P.A. Navarrete-Encina

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.

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.

Electrochemical and EPR Characterization of 1,4-dihydropyridines. Reactivity Towards Alkyl Radicals

This work reports the electrochemical oxidation of a series of three synthesized 4-substituted-1,4-dihydropyridine derivatives in different electrolytic media. Also, an EPR characterization of intermediates and the reactivity of derivatives towards ABAP-derived alkyl radicals are reported. Dynamic, differential pulse and cyclic voltammetry studies on a glassy carbon electrode showed an irreversible single-peak due to the oxidation of the 1,4-dihydropyridine (1,4-DHP) ring via 2-electrons to the corresponding pyridine derivative. Levich plots were linear in different media, indicating that the oxidation process is diffusion-controlled. Calculated diffusion coefficients did not exhibit significant differences between the derivatives in the same medium. The oxidation mechanism follows the general pathway (electron, H + , electron, H + ) with formation of an unstable pyridinium radical. One-electron oxidation intermediate was confirmed with controlled potential electrolysis (CPE) and EPR experiments. On applying N-tert-butyl- f -phenylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as the spin trap, these unstable radical intermediates from the oxidation of 1,4-DHP derivatives were intercepted. The final product of the CPE, i.e. pyridine derivative, was identified by GC-MS technique. Direct reactivity of the synthesized compounds towards alkyl radicals was demonstrated by UV-Vis. spectroscopy and GC-MS technique. Results indicate that these derivatives significantly react with the radicals, even compared with a well-known antioxidant drug such as nisoldipine.

Phase characterization of two homologous series of LC methacrylic monomers based on ω-hexyl- and ω-butyl-oxysalicylaldimine groups with different alkoxy tail substitutions

The phase characterization of two homologous series of liquid crystalline methacrylic monomers based on ω-hexyl- and ω-butyloxysalicylaldimine groups, with different alkoxy tails, is presented. The liquid crystalline materials were characterized by polarising optical microscopy, differential scanning calorimetry, differential thermal analysis, and X-ray diffraction. All the monomers exhibit the simultaneous occurrence of smectic A and C phases. When the alkyl chain is short, a narrow nematic phase is observed, leading to an I-N-SmA-SmC phase sequence.

Electrochemical characterization of ortho and meta-nitrotoluene derivatives in different electrolytic media. Free radical formation

Abstract This paper reports a comprehensive study by tast polarography, d.p.p., and cyclic voltammetry on the electrochemical reduction in different electrolytic media of ortho - and meta -nitrotoluene derivatives. Controlled potential electrolysis was used to generate the nitro radical anions and its detection by cyclic voltammetry and UV–Vis spectroscopy was performed. In protic media (30% ethanol/0.1 M Britton–Robinson buffer pH 2–12) both derivatives gave a sharp irreversible well-defined peak in all the pH range on Hg in a reaction involving four electrons to give the hydroxylamine derivative. In this medium meta -nitrotoluene is easier reduced in approximately 80 mV than that of the ortho -nitrotoluene. In mixed aqueous organic media (0.015 M aqueous citrate/DMF: 60:40, 0.3 M KCl and 0.1 M TBAI) at pH>8, the isolation and the electrochemical characterization of the one-electron reduction product, the nitro radical anion was achieved. At a 1 mM of nitrotoluene concentration, the average dismutation second-order rate constant values, k 2 , were: 11,000±170 and 6900±72 M −1 s −1 for ortho -and meta -nitrotoluene, respectively. In aprotic media (0.1 M TBAI in DMF), the nitro radical anions were more stable than that of mixed media, with the following dismutation second-order rate constant values, k 2 : 5800±35 and 4700±42 M −1 s −1 for ortho - and meta -nitrotoluene, respectively. Also, a comparison between nitrotoluene derivatives and some nitrocompounds of pharmacological relevance relating the effects of substituents on nitrobenzene and the electrolytic media composition on both the easiness of formation and stability of radicals is presented.

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 111M-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.

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.

Chromenopyridines: Promising Scaffolds for Medicinal and Biological Chemistry

Chromenopyridines constitute a structurally diverse class of compounds with a wide range of bioactivities and increasing presence in drugs. Here we analyze the scope of the synthetic methodology to access this nucleus with emphasis on multicomponent reactions and robust methodologies. Reactivity issues, medicinal applications and other properties are also reviewed.

Synthesis of Some C‐3,4,5‐Substituted 2,6‐Dimethyl‐1,4‐dihydropyridines (4‐DHPs)

Abstract A series of C‐3,4,5‐substituted 2,6‐dimethyl‐1,4‐dihydropyridines (1,4‐DHPs) with pharmacological properties were prepared by a variation from the classical Hantzsch synthesis. The procedure involves treatment of the respective aldehyde with either ethyl‐3‐aminocrotonate or 3‐aminocrotonitrile in anhydrous acetic acid at temperatures not exceeding 60°C, thus minimizing by‐product formation. The structures of title compounds were elucidated by 1H NMR, 13C NMR, FTIR, and elemental analysis.

Substituent effects on the electrochemistry and photostability of model compounds of calcium channel antagonist drugs

We have synthesized three nitrocompounds in order to mimic the model structure of some relevant drugs such as nifedipine. nitrendipine, nisoldipine, nimodipine, and related ones, in order to investigate the effect of structural change on its electrochemical and photodegradation properties. We have found that ortho substitution with a nitro group produces a distortion of the coplanar arrangement, thus decreasing the resonance interaction between the nitro group and the aromatic system. A consequence of this fact is the observed cathodic peak potential shift toward negative values in the ortho-substituted isomer. It is observed that the position of the nitro substitution also produced differences in the photostability of the studied compounds. Stability studies of the compounds in buffered solutions (pH 7) stored in room light conditions show that only the ortho derivative was unstable in the time scale of the experiment (2 h). The instability of the ortho derivative may be explained if we consider that in this isomer, the photoexcited state of the nitro group is not stabilized by resonance as a consequence of the loss of coplanarity between the nitro group and the aromatic ring. Using molecular modeling, we have found that the configuration of minimal energy shows torsion angles of 70, 7.5, and 2.2° for ortho- meta- and para-derivatives, respectively, confirming the lost of coplanarity between the nitro group and the aromatic ring in the ortho derivative.