Oxidation Of Phenothiazines Research Articles

Electrochemical generation of phenothiazin-5-ium. A sustainable strategy for the synthesis of new bis(phenylsulfonyl)-10H-phenothiazine derivatives

In this work, the electrochemical generation of phenothiazin-5-ium (PTZox) from the direct oxidation of phenothiazine (PTZ) in a water/acetonitrile mixture using a commercial carbon anode and conventional stainless steel cathode is reported. PTZox is a reactive intermediate with high potential synthetic applications, which is used in this paper for the synthesis of new phenothiazine derivatives. In this work a novel and simple electrochemical methodology for the synthesis of some bis(phenylsulfonyl)-10H-phenothiazine derivatives was established. In this paper, a mechanism for PTZ oxidation in the presence of arylsulfinic acids has been proposed based on the results obtained from voltammetric and coulometric experiments as well as spectroscopic data of the products. These syntheses are performed in a simple cell by applying constant current under mild conditions and at room temperature with high atom economy.

A comprehensive study on electrochemical oxidation of phenothiazine in water-acetonitrile mixture: Electrosynthesis of phenothiazine dimers

Electrochemical oxidation of phenothiazine (PTZ) was investigated in an acetonitrile/water (50/50, v/v) mixture using differential pulse voltammetry, cyclic voltammetry, choronopotentiometry, constant current electrolysis and controlled-potential coulometry. Our findings show that the oxidation pathway of PTZ at different pH values does not follow a simple pattern and varies with respect to pH. Our results show that the oxidation process at pH ≤ 1, occurs via two one-electron steps, while this process at 1 < pH ≤ 7 is a two-electron process. Surprisingly, this oxidation at pH values > 7 again turns into two one-electron steps. We have performed this study to achieve the following goals. (a) To gain in-depth insights into the oxidation mechanism of PTZ and (b) the development of a new strategy for PTZ dimerization. To achieve the second goal, we performed electrooxidation of PTZ at pH 3. Using the obtained electrochemical data, we succeeded in synthesizing two new types of PTZ dimer (D1 and D2). The structures of D1 and D2 are fully characterized by 1H NMR, 13C NMR, mass spectrometry, and FTIR techniques. The synthesis of D1 and D2 is performed in a mixture of acetonitrile and water (50/50, v/v), without the use of the oxidant or catalyst, using an undivided cell and carbon electrode, under mild conditions, using an air-assisted electrochemical method.

Observation of HOCl generation associated with diabetic cataract using a highly sensitive fluorescent probe

Diagnosis of diabetic cataract (DC) in the early stage is of great significance for drug intervention and surgery circumvention for DC patients. However, the lack of reliable imaging tools greatly limits the diagnosis of early DC. In this context, a fluorescent probe BBPy for hypochlorous acid (HOCl) is presented based on the oxidation of phenothiazine. The probe displays apparent emission enhancement at 562 nm toward HOCl with high selectivity, superb sensitivity (detection limit: 12.6 nM), and rapid response (within seconds). Using the probe, the HOCl generation in diabetic human lens epithelial cells was monitored, as well as the HOCl down-regulation during antioxidant treatment. Therefore, it is proposed that HOCl can be a promising biomarker for DC and fluorescence imaging technique can be regarded as a candidate tool for DC diagnosis.

Oxidation of phenothiazine based fluorescent probe for hypochlorite and its application to live cell imaging

New phenothiazine appended BODIPY derivative has been synthesized and characterized for the determination of hypochlorite in live cells. The fluorescent probe has exhibited 72 fold fluorescence enhancement upon addition of hypochlorite over other reactive oxygen species. Further, the studies proved that the probe has ability to detect the hypochlorite even at extremely low level (4.1 nM). Having less cytotoxicity and negligible auto-fluorescence, the probe was successfully used to monitor external addition and internal secretion of hypochlorite in RAW 264.7 cells.

Application of heme-containing biocatalysts for oxidation and determination of organosulfur compounds

The conditions of the oxidation of dibenzothiophene and aliphatic phenothiazines (promazine and chlorpromazine) in the presence of heme-containing biocatalysts (such as horseradish peroxidase and hemoglobin) have been optimized. It has been demonstrated that hemoglobin is an efficient catalyst for the fast and selective conversion of dibenzothiophene to the corresponding sulfoxide (yield is 91 ± 2% in 5 min); horseradish peroxidase is a more promising catalyst for the oxidation of phenothiazines. The effect of polar organic solvent (dimethyl sulfoxide) on the kinetics parameters of the reaction of oxidation of promazine in the presence of heme-containing biocatalysts has been studied. Procedures of determining phenothiazines based on spectrophotometric control of the rate of their oxidation have been developed. The applicable concentration ranges for the determination of promazine and chlorpromazine using horseradish peroxidase in aqueous medium were 10–100 μM and 10–200 μM respectively, and 20–500 μM for the determination of promazine in the presence of 10 vol % of dimethyl sulfoxide.

Spectrophotometric Determination of some Phenothiazines Using N-Chlorosuccinimide

A simple and sensitive spectrophotometric method has been developed for the determination of some phenothiazine derivatives as pure and in dosage form. The method is based on oxidation of phenothiazine s by N-chlorosucci nimide in hydrochloric acid medium to give red coloured species having maximum absorptions in the range 516.5534.5nm. Beer‘s law is obeyed over the concentration ranges 2-28, 2-32 and 4-40µg.ml -1 with apparent molar absorptivity of 6.16 ×10³, 5.89 ×10³ and 5.34×10³ l.mol -1 .cm -1 for phenothiazine, promethazine hydrochloride and chlorpromazine hydrochloride respectively. Additives and excipients normally found in dosage forms do not interfere.

Determination of Some Phenothiazines Compounds in Pharmaceuticals and Human Body Fluid by Electrocatalytic Oxidation at a Glassy Carbon Electrode Using Methylene Blue as a Mediator

A glassy carbon electrode plus Methylene blue as a mediator was employed to study and sense the electrocatalytic oxidation of phenothiazines, including chlorpromazine, perphenazine, promazine, and fluphenazine, using cyclic voltammetry and chronoamperometry as diagnostic techniques. The electron-transfer coefficient, alpha (= 0.45), for phenothiazines compounds at the surface of glassy carbon electrode was determined using a cyclic voltammetry technique. It was found that under a selected pH (8.6) the peak current due to the oxidation of Methylene blue at the surface of the electrode that occurrs at a potential of about − 180 mV is proportional to the phenothiazines concentration. Linear analytical curves were obtained in the ranges of 1.0 × 10−6 − 2.1 × 10−4 mol L−1 for the phenothiazines compounds. The influences of potentially interfering substances on the current response of the system were examined. The method was used for the determination of phenothiazines compounds, including chlorpromazine, perphenazine, promazine, and fluphenazine in human.

Challenges in Distinguishing Superexchange and Hopping Mechanisms of Intramolecular Charge Transfer through Fluorene Oligomers

The temperature dependence of intramolecular charge separation in a series of donor-bridge-acceptor molecules having phenothiazine (PTZ) donors, 2,7-oligofluorene FL(n) (n = 1-4) bridges, and perylene-3,4:9,10-bis(dicarboximide) (PDI) acceptors was studied. Photoexcitation of PDI to its lowest excited singlet state results in oxidation of PTZ via the FL(n) bridge. In toluene, the temperature dependence of the charge separation rate constants for PTZ-FL(n)-PDI, (n = 1-4) is relatively weak and is successfully described by the semiclassical Marcus equation. The activation energies for charge separation suggest that bridge charge carrier injection is not the rate limiting step. The difficulty of using temperature and length dependence to differentiate hopping and superexchange is discussed, with difficulties in the latter topic explored via an extension of a kinetic model proposed by Bixon and Jortner.

Trypanosoma cruzi Dihydrolipoamide Dehydrogenase as Target for Phenothiazine Cationic Radicals. Effect of Antioxidants

Myeloperoxidase (MPO), myoglobin (Mb) and horseradish peroxidase (HRP), catalyzed the generation of radical-cations by one-electron oxidation of phenothiazines (PTZ). The transient formation of these radicals (PTZ+.) was confirmed by ESR and optical spectroscopy. These species are reactive towards Trypanosoma cruzi LADH (T. cruzi LADH), T. cruzi trypanothione reductase (T. cruzi TR) and possibly other macromolecule targets. Both T. cruzi enzymes were irreversibly inactivated. T. cruzi LADH inactivation depended on: a) PTZ structure, peroxidase nature and the rate production of PTZ+. radical cations; b) incubation time; c) the presence of an antioxidant that intercepts free radicals. The production of PTZ+. radical cations, which is essential for T. cruzi LADH inactivation, is correlated with the electron donor ability of the substrates, as qualified by the Hammett sigmapara constant for the subtituent in the 2-position of the PTZ. Promazine (PZ), trimeprazine (TMPZ) and thioridazine (TRDZ) were the most effective inactivating agents, whereas trifluophenothiazines with CF3 group at 2-position (Trifluoperazine (TFP), fluphenazine (FFZ) and trifluopromazine (TFPZ)), and propericyazine (PCYZ) with CN group at 2-position, were much less active or inactive, all in close agreement with their higher or lowest electron donor ability, respectively. Comparison of inactivation values for T. cruzi LADH and mammalian heart LADH demonstrated a greater sensitivity of T. cruzi LADH to various PTZ studied. Thiol compounds, tyrosine, dopa, tryptophan, NADH, ascorbate and trolox prevented T. cruzi LADH inactivation by the peroxidase/H2O2 systems in agreement with their ability to suppress PTZ+. radical cations. The role of these radicals as enzyme inhibitors, or as generators of secondary free radicals and metabolite depletors may contribute to explain the trypanocidal effect as well as other chemotherapeutic actions of PTZ.

Phenothiazine as Stabilizer for Acrylic Acid

For the safe and trouble-free operation of a manufacturing plant and the safe storage of acrylic monomers a sufficiently effective polymerization inhibitor is necessary. As stabilizers different radical interceptors are used. Hydroquinone monomethyl ether (MeHQ) and phenothiazine (PTZ) are the standard stabilizers. In this paper, the decomposition kinetics of PTZ was investigated under process conditions. In acrylic acid a linear PTZ consumption was detectable under process conditions, whereby five different decomposition products were formed. The PTZ consumption was caused by thermal decomposition and by radical and oxidation reactions. With increasing temperature the portion of the total PTZ consumption caused by radical reactions decreased rapidly (68 % at 60 °C → 38 % at 90 °C) and the part of the oxidation reactions of the inhibitor increased (27 % at 60 °C → 54 % at 90 °C). Comparative investigations in air and nitrogen atmosphere resulted in different values for PTZ consumption and radical formation rates. Measurements of oxygen and PTZ consumption in air atmosphere showed a ratio of 2:1 mol mol–1 (60 °C) which increased with temperature up to 4:1 mol mol–1 (90 °C). The data showed that in acrylic acid stabilized with PTZ the oxygen consumption could not be totally prevented. This indicates that one part of the oxygen is consumed by the oxidation of PTZ while another part reacts directly with the primary radicals which are not trapped by the inhibitor. With the results of this work it is possible to optimize the PTZ stabilization of acrylic acid under process conditions in the presence and absence of oxygen.

Wire-like charge transport at near constant bridge energy through fluorene oligomers.

The study of photoinitiated electron transfer in donor-bridge-acceptor molecules has helped elucidate the distance dependence of electron transfer rates and behavior of various electron transfer mechanisms. In all reported cases, the energies of the bridge electronic states involved in the electron transfer change dramatically as the length of the bridge is varied. We report here, in contrast, an instance in which the length of the bridge, and therefore the distance over which the electron is transferred, can be varied without significantly changing the energies of the relevant bridge states. A series of donor-bridge-acceptor molecules having phenothiazine (PTZ) donors, 2,7-oligofluorene (FL(n)) bridges, and perylene-3,4:9,10-bis(dicarboximide) (PDI) acceptors was studied. Photoexcitation of PDI to its lowest excited singlet state results in oxidation of PTZ via the FL(n) bridge. In toluene, the rate constants for both charge separation and recombination as well as the energy levels of the relevant FL(n)(+.) bridge states for n = 1-4 are only weakly distance dependent. After the initial photo-generation of (1)(PTZ(+.)-FL(n)-PDI(-.)), radical pair intersystem crossing results in formation of (3)(PTZ(+.)-FL(n)-PDI(-.)) that recombines to give (3.)PDI. The dependence of the (3.)PDI yield on an applied magnetic field shows a resonance, which gives the singlet-triplet splitting, 2J, of the radical ion pair. The magnitude of 2J directly monitors the contribution of coherent charge transfer (superexchange) to the overall electron transfer rate. These data show that charge recombination through FL(n) is dominated by incoherent hopping at long distances.

ESR study of photooxidation of phenothiazines in aqueous micellar solutions

The mechanism of photooxidation of phenothiazine in liquid and frozen (77 K) aqueous micellar solutions of the surfactant (sodium dodecyl sulfate) was studied by ESR. The main reaction of electrons formed by the photochemical oxidation of phenothiazine in a liquid micellar solution of the anionic surfactant is the reduction of molecular oxygen dissolved in the aqueous bulk phase. 10-Methylphenothiazine was used as a stable radical cation probe in a liquid solution. The influence of electrolytes on the photoionization yield in both frozen and liquid solutions of the surfactant was studied.

Continuous photometric method for the screening of human urines for phenothiazines

A fully automated urinary screening system for five phenothiazines has been developed. The method is based on the oxidation of phenothiazines in acid medium to colourless sulphoxides via orange or purple coloured intermediates, which are continuously monitored at 520 nm. Two innovations have been implemented versus the conventional method; first, sulphuric acid (ideal reaction medium) has been changed by nitric acid (less corrosive, and compatible with pumping tubes) and second, problems associated with the instability of phenothiazonium radical cation are eliminated as the measurements are carried out simultaneously to the formation of the coloured products in the flow system. The configuration adopted permits selective retention of phenothiazines on a LiChrolut ®-EN sorbent column before their oxidation with hexacyanoferrate(III) ions in acid medium. The proposed method allows phenothiazines determination within the interval 3–50 μM (1–20 μg ml −1), with a throughput of 12 h −1; an average relative S.D. of 4% ( n=11) was obtained for phenothiazine concentration of 5 μM. Finally, a comprehensive study of 50 real urine samples (phenothiazines free) obtained from different individuals provided 6% of false positives and 0% false negatives for chlorpromazine concentrations of 1.5 and 3 μM, respectively.

Titrimetric micro-determination of therapeutically active phenothiazines using periodate

Two new simple, accurate and precise titrimetric micro-procedures are described for the analysis of phenothiazines in pure sample, tablets, injections and syrup using periodate as the oxidant. The first method is based on the oxidation of phenothiazines with periodate in acid medium and the iodate formed in the reaction is determined by reacting it with iodide and titrating the liberated iodine with thiosulfate after masking the excess of periodate with molybdate. In the second procedure, the unreacted (excess) periodate is determined iodometrically under basic conditions. The reaction conditions have been optimised and the stoichiometry of the reaction has been evaluated. A linear relationship exists between the amount of the drug and the titration end-point as shown by the values of correlation coefficient, r (0.9991–0.9999). The slope of the linear relationship has been calculated and found to be in the range, 0.1457–0.3120. The methods were applied to the analysis of dosage forms with results comparable to those given by the official methods. Both the methods are indirect visual titration methods, and are simpler than, and superior to, many existing methods for the assay of phenothiazines.

Application of potassium dichromate and iron–thiocyanate in the spectrophotometric investigations of phenothiazines

A spectrophotometric procedure for the determination of phenothiazines in pure form and in a number of their pharmaceutical preparations has been developed that offers the advantages of simplicity, accuracy, precision and sensitivity over many other methods. The method is based on the oxidation of phenothiazines by a known excess amount of potassium dichromate followed by the estimation of unreacted amount of dichromate by reacting with excess of iron(II) and measuring the iron(III) formed by complexing with thiocyanate. The reacted oxidant corresponds to the drug content. Different variables affecting the reaction between drugs and dichromate were studied and optimized. At the maximum absorption of 480 nm, Beer's law is obeyed in the range 2.5–29.75 μg/ml. The molar absorptivity and Sandell sensitivity of the procedure were calculated in addition to detection limit. Statistical treatment of the experimental results indicates that the procedure is precise and accurate. Excipients used as additives in pharmaceutical formulations did not interfere in the proposed procedure. The reliability of the method was established by parallel determination against the official BP methods. The procedure described was successfully applied to the determination of the bulk drugs and in pharmaceutical formulations.

ANALYTICAL STUDY OF THE REACTION OF PHENOTHIAZINES WITH SOME OXIDANTS, METAL IONS, AND ORGANIC SUBSTANCES (REVIEW ARTICLE)

Phenothiazines substituted in the 2 and 10 positions exhibit many valuable analytical properties. They are easily oxidized in acidic medium with a number of oxidants, e.g., K2Cr2O7, NH4VO3, Ce(SO4)2, KBrO3, KIO3, KIO4, NaNO2, H2O2, and chloramine T, with the formation of colored oxidation products. This property enable certain phenothiazines to be used as redox indicators for the determination of Fe(II), Sn(II), U(IV), Mo(V), ascorbic acid, etc. Oxidation reactions of phenothiazines were also used for their determination by spectrophotometric and flow injection methods. Some ions, such as iron, vanadium, iodide, or nitrite have a catalytic effect on the oxidation of phenothiazines. Owing to these properties several catalytic methods for the determination of metals, iodide, and nitrite have been proposed. Phenothiazines react in acidic media with platinum metals, e.g., Pd(II), Ru(III), and Pt(IV), the formation of colored complexes. They also react with thiocyanate anionic complexes of metals, e.g., Co(II), Pd(II), Fe(III), Bi(III), Cr(III), Ti(IV), Nb(V), Mo(V), and U(VI). Some organic substances (e.g., picric acid, flavianic acid, alizarin S, titan yellow, brillant blue, pyrocatechol violet) form with phenothiazines colored ion-association compounds sparingly soluble in water. These complexes are the basis for an extractive spectrophotometic determination of some metals or phenothiazines.

Oxidation of phenothiazine and phenoxazine by Cunninghamella elegans

1. To determine the ability of fungi to metabolize sulphur- and oxygen-containing azaarenes, Cunninghamella elegans ATCC 9245 was grown in 125-ml flasks containing fluid Sabouraud medium. The cultures and controls were incubated at 28°C with shaking and dosed with 16.7 mM phenothiazine or phenoxazine. After incubation for 72h, the mycelia and filtrates were extracted with ethyl acetate and the combined residues analysed by high-performance liquid chromatography. Residual phenothiazine and phenoxazine were 21 and 22%, respectively, of the total UV absorbance at 254 nm. 2. The metabolites were identified by mass spectrometry and proton nuclear magnetic resonance spectroscopy. The fungus oxidized phenothiazine to phenothiazine sulphoxide, 3-hydroxyphenothiazine sulphoxide, phenothiazin-3-one, and 3-hydroxyphenothiazine and oxidized phenoxazine to phenoxazin-3-one. 3. Three of the four compounds produced by C. elegans from phenothiazine were identical to those produced by mammals, supporting the use of the fungus as a microbial model for drug metabolism.

Determination of some antipsychotropic and anticholinergic phenothiazine drugs by vanadium (V) titration

Three simple, rapid and accurate titrimetric procedures using ammonium metavanadate have been developed for the determination of six phenothiazine drags in pure form and in dosage forms. The procedures are based on the oxidation of phenothiazines in acid medium to colourless sulphoxides via orange or purple coloured intermediates. In the first method, phenothiazines are titrated directly in H2SO4-H3PO4 medium to a colourless end-point. In the second procedure, a known excess of oxidant is added and after a specified time, the residual oxidant is determined using standard ammonium ferrous sulphate titration. The third method employs electrometric end-point detection. The optimum reaction conditions and other analytical parameters are evaluated. The influence of the substrates commonly employed as excipients with phenothiazine drags has been studied. Statistical comparison of the results with those of an official method shows excellent agreement and indicates no significant difference in precision.

Oxidimetric Titration of Some Phenothiazine Neuroleptics and Antiallergics with Potassium Dichromate

Three simple, rapid and accurate titrimetric procedures using potassium dichromate as titrant are described for the determination of six phenothiazine drugs in a pure form and in dosage forms. The procedures are based on the oxidation of phenothiazines in an acid medium to colorless sulfoxides via orange- or purple-colored intermediates. In the first method, phenothiazines are titrated directly in a H2SO4 medium to a colorless end-point. In the second procedure, a known excess of oxidant is added, and after a specified time the residual oxidant is determined iodometrically. The third method employs potentiometric end-point detection. The optimum reaction conditions and other analytical parameters are evaluated and the molar-ratio of the reaction is also calculated. The influence of the substrates commonly employed as excipients with phenothiazine drugs has been studied. A statistical comparison of the results obtained for pure drugs with those of an official method shows excellent agreement and indicates no significant difference in precision.

Titrimetric micro determination of some phenothiazine neuroleptics with potassium hexacyanoferrate(III)

Three simple, rapid and accurate titrimetric procedures using potassium hexacyanoferrate(III) have been developed for the micro determination of five phenothiazine drugs in pure form and in dosage forms. The procedures are based on the oxidation of phenothiazines in an acid medium to colourless sulphoxides via orange or purple coloured products. In the first procedure, phenothiazines are titrated directly in H 2SO 4–H 3PO 4 medium to a colourless end point. In the second method, a known excess of the oxidant is added and after a specified time, the residual oxidant is determined iodometrically. The third method employs electrometric end-point detection. The optimum reactions conditions and other analytical parameters are evaluated. The influence of the substrates commonly employed as excipients with phenothiazine drugs has been studied. Statistical comparison of the results with those of an official method shows excellent agreement and indicates no significant difference in precision.