Potent 5-nitrofuran derivatives inhibitors of Trypanosoma cruzi growth: electrochemical, spectroscopic and biological studies

Cyclic voltammetry and electron spin resonance techniques were used in the investigation of several potential antiprotozoal containing thiosemicarbazone and carbamate nitrofurans. In the electrochemical behaviour, a self-protonation process involving the nitro group was observed. The reactivity of the nitro anion radical for these derivatives with glutathione, a biological relevant thiol, was also studied in means of cyclic voltammetry. These studies demonstrated that glutathione could react with radical species from 5-nitrofuryl system. Furthermore, from the voltammetric results, some parameters of biological significance as E(7)(1) (indicative of the biological nitro anion radical formation), and [Formula: see text] (thermodynamic indicator the of oxygen redox cycling) have been calculated. We also evaluated the stability of the nitro anion radical in terms of the dimerization constant (k(d)). The nitrofuran-free radicals from cyclic voltammetry were characterized by electron spin resonance. A clear dependence between both the thiosemicarbazone or carbamate substructure and the length of the linker, furyl- or furylpropenyl-spacer, and the delocalization of the unpaired electron was observed. Through of biological assays we obtained important parameters that account for the selective anti-trypanosomal activity of these derivatives. The trypomastigote viability study showed that all derivatives are as active as in the epimastigote form of the parasite in a doses dependent manner.     

Voltammetric Study of Nitro Radical Anion Generated from Some Nitrofuran Compounds of Pharmacological Significance

The electrochemical behavior of 2‐(5‐amino‐ 1,3,4‐oxadiazolyl)‐5‐nitrofuran (NF359) and its comparison with well‐known drugs such as nifurtimox (NFX) and nitrofurazone (NFZ) in protic, mixed and aprotic media by cyclic voltammetry, tast and differential pulse polarography was studied. All the compounds were electrochemically reducible in all media being the reduction of the nitrofuran group the main voltammetric signal. The one‐electron reduction couple due to the nitro radical anion formation was visualized in mixed (for NF359 and NFZ) and aprotic media (for all compounds). By applying a cyclic voltammetric methodology we have calculated the decay constants (k₂) of the corresponding nitro radical anions in mixed and aprotic media. In mixed medium data fit well with a disproportionation reaction of the nitro radical anion but in aprotic medium fit better with a dimerization reaction. Also, considering cyclic voltammetric measurements in aprotic media we have estimated the reduction potential of the RNO₂/RNO₂^.? couple in aqueous medium, pH 7 (E¹₇ values) finding very good correlation with E¹₇ values obtained by pulse radiolysis. Furthermore we have calculated the equilibrium constants from the electron transfer from nitro radical anion to oxygen (k_O2) finding that nitro radical anion from NF359 is thermodynamically favored to react with oxygen in respect to both NFZ and NFX.     

Electrochemical Study of 4‐Substituted Analogues of Megazol

The electrochemical behavior of three different megazol analogues substituted at position 4 and their comparison with the parent compound megazol in protic and aprotic media by cyclic voltammetry, Tast and differential pulse polarography was studied. All the compounds were electrochemically reducible in both media with the reduction of the nitroimidazole group the main voltammetric signal. The one‐electron reduction couple due to the nitro radical anion formation was visualized only in aprotic media for all these compounds. By applying cyclic voltammetric methodology we have calculated the dimerization reaction decay constants (k₂) of the corresponding nitro radical anions in aprotic media. The nitro radical anion obtained from the synthesized nitroimidazole compound having a bromine substituent in 4‐position (GC‐141) was significantly more stable than the corresponding radical formed from the compound lacking of the substituent in 4‐position, megazol.     

ESR and electrochemical study of 5-nitroindazole derivatives with antiprotozoal activity

The electrochemistry of 3-alkoxy- and 3-hydroxy-1-[omega-(dialkylamino)alkyl]-5-nitroindazole derivatives were characterized using cyclic voltammetry in DMSO. The nitro reduction process was studied and this was affected by the acid moieties present in these compounds. A nitro anion self-protonation process was observed. This phenomenon was studied by cyclic voltammetry in presence of increasing amount of NaOH. The reactivity of the nitro anion radical of these derivatives with glutathione was also studied by cyclic voltammetry. The oxidizing effect of glutathione is supported by the parallel decrease of the anodic peak current and increase of the cathodic peak in the cyclic voltammograms, corresponding to the wave of the nitro anion radical from uncharged species with the addition of glutathione. Nitro anion radicals obtained by electrolytic reduction of these derivatives were measured and analyzed in DMSO using electron spin resonance spectroscopy.     

Analysis of the substituent effect on the reactivity modulation during self-protonation processes in 2-nitrophenols

A voltammetric and spectroelectrochemical ESR study of the reduction processes of five substituted 4-R-2-nitrophenols (R = -H, -OCH(3), -CH(3), -CN, -CF(3)) in acetonitrile was performed. In the potential range considered here (-0.2 to -2.5 V vs Fc+/Fc), two reduction signals (Ic and IIc) were detected; the first one was associated with the formation of the corresponding hydroxylamine via a self-protonation pathway. The voltammetric analysis at the first reduction signal showed that there are differences in the reduction pathway for each substituted 4-R-2-nitrophenol, being the E1/2 values determined by the inductive effect of the substituent in the meta position with respect to the nitro group, while the electron-transfer kinetics was determined by the protonation rate (k(1)+ ) of the anion radical electrogenerated. However, at potential values near the first reduction peak, no ESR signal was recorded from stable radical species, indicating the instability of the radical species in solution. Nevertheless, an intense ESR spectrum generated at the second reduction peak was detected for all compounds, indicating the monoelectronic reduction of the corresponding deprotonated 4-R-2-nitrophenols. The spin-coupling hyperfine structures revealed differences in the chemical nature of the electrogenerated radical; meanwhile, the -CF(3) and -CN substituents induced the formation of a dianion radical structure, and the -H, -CH(3), and -OCH(3) substituents provoked the formation of an anion radical structure due to protonation by acetonitrile molecules of the initially electrogenerated dianion radical. This behavior was confirmed by analyzing the ESR spectra in deuterated acetonitrile and by performing quantum chemical calculations of the spin densities at each site of the electrogenerated anionic radicals.     

Acid-promoted reactions of ethyl linoleate with nitrite ions: formation and structural characterization of isomeric nitroalkene, nitrohydroxy, and novel 3-nitro-1,5-hexadiene and 1,5-dinitro-1, 3-pentadiene products

The reaction of ethyl linoleate (1) with NO(2)(-) in different air-equilibrated acidic media resulted in the formation of complex patterns of products, some of which could be isolated by repeated TLC fractionation and were formulated as the nitroalkenes 2-5, the novel (1E, 5Z)-3-nitro-1,5-hexadienes 6/7, the novel (E,E)-1, 5-dinitro-1,3-pentadiene derivatives 8 and 9, and the nitro alcohols 10/11 and 12/13 by extensive GC-MS and 2D NMR analysis, as aided by 1D Hartmann-Hahn proton mapping experiments. Similar reaction of methyl oleate gave mainly nitroalkene (14/15) and allylic nitro derivatives (16/17). Formation of 2-13 may be envisaged in terms of HNO(2)-mediated nitration pathways in which regioisomeric beta-nitroalkyl radical intermediates derived from attack of NO(2) to the 1,4-pentadiene moiety of 1 evolve through competitive H-atom abstraction and free radical combination routes.     

Electrochemical reduction of 5-halo-5-nitro-1,3-dioxanes and 2-halo-2-nitro-1,3-propanediols

The character of the first stage of reduction of 5-X-5-nitro-1,3-dioxanes 1—10 and 2-X-2-nitro-1,3-propanediols 11 and 12 is independent of the nature of halogen (X = Br, Cl) and substituents in position 2 of the dioxane cycle. The transfer of two electrons to a molecule of compound 1—12 is accompanied by the anionoid elimination of halogen and formation of the anion of nitronic acid. The high mobility of halogen is mainly due to the acceptor nitro group capable of further transformations in the -position to halogen. The direction of further reduction involving the electron transfer to electrochemically active groups in the aromatic fragment of the molecule is determined by the nature of these groups. Chloro-, bromo-, and iodophenyl-substituted derivatives 4, 5, and 8—10 are reduced as typical halobenzenes. In the case of nitrophenyl-substituted compounds 3 and 7, the dioxane cycle opens to form dianions of p- and m-nitrobenzaldehydes along with the reduction of the nitroso group through the stages of formation of the radical anion and radical anion of the nitroso group. The radical anions of the nitro and nitroso derivatives were identified by ESR.     

若干D环带硝基的小檗因衍生物的光环化合成

通过酰烯胺的光环化反应, 合成了六个D环带硝基的小檗因类化合物。在酰烯胺的制备中, 还得到了几个非预期的副产物, 阐明了它们的结构。     

Nitroradical Anion Formation from some Iodo‐Substituted Nitroimidazoles

The electrochemical behavior of iodo nitroimidazole derivatives such as 1‐methyl‐4‐iodo‐5‐nitroimidazole (M‐I‐NIm) and 1‐methyl‐2,4‐diiodo‐5‐nitroimidazole (M‐I₂‐NIm) and the parent compound 1‐methyl‐5‐nitroimidazole (M‐NIm), was studied in protic, mixed and non‐aqueous media. The electrochemical study was carried out using Differential Pulse Polarography (DPP), Cyclic Voltammetry (CV), Differential Pulse Voltammetry (DPV) and coulometry and as working electrodes mercury and glassy carbon were used. As can be expected, in all media, the effect of introduce iodo as substituent in the nitroimidazole ring produced a decrease of the energy requirements of the nitro group reduction. Certainly, this fact can be explained by the electron withdrawing character of the iodo substituent that acts diminishing the electronic density on the nitro group thus facilitating their reduction. In all the studied media the reduction of M‐NIm produced a detectable signal for a nitro radical anion derivative. In the case of M‐I‐NIm the nitro radical anion was only detectable in both mixed and non‐aqueous media. On the other hand the nitro radical anion for the M‐I₂‐NIm was detected only in non‐aqueous medium. When glassy carbon electrode was used as the working electrode in a mixed medium a detectable nitro radical anion derivative appeared for all compounds, thus permitting an adequate comparison between them. The obtained values of k₂ for M‐NIm, M‐I‐NIm and M‐I₂‐NIm in non‐aqueous medium were 5.81×10², 132×10² and 1100×10² M^?1 s^?1, respectively. From the obtained k₂ and t_1/2 values in this medium, it is concluded that there is a direct dependence between the presence of iodo substitution in the nitroimidazole ring with the stability of the nitro radical anion.     

SPECTROSCOPIC STUDIES OF CUTANEOUS PHOTOSENSITIZING AGENTS—VI. IDENTIFICATION OF THE FREE RADICALS GENERATED DURING THE PHOTOLYSIS OF MUSK AMBRETTE, MUSK XYLENE AND MUSK KETONE

Musk ambrette (4-tert-butyl-3-methoxy-2,5-dinitrotoluene), a common component of perfumes, soaps, and some food flavorings, can cause cutaneous photosensitization reactions including photoallergy. These may be mediated through free radicals formed during photolysis. When musk ambrette was photolyzed under nitrogen in basic methanol, two distinct nitro anion radicals were identified by electron spin resonance. One radical was centered on a nitro group in the plane of the aromatic ring, while the other was centered on a nitro group twisted out of the plane of the ring due to steric hindrance by bulky substituents on either side of the group: the two radicals appeared to interconvert and maintain an equilibrium concentration ratio. Two closely related compounds which are also used in perfumes, but have not been reported to cause photosensitizing reactions, also produced free radicals during photolysis. Musk xylene (2,4,6-trinitro-1,3-dimethyl-5-tert-butylbenzene) generated two nitro anion radicals, both of which were centered on twisted nitro groups, while musk ketone (3,5-dinitro-2,6-dimethyl-4-tert-butylacetophenone) produced only one nitro anion radical, which is also twisted. Athough these nitro anion radicals are probably the first step in the photolysis of these nitroarornatic molecules, it seems likely that in vivo they will undergo further reduction to produce more reactive species including the corresponding nitroso and hydroxylamine derivatives. In addition, autoxidation of the nitro anion radical intermediate forms superoxide.     

Polarography of some 2,1,3-benzothiadiazoles,benzofurazans, 2,1,3-benzoselenadiazoles,and 3,4-disubstituted and fused 1,2,5-thiadiazoles

The redox behavior has been determined in acetonitrile solutions at a mercury and platinum electrode for 2,1,3-benzo(group VI)diazoles, and 3,4-disubstituted and fused 1,2,5-thiadiazoles. The derivatives studied contained alkyl, phenyl, bromo, chloro, cyano, nitro, methylsulfonyl, and trifluoromethylsulfonyl groups. All ring systems and their derivatives are reversibly reduced initially in a one-electron step, to their respective radical anion, but the nitro and bromo derivatives are reduced preferentially at the substituent group. The potential at which the production of the radical anion occurred became more anodic as the electron withdrawing ability of the substituent and the number of substituents increased.     

Voltammetric oxidation of acetophenone derivatives and benzophenone in acetonitrile on a platinum and glassy carbon electrode

The voltammetric oxidation of five para-substituted acetophenone derivatives (containing nitro, chloro, bromo, methyl and hydroxyl groups as substituents) and that of benzophenone was studied on a platinum and glassy carbon electrode in acetonitrile media. Electrode passivation was observed in the case when all selected compounds are on a glassy carbon electrode; an oxidation peak appeared between 2.5 and 3 V. The voltammograms of 4′-hydroxyacetophenone showed an additional peak around 2 V, which may be associated with the oxidation of the phenol moiety. In the case of a platinum electrode, no relevant peaks appeared on the voltammograms, reflecting the absence of passivation. The use of a redox probe 1,4-dihydroxybenzene showed that the glassy carbon electrode, after cyclization in the solutions of the outlined compounds, has higher sensitivity towards the oxidation product (1,4-benzoquinone) of this compound.     

Effect of ortho substitution on the charge localization of dinitrobenzene radical anions

Optical and electron paramagnetic resonance spectroscopies were used to study the radical anions of several m-dinitrobenzenes and p-dinitrobenzenes with substituents on ortho positions relative to the nitro groups. 1,4-Dinitrobenzene, 1,4-dimethyl-2,5-dinitrobenzene, and 2,5-dinitrobenzene-1,4-diamine radical anions are delocalized (class III) mixed valence species, but in the dinitrodurene radical anion the nitro groups are forced out of the ring plane due to the steric hindrance, which results in localization of the charge. The radical anions m-dinitrobenzene, 2,6-dinitrotoluene, and dinitromesitylene are all localized (class II) mixed valence species, as is common for m-dinitrobenzenes, and the rate of intramolecular electron transfer reaction strongly decreases with the number of methyl substituents. The same mechanism of rotation of the nitro groups out of the ring plane due to steric hindrance caused by neighboring methyl groups is also responsible for slowing the reaction. However, 2,6-dinitroaniline radical anion and 2,6-dinitrophenoxide radical dianion are charge-delocalized because the strong electron releasing amino and oxido groups increase the conjugation between the two charge-bearing units.     

Inner reorganization during the radical-biradical transition in a nor-beta-lapachone derivative possessing two redox centers

In this work, the electrochemical behaviour of an antitumoral nitro o-quinone derivative obtained from 3-bromo-nor-beta-lapachone was studied. Cyclic voltammetric experiments, in acetonitrile solution, revealed that both quinone and nitro functions are reduced independently as quasi-reversible one-electron transfer processes in this order. Depending on the reduction potential, a radical anion or a biradical dianion is obtained. The formation of these paramagnetic species was confirmed by performing in situ Electrochemical-Electron Spin Resonance (E-ESR) experiments. Analysis of the kinetics of electron transfer associated to those electron uptake processes, in terms of the Marcus-Hush-Levich model, revealed differences in the reorganization energy (lambda((k))) for both steps (lambda((I)): 1.07-1.11 eV; lambda((II)): 1.21-1.30 eV). By evaluating the conformations of the radical and biradical systems by calculations at the BLYP//TZVP level of theory, it was found that the inner component, for the second reduction process (lambda((II))) was approximately 72% of lambda((II)), reflecting modifications in the molecular structure during the radical anion-biradical dianion transition. This change is also reflected in the differences presented by line widths of the ESR signals of both electrogenerated radical and diradical species.     

Studies of potential inversion in the electrochemical reduction of 11,11,12,12-tetracyano-9,10-anthraquinodimethane and 2,3,5,6-tetramethyl-7,7,8,8-tetracyano-1,4-benzoquinodimethane

The electrochemical reduction of the title compounds, 2a and 3a, and 7,7,8,8-tetracyanoquinodimethane, 1a, was studied in acetonitrile. The reduction of 1a shows normal ordering of potentials, i.e., the potential for insertion of the first electron, E degrees1, is more positive than the potential for the second step of reduction, E degrees2. Thus, E degrees1 - E degrees2 > 0. By contrast, 2a and 3a show inversion of potentials where introduction of the second electron occurs with greater ease than the first (E degrees1 - E degrees2 < 0). The extent of inversion has been determined by simulation of the cyclic voltammograms obtained at 298 and 257 K. Electron paramagnetic resonance measurements at room temperature of solutions containing equimolar mixtures of the neutral and dianion allow determination of the concentration of anion radicals from which the disproportionation equilibrium constant and E degrees1 - E degrees2 can be calculated. The results were in good agreement with the voltammetric determinations. Calculations were conducted to characterize the structural changes accompanying reduction to the anion radical and dianion forms. Fast scan experiments at low temperatures (up to 10 000 V/s at 257 K; 500 V/s at 233 K) were conducted in an attempt to detect intermediates in the reduction, but none was found. Thus, it is not possible to state whether structural change and electron transfer are concerted or occur in discrete steps.     

Hydroxylation of nitrated naphthalenes with KO2/crown ether

Superoxide radical anion (O2*-), generated by KO2/crown ether, is effective for hydroxylation of nitronaphthalenes. When mono- and di-nitronaphthalenes are treated with KO2/crown ehter, hydroxylation results at the electron-deficient site caused by the electron withdrawing effect of the substituted nitro group. Kinetic experiments suggest that the hydroxylation proceeds by two different mechanisms dependent on the first one-electron reduction potential of nitronaphthalenes.     

Electron spin resonance studies of several anion radicals of nitro-substituted thioacylpiperidines and morpholines

The radical anions of m- and p- nitro-substituted derivatives of several classes of N-(thioacyl)-piperidines and -morpholines have been studied by ESR spectroscopy. The anion radicals were found to be centred on the nitro group, and the distribution of the unpaired electron was found to be dependent on the extent of conjugation between the thiocarbonyl group and the aromatic moiety of the molecule. The hfs constants were discussed in terms of the spin densities calculated by the McLachlan procedure.     

Synthesis of new type benzo[b]thiophene fused quinones and their tetracyanoquinodimethane derivatives

A series of new type of benzo[b]thiophene-fused 1,4-benzoquinones and their tetracyanoquinodimethane derivatives were synthesized. The cyclic voltammetric data of new type quinones and tetracyanoquinodimethane derivatives displayed different behavior. All new quinones exhibit two reduction waves corresponding to the radical anion and dianion. On the other hand, most tetracyanoquinodimethane derivatives display a singlewave reduction to the dianion. The benzo[b]thiophene moiety fused tetracyanoquinodimethane derivatives reveal more negative reduction potentials than that of tetracyanoquinodimethane.     

New reactivity of 1-(2-pyridyl)-2-propen-1-ol with nitro derivatives

1-(2-Pyridyl)-2-propen-1-ol showed an unprecedented reactivity behaving as Hantzsch ester 1,4-dihydropyridine mimic for the metal-free reduction of the nitro group of electron-deficient aromatic and heteroaromatic nitro compounds to the corresponding amino function. The redox mechanism is part of a domino process involving a direct trapping of the amino derivatives through aza-Michael addition to the vinyl ketone intermediate leading to the one-pot formation of new functionalised aminoacylpyridines.     

Kinetic study of the electron-transfer oxidation of the phenolate anion of a vitamin E model by molecular oxygen generating superoxide anion in an aprotic medium

Electron-transfer reduction of molecular oxygen (O2) by the phenolate anion (1-) of a vitamin E model, 2,2,5,7,8-pentamethylchroman-6-ol (1H), occurred to produce superoxide anion, which could be directly detected by a low-temperature EPR measurement. The rate of electron transfer from 1- to O2 was relatively slow, since this process is energetically unfavourable. The one-electron oxidation potential of 1- determined by cyclic voltammetric measurements is sufficiently negative to reduce 2,2-bis(4-tert-octylphenyl)-1-picrylhydrazyl radical (DOPPH*) to the corresponding one-electron reduced anion, DOPPH-, suggesting that 1- can also act as an efficient radical scavenger.