Electrochemical and ESR study of 5-nitrofuryl-containing thiosemicarbazones antiprotozoal drugs

Cyclic voltammetry and electron spin resonance (ESR) techniques were used in the investigation of several potential antiprotozoal thiosemicarbazones nitrofurane derivatives. A self-protonation process involving the protonation of the nitro group due to the presence of an acidic proton in the thiosemicarbazone moiety was observed in the first step of a CEE(rev) reduction mechanism of these derivatives. ESR spectra of the free radicals obtained by electrolytic reduction were characterized and analyzed. AM1 methodology was used to obtain the optimized geometries and UB3LYP calculations were performed to obtain the theoretical hyperfine coupling constants. The theoretical study exhibited an unusual assignment of the spin densities showing a free radical centered in the thiosemicarbazone moiety rather than the nitro which are in agreement with the experimental hyperfine pattern.     

Preparation of 3-methyl-4-vinyl-1,2,5-oxadiazole and 3-methyl-4-vinyl-1,2,5-thiadiazole

Short and high yielding preparations of 3-Methyl-4-vinyl-1,2,5-oxadiazole ( 6a ) and 3-Methyl-4-vinyl-1,2,5-thiadiazole ( 6b ) are described.     

Recent advances in the synthesis and functionalization of 1,2,5-oxadiazole 2-oxides

Among the variety of nitrogen heterocycles, the furoxan (1,2,5-oxadiazole 2-oxide) scaffold has attracted considerable attention owing to its ability to release NO under physiological conditions. Therefore, significant efforts of organic chemists have been directed toward the construction of new drug candidates containing the NO-donor furoxan subunit connected to a known pharmaceutical or a potential pharmacophore by CC/CN bonds or through an appropriate linker. This digest summarizes the recent information concerning both new synthetic approaches for the furoxan ring construction and various methods for the functionalized furoxan synthesis with particular focus on the last three years. Methods for the furoxan ring formation including cyclodimerization of nitrile oxides, nitrosation of unsaturated compounds, and acylation of dinitromethane sodium salt are reviewed. The functionalization of furoxan ring is represented by nucleophilic substitution of nitro and arylsulfonyl groups as well as by different condensations of cyano-, carbonyl- and carboxyfuroxan derivatives. Synthesis of hybrid structures combining NO-donor furoxan ring and some pharmacophoric moiety is also considered.     

Electron spin resonance studies and theoretical quantum calculations of free radicals generated from anthracenetrione by electrochemical and microsomal reduction

The ESR spectra of radicals obtained by electrolytic reduction of 4,4-dimethylanthracene-1,9,10 (4H)-trione (1) and the regioisomeric quinones 8-acetyloxymethyl-4,4,5-trimethyl- (2), and 5-acetyloxy-methyl-4,4,8-trimethyl-(4H)-1,9,10-anthracenetrione (3) were measured in DMSO and analyzed by quantum chemical calculations. The electrochemistry of these compounds was characterized using cyclic voltammetry, in DMSO and DMF solvents and compared with nifurtimox. The quinones were also reduced by microsomal NADPH-cytochrome P-450 reductase and the corresponding radicals species were also detected by ESR spectroscopy. AMI, INDO, and ADF calculations were performed to obtain the optimized geometries, theoretical hyperfine constants, and spin distributions, respectively. Density functional theory was used to rationalize the reduction potential of these compounds.     

Reactions with dye free radicals reveal weak redox properties of drugs

The calcium release channel (CRC) of the skeletal sarcoplasmic reticulum is rich in thiol groups and is strongly regulated by covalent modification of these thiols. Oxidizing reagents activate the release channel, whereas reducing reagents inhibit the channel. However, most CRC regulators are not thiol reagents. Here, we propose that reversible redox interactions are involved in regulation of the CRC by nonthiol reagents. This hypothesis was tested with several CRC regulators. The local anesthetics tetracaine, procaine and QX-314, which block the CRC, behaved as electron donors in reactions with dye free radicals. In contrast, ryanodine, caffeine, doxorubicin and daunorubicin, compounds known to activate the release channel, all accepted electrons from dye anion radicals. Moreover, release of Ca2+ from SR initiated by doxorubicin (acceptor) was antagonized by local anesthetics (donors). Based on the redox characterization of CRC modulators, we propose a functional model in which channel inhibitors and activators act as weak electron donors and acceptors, respectively, and shift the thiol-disulfide balance within the release protein. The consequence of this model is that, in spite of the chemical diversity of CRC modulators, a common mechanism of channel regulation involves the transient exchange of electrons between the activator/inhibitor and the CRC.     

A potential source of free radicals in iodine-based chemical oscillators

The iodide-peroxide system in an acidic medium was investigated as a potential source of free radicals in iodine-based chemical oscillators. The radicals were detected by EPR spin-trapping using spin-trap 5-(tert-butoxycarbonyl)-5-methyl-1-pyrroline N-oxide (BMPO), which forms stable spin-adducts with oxygen-centered radicals. The iodide-peroxide system is introduced as an easily available laboratory source of free radicals.     

Diffusion of free radicals as studied by tomography

A linear magnetic field gradient superimposed on the main static field was used to study one-dimensional diffusion of perchlorotriphenylmethyl radicals in decalin and of oxygen molecules in polytetrafluoroethylene. A simple method is developed for deducing diffusion coefficients from both time-dependent and single-scan experiments provided that the natural linewidth is small relative to the field change over the diffusion distance.     

Investigation of free radicals from N-substituted dihydrophenazines

A number of N-substituted dihydrophenazines were synthesized. New, neutral radicals of the phenazine series were obtained by oxidizing them with lead dioxide, and several of their properties were studied (EPR spectra and electronic spectra).Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1428–1431, October, 1970.     

Electrochemical Reduction and Oxidation of 3,4-Disubstituted 1,2,5-Thiadiazoles

The electron-acceptor nitrogen and sulfur atoms in 3,4-disubstituted 1,2,5-thiadiazoles are responsible for much decreased reduction potentials and much increased oxidation potentials of these compounds compared with the corresponding carbocyclic derivatives. The thiadiazole ring is resistant to oxidation, and the reversible electron transfer gives rise to fairly stable radical cations. Reductive stability of the heterocycle depends on the nature of its substituents and on the medium: When nucleofuge substituents are present, two-electron transfer in aprotic media results in heteroring opening with iminonitrile formation, whereas in the presence of two readily leaving groups, the electron transfer induces cleavage of the complete heteroring into inorganic anions.     

Synthesis and properties of vinyl ethers of 3,4-di(hydroxymethyl)-1,2,5-oxadiazole

The direct vinylation of 3,4-di(hydroxymethyl)-1,2,5-oxadiazole by acetylene was accomplished for the first time; its mono- and divinyl ethers were synthesized in the presence of cadmium acetate. The physicochemical and spectral properties and conformational structure of the synthesized compounds were studied. It was shown that the s-trans-trans-conformation is the most profitable for the divinyl ether of 3,4-di(hydroxymethyl)-1,2,5-oxadiazole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1044–1047, August, 1984.     

Studies in the chemistry of 1,2,5-oxadiazole (II). Synthesis and properties of furazanodiazepines

This paper describes the synthesis and the properties of some furazanodiazepine derivatives obtained by condensing the appropriate β-diketones with 3,4-diaminofurazan. On the basis of U.V., I.R. and N.M.R. evidence a mono-imino structure is suggested for the compounds obtained. Low temperature N.M.R. spectra suggest a rapid tautomensm for the dimethyl derivative.     

Intramolecular reactions of free radicals formed from artemisinin

Two cyclic alkoxyl radicals are formed as a result of peroxide bridge scission in artemisinin. Intramolecular reactions of these radicals induce the cascade of reactions of isomerization, decyclization, and decomposition of formed free radicals. It includes 14 reactions of intramolecular free radical hydrogen transfer, 17 reactions of decyclization of alkoxyl and alkyl radicals, and 4 reactions of decomposition of alkoxyl, acyl, and carboxyl radicals. The enthalpies of these 35 reactions are calculated. Using intersection parabolas method, activation energies and rate constants of all these reactions are calculated. The most rapid reactions are selected for every intermediate free radical. © 2005 Wiley Periodicals, Inc. Int J Chem Kinet 37: 554–565, 2005     

Design and synthesis of oxaprozin-1,3,4-oxadiazole hybrids as potential anticancer and antibacterial agents

In the present study, we report design, synthesis and screening of new novel 5-substituted-2-mercapto-1,3,4-oxadiazole analogues appended to oxaprozin for their in vitro anticancer and antibacterial activity. The synthesised compounds were characterized using various spectroscopic techniques. Furthermore, the structure of 5b (2-(2-[4,5-diphenyloxazol-2-yl]ethyl)-5-(ethylthio)-1,3,4-oxadiazole) was unequivocally confirmed by X-ray analysis. Among the series 5c (2-(2-[4,5-diphenyloxazol-2-yl]ethyl)-5-(propylthio)-1,3,4-oxadiazole) showed most promising anticancer activity against A549 cancer cell line and all the reported analogues manifested satisfactory safety profiles against human normal cell line HEK293T. The products exhibited good antibacterial activity and among the tested 5j (2-(2-[4,5-diphenyloxazol-2-yl]ethyl)-5-([4-fluorobenzyl]thio)-1,3,4-oxadiazole) exhibited most potent.     

EPR of free radicals formed from 3-hydroxyesculetin and related derivatives

EPR spectroscopy of 3-hydroxyesculetin (1, solid and in solution) and of the radicals formed during the aerobic oxidation of alkaline solutions of 1 and related compounds was investigated. 1 in the solid state was studied by pulsed EPR experiments and showed a radical character. The aerobic oxidation of alkaline solutions of 1 was also followed by EPR spectroscopy. A ring contraction occurred leading to a 5,6-dihydroxybenzofuran-2-carboxylate radical. The autoxidation of an alkaline solution of (Z)-3-(3,4-dihydroxyphenyl)-2-hydroxypropenoic acid allowed the observation of a spectrum attributable to 5,6-dihydroxybenzofuran-3-one-2-carboxylate radical. The formation mechanisms of these radicals are discussed.     

The role of melanin as protector against free radicals in skin and its role as free radical indicator in hair

Throughout the body, melanin is a homogenous biological polymer containing a population of intrinsic, semiquinone-like radicals. Additional extrinsic free radicals are reversibly photo-generated by UV and visible light. Melanin photochemistry, particularly the formation and decay of extrinsic radicals, has been the subject of numerous electron spin resonance (ESR) spectroscopy studies. Several melanin monomers exist, and the predominant monomer in a melanin polymer depends on its location within an organism. In skin and hair, melanin differs in content of eumelanin or pheomelanin. Its bioradical character and its susceptibility to UV irradiation makes melanin an excellent indicator for UV-related processes in both skin and hair. The existence of melanin in skin is strongly correlated with the prevention against free radicals/ROS generated by UV radiation. Especially in the skin melanin (mainly eumelanin) ensures the only natural UV protection by eliminating the generated free radicals/ROS. Melanin in hair can be used as a free radical detector for evaluating the efficacy of hair care products. The aim of this study was to investigate the suitability of melanin as protector of skin against UV generated free radicals and as free radical indicator in hair.     

Eccentric orbitals for sigma free radicals: vinyl and phenyl as test-cases

Enlarging the set of atomic orbitals of a free radical by basis functions located outside towards the gravity center of the unshared electron in a quasi-localized picture is shown to be possible for σ systems as vinyl and phenyl. The restricted open-shell theory has been used to optimize the characteristics of the free-electron orbital in vinyl, and additional unrestricted calculations performed in order to study its effect on spin densities.