- Spatially Resolved Spectroelectrochemical Examination of the Oxidation of Dopamine by Chlorpromazine Cation Radical
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Spatially resolved absorption measurements of electrogenerated chlorpromazine cation radical (CPZ.+) were used to monitor the kinetics of the homogeneous oxidation of dopamine (DA) in the solution near planar and cylindrical electrodes.Complete concentration vs distance profiles for CPZ.+ were obtained for both planar and convergent diffusion and were used to determine the reaction mechanism and rate constants.The oxidation of DA by CPZ.+ to dopamine orthoquinone involves successive one-electron transfers, and the results are inconsistent with disproportionation of the DA semiquinone.The observed kinetics and rate-limiting step were dependent on the position within the diffusion layer.Near the electrode surface the rate law is first order in CPZ.* and DA, and a second-order rate constant of 2.1 x 105 M-1s-1 was obtained.Further away from the electrode the reaction is second order in CPZ.+ due to the involvement of the second step, and several kinetic parameters for the second electron transfer were obtained.A change in diffusion geometry which occurs at a microwire electrode further perturbs local concentration distributions, and the reaction reaches equilibrium under certain conditions.In all cases, the observed rate laws were consistent with a general expression for the stepwise electron transfer.This report represents the first application of spatially resolved spectroelectrochemistry to a kinetic system and provides unprecedented detail about the CPZ.+/DA reaction.
- Deputy, Andrew,Wu, Huan-Ping,McCreery, Richard L.
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- Halogenated Alkylperoxyl Radicals as Oxidants: Effects of Solvents and of Substituents on Rates of Electron Transfer
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The peroxyl radicals CCl3O2., CHCl2O2., CH2ClO2., CCl3CCl2O2., CFCl2O2., CH3CCl2O2., CF3CHClO2., and CBr3O2. were produced by pulse radiolysis of aerated solutions of the appropriate halogen compound in 2-propanol or 2-propanol-water solutions.Rate constants for one-electron oxidation of chloropromazine by these radicals were determined by kinetic spectrophotometry in various solvent mixtures.The second-order rate constants were found to vary from 1 * 105 to 1 * 109 M-1 s-1.They depend very strongly on the solvent polarity and a reasonable correlation is obtained between log k for a certain peroxyl radical and the dielectric constant of the solvent mixture.The rate constants in the same solvent are strongly dependent of the substituents on the methylperoxyl radical and give a good correlation with the polar substituent constants ?*.
- Alfassi, Zeev B.,Mosseri, S.,Neta, P.
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- One-Pot Tandem Access to Phenothiazine Derivatives from Acetanilide and 2-Bromothiophenol via Rhodium-Catalyzed C-H Thiolation and Copper-Catalyzed C-N Amination
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A one-pot and step economic reaction involving Rh(III)-catalyzed C-H thiolation and relay Cu(II)-catalyzed C-N amination of acetanilide and 2-bromothiophenol is reported here, with several valuable phenothiazine products obtained. This synthesis protocol proceeds from easily starting materials, demonstrating high atom economy, broad substrate scope, and good yield. Furthermore, the directing group can be easily eliminated, and chlorpromazine is provided in a large scale; thus this synthesis protocol could be utilized to construct phenothiazine scaffolds.
- Rui, Xiyan,Wang, Chao,Si, Dongjuan,Hui, Xuechao,Li, Keting,Wen, Hongmei,Li, Wei,Liu, Jian
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p. 6622 - 6632
(2021/05/29)
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- A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential
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Overcoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol, which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bc showed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases and attenuates microglial activation by reducing iNOS expression.
- Uliassi, Elisa,Pena-Altamira, Luis Emiliano,Morales, Aixa V.,Massenzio, Francesca,Petralla, Sabrina,Rossi, Michele,Roberti, Marinella,Martinez Gonzalez, Loreto,Martinez, Ana,Monti, Barbara,Bolognesi, Maria Laura
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p. 279 - 294
(2018/10/20)
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- The design and synthesis of an antibacterial phenothiazine-siderophore conjugate
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Siderophore-antibiotic conjugates consist of an antibiotic covalently linked by a tether to a siderophore. Such conjugates can demonstrate enhanced uptake and internalisation to the bacterial cell resulting in significantly reduced MIC values and extended spectrum of activity. Phenothiazines are a class of small molecules that have been identified as a potential treatment for multidrug resistant tuberculosis and latent TB. Herein we report the design and synthesis of the first phenothiazine-siderophore conjugate. A convergent synthetic route was developed whereby the functionalised phenothiazine component was prepared in four steps and the siderophore component also prepared in four steps. In M. smegmatis the functionalised phenothiazine demonstrated an equipotent MIC value in direct comparison to the parent phenothiazine from which it was derived. The final conjugate was synthesised by amide bond formation between the two components and global deprotection of the PMB protecting groups to unmask the catechol iron chelating groups of the siderophore. The synthesis is readily amenable to the preparation of analogues whereby the siderophore component of the conjugate can be modified. The route will be used to prepare a library of siderophore-phenothiazine conjugates for full biological evaluation of much needed new antibacterial agents.
- Tarapdar, Abed,Norris, James K.S.,Sampson, Oliver,Mukamolova, Galina,Hodgkinson, James T.
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supporting information
p. 2646 - 2650
(2018/11/03)
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- A mechanistic study on the disproportionation and oxidative degradation of phenothiazine derivatives by manganese(III) complexes in phosphate acidic media
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The oxidative degradation of phenothiazine derivatives (PTZ) by manganese(III) was studied in the presence of a large excess of manganese(III)-pyrophosphate (P2O7 2-), phosphate (PO4 3-), and H+ ions using UV-vis. spectroscopy. The first irreversible step is a fast reaction between phenothiazine and manganese pyrophosphate leading to the complete conversion to a stable phenothiazine radical. In the second step, the cation radical is oxidized by manganese to a dication, which subsequently hydrolyzes to phenothiazine 5-oxide. The reaction rate is controlled by the coordination and stability of manganese(III) ion influenced by the reduction potential of these ions and their strong ability to oxidize many reducing agents. The cation radical might also be transformed to the final product in another competing reaction. The final product, phenothiazine 5-oxide, is also formed via a disproportionation reaction. The kinetics of the second step of the oxidative degradation could be studied in acidic phosphate media due to the large difference in the rates of the first and further processes. Linear dependences of the pseudo-first-order rate constants (k obs) on [Mn III] with a significant non-zero intercept were established for the degradation of phenothiazine radicals. The rate is dependent on [H+] and independent of [PTZ] within the excess concentration range of the manganese(III) complexes used in the isolation method. The kinetics of the disproportionation of the phenothiazine radical have been studied independently from the further oxidative degradation process in acidic sulphate media. The rate is inversely dependent on [PTZ+.], dependent on [H+], and increases slightly with decreasing H+ concentration. Mechanistic consequences of all these results are discussed.
- Wisniewska, Joanna,Rzesnicki, Pawel,Topolski, Adrian
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scheme or table
p. 767 - 774
(2012/07/01)
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- Assembly of substituted phenothiazines by a sequentially controlled CuI/L-proline-catalyzed cascade C-S and C-N bond formation
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(Chemical equation presented) In the pro-line of fire: A general and efficient cascade reaction approach to substituted phenothiazines, which relies on controlled sequential Cul/L-prolinecatalyzed C-S and C-N bond formations, is described. DMSO = dimethylsulfoxide.
- Dawei, Ma.,Geng, Qian,Zhang, Hui,Jiang, Yongwen
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supporting information; experimental part
p. 1291 - 1294
(2010/05/17)
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- Palladium-catalyzed three-component approach to promazine with formation of one carbon-sulfur and two carbon-nitrogen bonds
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(Chemical Presented) Zip it up! The use of a Pd/dppf catalyst gives access to the tricyclic phenothiazine scaffold starting from 1-bromo-2-iodobenzenes, aliphatic or aromatic amines, and 2-bromothiophenols in a single reaction flask (see scheme; dppf=1,1′-bis(diphenylphosphanyl) ferrocene; dba=dibenzylidineacetone). This transformation involves thioether formation and subsequent intermolecular and intramolecular aryl amination reactions. The reaction occurs in good overall yield and selectivity.
- Dahl, Troels,Tornoe, Christian W.,Bang-Andersen, Benny,Nielsen, Poul,Jorgensen, Morten
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supporting information; scheme or table
p. 1726 - 1728
(2009/02/06)
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- Heterocyclic compounds
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A compound of formula (I): STR1 in which X, n, B and Y are as defined in the description. useful as cytokine inhibitors.
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- Radiolytic Reductions and Oxidations in Dimethyl Sulfoxide Solutions. Solvent Effects on Reactivity of Halogen Atom Complexes
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Radiolysis of dimethyl sulfoxide (DMSO) solutions containing various additives was used to achieve clean one-electron reduction or oxidation of solutes.Pulse radiolysis of benzoquinone in DMSO solutions containing acetone and triethylamine permitted conversion of all primary radicals into reducing species.The total yield of reduction in the γ-radiolysis of methyl viologen solutions was found to be 0.37 μmol/J.In the pulse radiolysis of TMPD and triphenylamine in aerated DMSO containing LiCl and/or CCl4, all the primary radicals were converted into oxidizing species and gave a maximum yield of 0.39 μmol/J.In the latter systems, oxidation was partly by halogen atom complexes.The reactivity of complexes of DMSO (DMSO*Cl, DMSO*Br) and of halide ions (Br2.1-, I2.1-) was examined for several organic compounds.DMSO*Cl oxidizes chlorpromazine, triphenylamine, and zinc porphyrin with rate constants of the order of 1E7-1E8 M-1 s-1, and the rates increase upon addition of CH2Cl2 as well as upon addition of water and formamide.DMSO*Cl also reacts with olefins by addition of Cl to the double bond; the rate constants increase upon increasing the electron-donating properties of the substituents on the double bond.The rate constants for oxidation of chlorpromazine by Br2.1- and I2.1- increase by more than 2 orders of magnitude upon changing the solvent from DMSO gradually to water.The change was less with acetonitrile/water mixtures, and the difference is probably due to differences in ion solvation.
- Kumar, M.,Neta, P.
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p. 3350 - 3354
(2007/10/02)
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- Redox Reactions of Thiol Free Radicals with the Antioxidants Ascorbate and Chlorpromazine: Role in Radioprotection
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The interaction of the thiyl radical from glutathione, GS*, and its corresponding peroxyl radical adduct, GSO2*, with the reducing agents, ascorbate and chlorpromazine, have been studied in aqueous solution at pH 5.0-5.5 using the technique of pulse radiolysis with spectrophotometric detection.The rate constants determined for interaction of GS* with ascorbate and chlorpromazine are 5.4 * 108 and 9.0 * 108 dm3 mol-1 respectively.The reaction is thought to proceed via an electron transfer process.Further, the redox potential of GS*/GSH at pH 5.0 is estimated to be 0.91 V.In the presence of different concentrations of oxygen, it has been established that GSO2*, as observed at 540 nm, interacts with ascorbate and chloropromazine by electron transfer with rate constants of 2.1 * 108 and 5.0 * 108 dm3 mol-1 s-1 respectively.From these kinetic observations it is inferred that GSO2* is a weaker oxidant than GS*.From these findings the role of these glutathione radicals should be taken into account when considering the biological role of thiols in oxidative damage in biological systems.
- Tamba, Maurizio,O'Neill, Peter
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p. 1681 - 1685
(2007/10/02)
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- REGIO- AND CHEMOSELECTIVE N-C BOND FORMATION VIA CARBON DIOXIDE: A NEW SOURCE OF THE METHYL GROUP, APPLICATIONS TO N-METHYLATED SECONDARY AND TERTIARY AMINES
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Reductive carboxylation of a variety of secondary and primary amines to the corresponding N-methylated amines in the presence of various functional groups such as chlorosubstituents, carbon-carbon double bonds and phenolic hydroxyls is described.
- Ram, Siya,Spicer, Leonard D.
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p. 3561 - 3572
(2007/10/02)
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- Aminopyrine and Antipyrine Free Radical-cations: Pulse Radiolysis Studies of One-electron Transfer Reactions
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Absolute rate constants for the reaction of a variety of electrophilic free radicals with the pyrazoline derivatives aminopyrine and antipyrine have been measured by pulse radiolysis.In the case of aminopyrine the resulting radical cation is a particularly stable species ε325 5.35*103 dm3 mol-1 cm-1).Both compounds are readily oxidised to their respective radical-cations with the one-electron oxidation potential of antipyrine (E0 1.1-1.6 V) being higher than that of aminopyrine (E0 0.26-0.5 V).Studies of the reaction of the radical-cations with reducing agents suggest that aminopyrine in particular may prove to be a useful reference compound in studies of free radical one-electron oxidations.
- Forni, Luigi G.,Mora-Arellano, Victor O.,Packer, John E.,Willson, Robin L.
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p. 1579 - 1584
(2007/10/02)
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- Endor Studies of Cation Radicals from Pharmacologically Active Phenothiazines
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A variety of substituted phenothiazine cation radicals, including those from pharmacologically active derivatives, e.g. chloropromazine, alimemazine and laevomepromazine, have been studied by means of ENDOR and TRIPLE resonace spectroscopy.These techniques allowed accurate determinations of hyperfine coupling constants, including their signs.Conclusions concerning molecular structure (e.g. twist angles) could be drawn, supporting previous investigations of the interrelationship of molecular conformations with the pharmacological potential, i.e. neuroleptic, antihistaminic or anti-Parkinsonian.
- Helle, N.,Kurreck, H.,Bock, M.,Kieslich, W.
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p. 964 - 970
(2007/10/02)
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- Chemical Behavior of SO3- and SO5- Radicals in Aqueous Solutions
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The chemistry of the radicals SO3- and SO5- has been investigated by using pulse radiolysis with kinetic spectrophotometry.Rate constants for the oxidation by SO3- of a variety of organic compounds were measured and equilibrium constants determined for the reactions of SO3- with chlorpromazine and phenol.SO3- was found to be a mild oxidant with a redox potential of E(SO3-/SO32-) = 0.63 V (vs.NHE) at pH>7 and E(SO3-/HSO3-) = 0.84 V at pH 3.6.The reaction of SO3- with O2 was shown to produce SO5-.The oxidation of several compounds by SO5- was found to occur more rapidly than their oxidation by SO3-.E(SO5-/HSO3-) was estimated to be approximately 1.1 V at pH 7.
- Huie, Robert E.,Neta, P.
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p. 5665 - 5669
(2007/10/02)
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- Spectroelectrochemical Examination of Charge Transfer between Chlorpromazine Cation Radical and Catecholamines
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With chlorpromazine (CPZ) and dopamine (DA) in their reduced forms in solution, the potential of a platinum electrode was stepped to a value where both species were oxidized at diffusion controlled rates.The CPZ+. cation radical so generated then diffused away from the electrode and encountered reduced DA, which it oxidized.The rate of oxidation was determined by monitoring the absorbance due to CPZ+. or dopamine quinone (DPQ) using the glancing incidence reflection spectroelectrochemical technique.The kinetics of the process indicate that the rate law is first order in both CPZ+. and DA, implying that the first encouter of the two molecules is the rate limiting step, rather than some subsequent process.The rate constant for dopamine was compared with those for three other catechols, and the rate constant increased monotonically with driving force, as measured by the difference in redox potentials between catechol and CPZ.The advantages of the technique for studying homogeneous charge transfer reactions are noted, as is the implication of the results on the CPZ+./DA reaction on the biological effects of CPZ.
- Mayausky, J. S.,McCreery, R. L.
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p. 308 - 312
(2007/10/02)
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- Cation Radicals of Phenothiazines. Part 4. Electron Transfer Between Aquamanganase(III) and N-Alkylphenothiazines
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The kinetics of electron transfer between aquamanganase(III) and N-alkylphenothiazines, giving rise to the corresponding cation radicals, has been investigated in the range 0.20-1.50 mol dm-3 HClO4 at different temperatures.The main reaction path has been assigned to the unhydrolysed species Mn(3+)(aq), and there is a dependence of the rate constants on the corresponding reduction potentials.
- Pelizzetti, Ezio
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p. 484 - 486
(2007/10/02)
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- Substituted bis-hydroxyphenyl pentanes
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The present invention relates to new bis-hydroxyphenyl-alkanes of the formula I SPC1 wherein one of the radicals X1 to X4 represents halogen and the others represent hydrogen, halogen, or alkyl, process for their manufacture, agents which contain these new compounds, and to the use of the new compounds for combating microorganisms and for material protection.
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- Alkylphenols
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New alkylphenols of formula I SPC1 SPC2 method of preparing this new compounds and their use for the control of harmful microorganisms, and helminths and for protecting organic materials.
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