S. Bollo

Recent Developments in the Electrochemistry of Some Nitro Compounds of Biological Significance

The redox chemistry of different nitro compounds of biological significance is focused to understand how the reduction of the nitro group can play an active role in several aspects as: electroanalytical determinations, free radical generation and stability and free radical reactivity. We have focused our studies to a lot of pharmaceuticals belonging mainly to the following families: calcium antagonists as nitrobenzene substituted 1,4-dihydropyridines, antibacterial and anti protozoan agents as nitroimidazoles and nitrofurans. The formation of the nitro radical anion as the product of the one electron reduction of nitro compounds generates a series of important consequences passing from chemical to biological aspects. We have used electrochemical techniques to study the formation, stability and reactivity of this nitro radical anion in different media. From cyclic voltammetric experiments it is possible qualitatively to visualize the formation of the nitro radical anion through the one-electron reversible couple due to the redox system nitro / nitro radical anion . Furthermore also is possible the quantitative determination of the kinetic rate constant of the nitro radical anion decay and the interaction constants with other molecules. Although substituents may affect the redox potential and consequently the stability or reactivity of the nitro radical anions, other factors are important in regulation of these properties. Among these factors, it is possible to mention the nature of the reaction media making possible the occurrence of intermolecular reactions of the father-son type between the nitro radical anion and an acidic hydrogen present in the molecules.

Cyclic voltammetric studies on nitro radical anion formation from megazol and some related nitroimidazole derivatives

Abstract Megazol (2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazol, CAS 19622-55-0) and related nitroimidazole compounds are being tested as antichagasic drugs. Little is known on the mode of action of megazol. However, there is evidence that one-electron reduction of megazol to the corresponding nitro radical anion is a key step in the reaction mechanism. Consequently, this paper is focused on the cyclic voltammetric behaviour of megazol and related nitroimidazole derivatives with the aim of revealing the formation and stability of the corresponding nitro radical anions. All the compounds studied produce a well resolved nitro/nitro radical anion couple. The resolution of the couple was improved with the addition of tetrabutylammonium ions which hinders the protonation of the nitro radical anion at the electrode surface, thus enhancing the stability of the nitro radical anion. Only megazol produced a cyclic voltammogram distorted by the presence of a pre-peak due to strong adsorption of the corresponding nitro radical anion. The pre-peak occurs at potentials more positive than the diffusion controlled peak because the Gibbs energy of adsorption of the nitro radical anion makes the reduction of megazol to the adsorbed nitro radical anion easier than to the radical anion in solution. The sulphur atom in the thiadiazole ring plays a crucial role in the adsorption phenomena. Using the cyclic voltammetry theory for the disproportionation reaction, we have calculated the second-order decay rate constant, k2, and the half-life time, t1/2, for all the nitro radical anions of the studied nitroimidazole derivatives. The values obtained were compared with those of the corresponding nitro radical anions obtained from nifurtimox and benznidazole, the classic antichagasic drugs. Also, our results show that cyclic voltammetry is a good alternative to the classic pulse radiolysis method to obtain reliable values of the E17 parameter for nitro radical anions.

Voltammetric studies of aromatic nitro compounds: pH-dependence on decay of the nitro radical anion in mixed media

Abstract In this report we have chosen ethyl- m -nitrobenzoate (EMNB) as a prototype of a nitroaromatic compound in order to carry out a detailed cyclic voltammetric study focused on the coupled chemical reaction of the generated nitro radical anion. The study was carried out in mixed media (water+DMF) at different DMF contents and several pH values on both mercury and carbon electrodes. In order to study the coupled chemical reaction it was necessary to choose a narrow pH range between 8 and 10. The coupled chemical reaction follows second order kinetics and we have used Olmsteads procedure to calculate the second order rate constant k 2 . The k 2 values are strongly pH dependent. Typical values of k 2 =are 1.68×10 4 l mol −1 s −1 and 1.15×10 4 l mol −1 s −1 for 60% DMF, pH 9.5 on mercury and GCE, respectively. Considering an EMNB concentration of 0.1 mM the corresponding half life time values were 0.59 s and 0.86 s.

Nitro radical anion formation from nimodipine

Abstract Voltammetric studies of nimodipine using a mixed aqueous dimethylformamide (DMF) solvent have allowed us to generate the one-electron reduction product, the nitro radical anion RNO 2 . . The cyclic voltammetry technique has been employed to study the tendency of RNO 2 . to undergo further chemical reactions. This subsequent chemical reaction corresponds to a second-order process, a dismutation reaction which is initiated electrochemically. Data for rate constants and half-lives at pH 8.2 were determined in aqueous DMF media. A method which is able to generate selectively the RNO 2 . species electrochemically and to study its in-situ reactions is proposed.

Dispersion of bamboo type multi-wall carbon nanotubes in calf-thymus double stranded DNA

We report for the first time the use of double stranded calf-thymus DNA (dsDNA) to successfully disperse bamboo-like multi-walled carbon nanotubes (bCNT). The dispersion and the modified electrodes were studied by different spectroscopic, microscopic and electrochemical techniques. The drastic treatment for dispersing the bCNT (45min sonication in a 50% (v/v) ethanol:water solution), produces a partial denaturation and a decrease in the length of dsDNA that facilitates the dispersion of CNT and makes possible an efficient electron transfer of guanine residues to the electrode. A critical analysis of the influence of different experimental conditions on the efficiency of the dispersion and on the performance of glassy carbon electrodes (GCE) modified with bCNT-dsDNA dispersion is also reported. The electron transfer of redox probes and guanine residues was more efficient at GCE modified with bCNT dispersed in dsDNA than at GCE modified with hollow CNT (hCNT) dispersed in dsDNA, demonstrating the importance of the presence of bCNT.

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.

Nitrosobenzene: electrochemical, UV-visible and EPR spectroscopic studies on the nitrosobenzene free radical generation and its interaction with glutathione

Abstract This paper reports both the electrochemical characterization and the reactivity of the nitroso radical anion from nitrosobenzene with glutathione. The reduction of nitrosobenzene to the corresponding nitroso radical anion was kinetically characterized in acetonitrile. Free radicals exhibited a natural decay of second order, with a constant value of k 2 =15 555±321 M −1 s −1 . Also, the radicals were characterized by UV-Visible and EPR spectroscopy. Data obtained with these two independent techniques clearly substantiated the formation of the nitrosobenzene radical under our experimental conditions. Furthermore, we have unambiguously demonstrated that glutathione (GSH) scavenged the nitroso radical anion electrochemically generated from nitrosobenzene. The scavenging effect of GSH is supported by the following experimental facts: 1. The parallel decrease of the anodic peak current in the cyclic voltammograms, corresponding to the nitroso radical anion concomitantly with the addition of GSH. 2. The significant decrease of the visible band at 560 nm corresponds to the radical after the addition of GSH. 3. The drop of the EPR signal intensity of the nitroso radical after the addition of GSH. By using a spin trapping technique, thiyl radical (GS . ) was detected during the reaction between the nitroso radical anion with GSH.

Electroreduction of 4-(nitrophenyl) substituted 1,4-dihydropyridines on the mercury electrode in aprotic medium

Abstract Electrochemical studies on 4-(nitrophenyl) substituted 1,4-dihydropyridines of pharmacological importance have allowed us to generate the one-electron reduction product, the nitro radical anion, ArNO 2 .− , in aprotic media. Cyclic voltammetric technique have been employed to study the tendency of ArNO 2 .− to undergo further chemical reaction. Second order kinetics for the decay of ArNO 2 .− were established for all the 1,4-dihydropyridines examined. The 1,4-dihydropyridine derivatives that have the nitro group in the orto position in the ring shows a trend to give less stable radicals when comparing with meta substitution. The cyclic voltammograms of the couple ArNO 2 ArNO 2 .− has also been examined in the presence and absence of glutathione concluding that it does not exist interaction among glutathione and the nitro radical anions in aprotic media.

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).

Cyclic voltammetric and EPR spectroscopic studies of benzodiazepines: loprazolam and flunitrazepam

The present paper reports on the electrochemical characterization by cyclic voltammetry of two 1,4-benzodiazepines, loprazolam and flunitrazepam in protic, aprotic and mixed media. In protic media (ethanol + 15 mM citrate buffer pH 8.0) both drugs were irreversibly reduced at HDME involving 4 electrons to give the hydroxylamine derivative. In the optimal mixed media conditions (DMF + 15 mM citrate buffer, 0.1 M TBAI, pH 9.0) and in aprotic media (DMF + 0.1 M TBAI), the one-electron reduction product corresponding to the nitro radical anion was successfully isolated for both drugs. In both electrolytic media (mixed or aprotic media) loprazolam was reduced at less negative potentials compared with flunitrazepam. Radical decay follows second order kinetics. In mixed media the following second order decay constants and half-lives (for a 5 mM concentration) were found: k2 = 1573.6 ± 35.7 l mol−1 s−1, t12 = 0.13 s for flunitrazepam and k2 = 455.5 ± 16.6 l mol−1 s−1, t12 = 0.44 s, for loprazolam. EPR spectra recorded in situ using DMF as an electrolytic solvent showed well-resolved spectra, confirming the reduction of both benzodiazepine derivatives to their corresponding nitro radical anions. The experimental and the simulated hyperfine constant values obtained by INDO calculations are in agreement. The magnitude of such hyperfine splitting constants permits us to conclude that these radical anions are mainly restricted to the benzene ring of the molecules.