this photoproduct as 2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-tetrahydrofurfuryl 5-methyl diester. Polarography was the most useful technique to assess the photodegradation of this drug from the qualitative point of view, and quantitative kinetic data were similar to those obtained by HPLC and UV-vis spectroscopy.

Polarographic study of the photodecomposition of nimodipine.

Nimodipine, a calcium antagonist belonging to the dihydropyridine family, produces a well-defined polarographic peak due to the four-electron reduction of the nitro group. This peak was used to track the photodecomposition of nimodipine induced by UV light and daylight. Nimodipine was modified by UV irradiation with degradation following first-order kinetics. A degradation rate constant of 0.099 min-1, with a half-life of 7.78 min, for UV irradiation without a filter was obtained. Furthermore, a quantum yield of 1.32 x 10(-3) molecules/quantum absorbed was measured with a chemical actinometer. The UV degradation product, which was isolated and identified, showed that irradiation of nimodipine causes oxidation of the dihydropyridine ring and transmutation of the nitro group in the nitrobenzene moiety.

An electrochemical evidence of free radicals formation from flutamide and its reactivity with endo/xenobiotics of pharmacological relevance.

This paper reports the feasibility of free radicals formation from flutamide by using cyclic voltammetry. The electrochemical characteristics and the reactivity of the one-electron reduction product from flutamide in mixed media with thiol compounds and the nuclei acid bases are characterized. Results from this paper show the thermodynamic feasibility of free radical formation expressed for both the cathodic peak potential and the second-order rate constant values. The reactivity of the radical towards thiol compounds (glutathione, cysteamine, N-acetylcysteine) and the nuclei acid base, adenine, thymine and uracil were quantitatively assessed through the calculation of the respective interaction rate constants. Based on these results, the following tentative order of reactivity towards the xeno/endobiotics is as follows: cysteamine > uracil > glutathione > adenine > N-acetylcysteine > thymine. The stability of the nitro radical anion electrochemically generated from flutamide showed a linear dependence with pH.

Polarographic determination of ampicillin in capsules and tablets.

A new polarographic method is used for quantitative analysis of ampicillin dosage forms. The electroactive product is formed by acidic hydrolysis of ampicillin. It gives a well-developed reduction wave with half-wave potential of -0.91 V vs. SCE. The proposed method has good precision. A major advantage is the selectivity, which makes the determination of ampicillin possible without prior separation of the excipient.

Nifedipine: Differential pulse polarography and photodecomposition.

A method for the differential-pulse polarographic determination of nifedipine has been developed, based on the electrochemistry of the aromatic nitro group in the drug. Polarography has also been used in studies of the photodegradation of nifedipine, which is highly light-sensitive under ultraviolet light and artificial daylight.

Electrochemical reduction of nicergoline and its analytical determination in dosage forms.

Electrochemical reduction of nicergoline was studied at different pH and concentrations using differential pulse polarography and linear sweep voltammetry. Both techniques reveal that the reduction process occurs with strong adsorption of the product. Nicergoline is an excellent model for the previously developed theory related to the effects of strong adsorption of electroactive species in voltammetry. At concentrations below 0.1 mM, the adsorption prepeak is linearly dependent on nicergoline concentration. This peak was used to develop a new differential pulse polarographic method for the determination of the drug in pharmaceutical dosage forms. The method is simple and not time-consuming because nitrogen purging of samples and previous separation of the excipients were not needed. A comparative UV spectrophotometric assay was applied. Recovery data and composite and uniformity content studies for both methods are reported.

Anodic polarographic determination of flucloxacillin.

The hydrolysis of flucloxacillin at pH 4.9 yields a degradation product which is polarographically oxidizable. This derivative has not been identified, but would seem to contain a thiol group. It gives a diffusion-controlled anodic polarographic wave with a half-wave potential at -0.24 V vs. SCE. The method developed has been applied to the analysis of flucloxacillin capsules, and a recovery of 99% has been obtained.

Polarography of an acidic degradation product from cephalexin.

2-Hydroxy-3-phenyl-6-methylpyrazine is identified as the product obtained by acidic degradation of cephalexin in the presence of formaldehyde. In 5M hydrochloric acid this product gives a well-defined reduction wave with a half-wave potential of -0.45 V vs. SCE. The wave is irreversible and diffusion-controlled. The diffusion current shows a linear relation with the cephalexin concentration and can be used for determination of cephalexin in plasma.

Voltammetric study of ketorolac and its differential pulse polarographic determination in pharmaceuticals.

A differential pulse polarographic method for the quantitative determination of ketorolac is described. Ketorolac is an antiinflamatory-analgesic agent that is directly electroreducible at the mercury electrode. The polarographic reduction is due to the reduction of the benzoyl moiety in the ketorolac molecule. For analytical purposes, a very well resolved diffusion controlled differential pulse polarographic peak obtained at pH 9 was selected. This peak was used to develop a new method for the determination of ketorolac in pharmaceutical dosage forms. Recovery study shows that the method is sufficiently accurate and precise to be applied in the individual tablet assay of commercial samples.

Polarographic determination of loratadine in pharmaceutical preparations.

Loratadine, a potent antihistamine drug, is not directly electroreducible at a dropping mercury electrode; however, by means of a nitration procedure it is possible to obtain a nitro-loratadine derivative which has been identified as 4-(8-chloro-7-nitro-5,6-dihydro-11 H-benzo-[5,6]-cyclohepta-[l,2-b]-pyridin-l l-ylidene)-1-piperidine carboxylic acid ethyl ester. The electrochemical reduction of this derivative at different pHs and concentrations using polarography and cyclic voltammetry was studied. The derivative exhibits a differential pulse polarographic peak due to the reduction of the nitro group. This peak was used in order to develop an analytical procedure for determining loratadine in pharmaceutical dosage forms. The recovery study shows adequate accuracy and precision for the developed assay and the excipients do not interfere in the determination.