- Potential CNS antitumor agents - phenothiazines I: Nitrogen mustard derivatives
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Four phenothiazine derivatives containing the bis (β chloroethyl) aminopropyl side chain were prepared and evaluated in the murine L 1210, P 388 and B 16 melanoma intraperitoneal tumor systems. Moderate P 388 activity was observed. An aminoethyl phenothiazine mustard was compared with the aminopropyl analogs and was superior in all test systems. None of the compounds tested against the murine ependymoblastoma brain tumor system was active.
- Hirata,Driscoll
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- Synthesis of diverse phenothiazines by direct thioamination of arynes with S-(o-bromoaryl)-S-methylsulfilimines and subsequent intramolecular BuchwaldHartwig amination
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A facile method for the synthesis of diverse phenothiazines has been achieved by direct thioamination of aryne intermediates with S-(o-bromoaryl)-S-methylsulfilimines and subsequent intramolecular BuchwaldHartwig amination. Since various sulfilimines could be prepared easily by odorless copper-catalyzed ipso-thiolation of readily available o-bromoarylboronic acids followed by imination and hydrolysis, this approach enables the synthesis of a wide variety of multisubstituted phenothiazines.
- Matsuzawa, Tsubasa,Uchida, Keisuke,Yoshida, Suguru,Hosoya, Takamitsu
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- Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs
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Given the role of trypanothione in the redox defenses of pathogenic trypanosomal and leishmanial parasites, in contrast to glutathione for their mammalian hosts, selective inhibitors of trypanothione reductase are potential drug leads against trypanosomiasis and leishmaniasis. In the present study, the rational drug design approach was used to discover tricyclic neuroleptic molecular frameworks as lead structures for the development of inhibitors, selective for trypanothione reductase over host glutathione reductase. From a homology-modeled structure for trypanothione reductase, replaced in the later stages of the study by the X-ray coordinates for the enzyme from Crithidia fasciculata, a series of inhibitors based on phenothiazine was designed. These were shown to be reversible inhibitors of trypanothione reductase from Trypanosoma cruzi, linearly competitive with trypanothione as substrate and noncompetitive with NADPH, consistent with ping-pong bi bi kinetics. Analogues, synthesized to define structure-activity relationships for the active site, included N-acylpromazines, 2-substituted phenothiazines, and trisubstituted promazines. Analysis of K(i) and I50 data, on the basis of calculated log P and molar refractivity values, provided evidence of a specially favored fit of small 2-substituents (especially 2-chloro and 2-trifluoromethyl), with a remote hydrophobic patch on the enzyme accessible for larger, hydrophobic 2-substituents. There was also evidence of an additional hydrophobic enzymic region available to suitable N-substituents of the promazine nucleus. K(i) data also indicated that the phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site. Selected compounds were tested for in vitro activity against Trypanosoma brucei, T. cruzi, and Leishmania donovani, with selective activities in the micromolar range being determined for a number of them.
- Chan, Cecil,Yin, Hong,Garforth, Jacqui,McKie, James H.,Jaouhari, Rabih,Speers, Peter,Douglas, Kenneth T.,Rock, Peter J.,Yardley, Vanessa,Croft, Simon L.,Fairlamb, Alan H.
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- On the microwave-assisted synthesis of acylphenothiazine derivatives - Experiment versus theory synergism
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The microwave-assisted synthesis of a series of acylphenothiazine derivatives is described. 10H-Phenothiazine-3-carbaldehyde derivatives were obtained in moderate yields by the Duff formylation reaction, and 10-acetyl-phenothiazine derivatives were obtained in excellent yields by acetylating phenothiazine derivatives with acetic anhydride. A theoretical explanation for the chemoselectivity and regioselectivity of these acylation reactions applied to phenothiazine substrates was attempted by molecular-modeling analyses based on molecular mechanics, and semi-empirical and DFT calculations.
- Gaina, Luiza,Porumb, Dan,Silaghi-Dumitrescu, Ioan,Cristea, Castelia,Silaghi-Dumitrescu, Luminita
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- A ONE-STEP SYNTHESIS OF 2,3-DIHYDRO-1,4-BENZOTHIAZINES AND PHENOTHIAZINES FROM 1,3-THIAZOLIDINE DERIVATIVES OF CYCLOHEXANONES
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N-Acetyl-1,3-thiazolidine derivatives of cyclohexanones, when treated with a threefold excess N-bromosuccinimide in anhydrous chloroform at room temperature, smoothly afford N-acetyl-2,3-dihydro-1,4-benzothiazines.This represents the first general route to such heterocyclic system in one step from aliphatic precursors.The synthesis optically active N-acetyl-2,3-dihydro-1,4-benzothiazines is also reported.
- Caputo, Romualdo,Ferreri, Carla,Longobardo, Luigi,Mastroianni, Domenico,Palumbo, Giovanni,Pedatella, Silvana
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- Design of novel potent antihyperlipidemic agents with antioxidant/anti- inflammatory properties: Exploiting phenothiazine's strong antioxidant activity
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Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.
- Matralis, Alexios N.,Kourounakis, Angeliki P.
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- Structure-activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives
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A number of phenothiazine N-alkyl amide derivatives were synthesized in order to examine the structure-activity relationships for inhibition of human acetylcholinesterase and butyrylcholinesterase. Several lines of evidence indicate that inhibition of butyrylcholinesterase (BuChE) is important in the treatment of certain dementias. Further testing of this concept requires inhibitors that are both BuChE-selective and robust. N-alkyl derivatives (2, 3, 4) of phenothiazine (1) have previously been found to inhibit only BuChE in a mechanism involving π-π interaction between the phenothiazine tricyclic ring system and aromatic residues in the active site gorge. To explore features of phenothiazines that affect the selectivity and potency of BuChE inhibition, a series of N-carbonyl derivatives (5-25) was synthesized and examined for the ability to inhibit cholinesterases. Some of the synthesized derivatives also inhibited AChE through a different mechanism involving carbonyl interaction within the active site gorge. Binding of these derivatives takes place within the gorge, since this inhibition disappears when the molecular volume of the derivative exceeds the estimated active site gorge volume of this enzyme. In contrast, BuChE, with a much larger active site gorge, exhibited inhibition that increased directly with the molecular volumes of the derivatives. This study describes two distinct mechanisms for binding phenothiazine amide derivatives to BuChE and AChE. Molecular volume was found to be an important parameter for BuChE-specific inhibition.
- Darvesh, Sultan,McDonald, Robert S.,Penwell, Andrea,Conrad, Sarah,Darvesh, Katherine V.,Mataija, Diane,Gomez, Geraldine,Caines, Angela,Walsh, Ryan,Martin, Earl
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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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supporting information
p. 6622 - 6632
(2021/05/29)
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- Utilizing d–pπ Bonds for Ultralong Organic Phosphorescence
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Developing pure organic materials with ultralong lifetimes is attractive but challenging. Here we report a concise chemical approach to regulate the electronic configuration for phosphorescence enhancement. After the introduction of d–pπ bonds into a phenothiazine model system, a phosphorescence lifetime enhancement of up to 19 times was observed for DOPPMO, compared to the reference PPMO. A record phosphorescence lifetime of up to 876 ms was obtained in phosphorescent phenothiazine. Theoretical calculations and single-crystal analysis reveal that the d–pπ bond not only reduces the (n, π*) proportion of the T1 state, but also endows the rigid molecular environment with multiple intermolecular interactions, thus enabling long-lived phosphorescence. This finding makes a valuable contribution to the prolongation of phosphorescence lifetimes and the extension of the scope of phosphorescent materials.
- Tian, Shuai,Ma, Huili,Wang, Xuan,Lv, Anqi,Shi, Huifang,Geng, Yun,Li, Jie,Liang, Fushun,Su, Zhong-Min,An, Zhongfu,Huang, Wei
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supporting information
p. 6645 - 6649
(2019/04/04)
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- Synthesis and biological properties of aryl methyl sulfones
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A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1 = 0.04 and COX-2 = 0.10 μM, and naproxen: IC50 COX-1 = 11.3 and COX-2 = 3.36 μM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies. The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.
- Navarro, Lorena,Rosell, Gloria,Sánchez, Silvia,Boixareu, Núria,Pors, Klaus,Pouplana, Ramon,Campanera, Josep M.,Pujol, M. Dolors
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p. 4113 - 4126
(2018/07/06)
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- Synthesis and microbiological evaluation of some new phenothiazine derivatives
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A new series of 4-(10-acetyl-10H-phenothiazine-3-yl)-1-phenylazetidine-2-ones (6a-g) was prepared by intermolecular cyclization of Schiff bases (5a-g) and chloroacetyl chloride in the presence of base catalyst triethylamine. The microbiological evaluations of the compounds 6a-g were performed, and the compounds 6a, 6b, 6d, 6f, and 6g showed significant antimicrobial activities.
- Sen, Sandip,De, Biplab,Mallik, Arunabha,Roy, Biswabara,Kumar, Deepak
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p. 221 - 226
(2018/09/14)
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- Compounds and methods for treating tumors
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The present invention relates to pharmaceutical compositions and methods for controlling tumor growth in cancer patients. These compounds and pharmaceutical compositions modulate the P-glycoprotein multidrug transporter system and inhibit the activated PI3K/Akt/mTOR/p70S6K signaling pathway. The compounds and pharmaceutical compounds of the present invention are particularly useful for treating metastatic and drug-resistant tumors.
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(2015/12/17)
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- An efficient one-pot reaction for the synthesis of pyrazolones bearing a phenothiazine unit
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A simple one-pot approach for the synthesis of new pyrazolones containing a phenothiazine unit is reported. Compound 4b was evaluated for its antiproliferative activity on a NCI-60 cancer cell line panel and exhibited selective cytostatic activity toward CCRF-CEM, HL-60(TB), K-562, MOLT-4, and RPMI-8226 leukemia cell lines.
- Baciu-Atudosie, Lavinia,Ghinet, Alina,Belei, Dalila,Gautret, Philippe,Rigo, Beno?t,B?cu, Elena
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p. 6127 - 6131
(2012/11/13)
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- Synthesis and antifungal activity of some substituted phenothiazines and related compounds
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Several phenothiazines and related compounds were synthesized and their antifungal activity was evaluated in vitro. The results observed for α-chloro-N-acetyl phenothiazine led us to choose this compound as a lead in the search of antifungal agents.
- Sarmiento, Gabriela P.,Vitale, Roxana G.,Afeltra, Javier,Moltrasio, Graciela Y.,Moglioni, Albertina G.
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experimental part
p. 101 - 105
(2011/02/25)
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- A METHOD OF MANUFACTURING AN ORGANIC SILICON COMPOUND THAT CONTAINS A METHACRYLOXY GROUP OR AN ACRYLOXY GROUP
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A method of manufacturing an organic silicon compound that contains a methacryloxy group or an acryloxy group, the method being characterized by the fact that manufacturing or conducting purification by distillation is carried out in the presence of a phenothiazine derivative having a molecular weight equal to or higher than 240. And a stable composition comprising an organic silicon compound that contains a methacryloxy group or an acryloxy group and a phenothiazine derivative having a molecular weight equal to or higher than 240 and used in an amount sufficient to stabilize the aforementioned organic silicon compound.
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(2008/06/13)
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- Novel derivatives of 2-hydroxytetrahydrofuran and their use as medicaments
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The invention relates to derivatives of 2-hydroxytetrahydrofuran corresponding to general formula (I) in which A represents the radical, in which R1, R2, R4, R5 and R6 represent (in particular), independently, H, a halogen atom, OH, alkyl or alkoxy, R3 represents H, alkyl or —COR10, R10 representing H, alkyl or alkoxy, and W represents a bond, —CH2—CH2—, —CH═CH—, —O—, —S— or —NR11— in which R11 represents H or alkyl; X represents —CO—, —Y—CO—, —O—Y—CO— or —NR12—Y—CO—, Y represents an alkylene or haloalkylene alkyl, R12 represents H, alkyl or —COR13, R13 represents H, alkyl, haloalkyl or alkoxy, AA represents, each time that it occurs, a natural or non-natural amino acid; n represents 2 or 3; and finally R represents H, alkyl or —CO—R19, R19 representing alkyl. These compounds have a calpain inhibiting activity and/or an activity which traps the reactive oxygen species and can be used for preparing a medicament intended to treat the inflammatory and immunological diseases, cardio-vascular and cerebro-vascular diseases, disorders of the central or peripheral nervous system, cachexia, osteoporosis, muscular dystrophy, proliferative diseases, cataract, rejection reactions following organ transplants and autoimmune and viral diseases.
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(2008/06/13)
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- Synthesis and psychotropic evaluation of some new N-substitutedbenzothia/ oxazepinylphenothiazines
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A number of N-[2-substitutedaryl-3-substitutedarylaminomethylene-2, 3-dihydro-1,5-benzothia/oxazepin-4-yl]phenothiazines 4a-p and 4a′-p′ have been synthesized from N-[2-substitutedaryl-2, 3-dihydro-1, 5-benzothia/oxazepin-4-yl]phenothiazines by Mannich reaction, on the 3 rd position of benzothia/oxazepine ring. The structure of these compounds have been confirmed by IR, 1H NMR and Mass analysis. The newly synthesized compounds have been evaluated for their psychotropic activities and acute toxicity studies. Compound 4i is found to be most potent compound of this series.
- Bajaj, Kiran,Srivastava,Kumar, Ashok
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p. 157 - 161
(2007/10/03)
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