- Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors
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Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.
- Xie, Yiyue,Tummala, Padmaja,Oakley, Aaron J.,Deora, Girdhar Singh,Nakano, Yuji,Rooke, Melissa,Cuellar, Matthew E.,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Casarotto, Marco G.,Board, Philip G.,Baell, Jonathan B.
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p. 2894 - 2914
(2020/04/08)
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- Design, synthesis and agricultural evaluation of derivatives of N-Acyl-N-(m-fluoro-benzyl)-6-amino-coumarin
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ABTRACT: This study aims to design and synthesize a series of N-Acyl-N-(m-fluoro- benzyl)-6- amino-coumarins through the principle of active substructure stitching, which are based on the core structure of N-(m-fluoro-benzyl)-6-amino-coumarin. The structures of target compounds e1–e25 have been characterized by 1H NMR, 13C NMR, ESI-MS and elemental analysis. Meanwhile, their agricultural activity have been evaluated in two weeds (Amaranth and Crabgrass) and four widespread noxious pathogens (V.mali, B.cinerea, F.axysporium and C.bacteria). The herbicidal activity results showed that almost all synthetic molecules have a greater impact on the stem system than on the root. Excellent inhibition rates were discovered from compounds e2–e5 and e20–e23 against Amaranth on stems, which were above 58percent(20 mg/L), 68percent(100 mg/L) respectively. Compounds e2 and e21 also exhibited striking inhibition on stems growth of both weeds. Anti-pathogenic activity showed that all the compounds exerted a better inhibitory activity on B.cinerea at 20 ppm compared to control carbendazim. All the heterocyclic substituted compounds (e17–e24, >57percent) made a better influence than the control (54.1percent) at the100 ppm. This research provides promising herbicidal and anti-pathogenic agents that have the better effects and can be potential for further development.
- Ding, Yin-hao,Dong, Jing-jing,Feng, Bai-cheng,Hao, Shuang-hong,Jin, Yan,Wei, Yan
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supporting information
(2020/08/19)
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- Synthesis and bioactivities of diamide derivatives containing a phenazine-1-carboxamide scaffold
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Taking natural product phenazine-1-carboxamide (PCN) as a lead compound, a series of novel phenazine-1-carboxylic acid diamide derivatives were designed and synthesised. Their structures were confirmed by 1H-NMR and HRMS. The bioassays showed that some of the target compounds exhibited promising in vitro fungicidal activities, and exhibited excellent and selective herbicidal activities. Particularly, compounds c, h, o and s displayed root length inhibition activities against barnyard grass with the rate of more than 80%. Compound c exhibited the best activity among all the target compounds against barnyard grass stalk length with the IC50 value of 0.158?mmol/L, and compound o exhibited the best and wide spectrum inhibition against barnyard grass root length and rape in both root length and stalk length herbicidal activities with its IC50 values of 0.067, 0.048 and 0.059?mmol/L respectively. The analysis of preliminary Structure-Activity Relationships provides the theoretical basis for further design of phenazine-1-carboxylic acid.
- Zhu, Xiang,Zhang, Min,Yu, Linhua,Xu, Zhihong,Yang, Dan,Du, Xiaoying,Wu, Qinglai,Li, Junkai
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supporting information
p. 2453 - 2460
(2018/03/29)
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- Synthesis method of alpha-chloropropionyl chloride
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The invention discloses a synthesis method of alpha-chloropropionyl chloride. The synthesis method comprises the following steps: (1) adding propionic acid, an acyl chloride catalyst and solvent into a reactor, starting to stir, introducing chlorine gas to perform substitution reaction, and distilling to collect an alpha-chloropropionic acid fraction directly used for next step of reaction after the reaction is completed; and (2) adding the alpha-chloropropionic acid obtained in the previous step and a catalyst into the reactor, starting to stir, slowly heating, introducing phosgene to react, and performing reduced pressure distillation after the reaction is completed to obtain the alpha-chloropropionyl chloride. The preparation method disclosed by the invention has the advantages of simple operation, high yield, no wastewater production during aftertreatment, mild reaction conditions and the like; and the acyl chloride catalyst used in the chlorination reaction of the first step can be recycled.
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Paragraph 0013
(2017/08/30)
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- Terpene Cyclizations inside a Supramolecular Catalyst: Leaving-Group-Controlled Product Selectivity and Mechanistic Studies
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The tail-to-head terpene cyclization is arguably one of the most complex reactions found in nature. The hydrogen-bond-based resorcinarene capsule represents the first man-made enzyme-like catalyst that is capable of catalyzing this reaction. Based on noncovalent interactions between the capsule and the substrate, the product selectivity can be tuned by using different leaving groups. A detailed mechanistic investigation was performed to elucidate the reaction mechanism. For the cyclization of geranyl acetate, it was found that the cleavage of the leaving group is the rate-determining step. Furthermore, the studies revealed that trace amounts of acid are required as cocatalyst. A series of control experiments demonstrate that a synergistic interplay between the supramolecular capsule and the acid traces is required for catalytic activity.
- Zhang, Qi,Catti, Lorenzo,Pleiss, Jürgen,Tiefenbacher, Konrad
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supporting information
p. 11482 - 11492
(2017/08/30)
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- Rapid degradation of cyclic peroxides by titanium and antimony chlorides
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First responders face extraordinary risks when dealing with organic peroxides such as TATP due to the extreme sensitivity of this class of explosives, and to a lack of a robust chemical means of safe and rapid neutralisation. The Lewis acids TiCl4 and SbCl3 have been found to demonstrate a novel degradation mechanism, with TiCl4 degrading a model cyclic peroxide in minutes when used in a two-fold excess, or ~3 hours at half equivalence. The products cannot re-form peroxide compounds as is the case with acid degradation, suggesting the two mechanisms are fundamentally different. The Lewis acids mediate a rearrangement reaction in the cyclic peroxide backbone leading to relatively innocuous products through deactivation of oxidising O. Sub-stoichiometric TiCl4 reactions highlight a secondary reaction pathway that also leads to some oxidative chlorination products, possibly mediated by an unconfirmed titanium-oxychloride species. SbCl3 was found to exhibit similar reactivity to TiCl4, although at a slower rate. A mechanism is proposed, consistent with the observations for both stoichiometric and sub-stoichiometric quantities of TiCl4.
- Bali, Mark S.,Armitt, David,Wallace, Lynne,Day, Anthony I.
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p. 6775 - 6783
(2015/04/14)
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- Synthesis and evaluation of novel monosubstituted sulfonylurea derivatives as antituberculosis agents
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A series of novel monosubstituted sulfonylurea derivatives 10a-y were synthesized and characterized by 1H NMR, 13C NMR and HRMS. These compounds were evaluated against Mycobacterium tuberculosis H37Rv in vitro. The results showed compounds 10f, 10k and 10s exhibited moderate antituberculosis activities with MIC values in the range of 20-100 mg/L. Compounds 10b and 10o displayed good antituberculosis activities (MIC 10 mg/L), which were comparable with that of the sulfometuron methyl. Both of the two compounds showed little cytotoxicities, with an IC50 against THP-1 cells greater than 100 mg/L.
- Pan, Li,Jiang, Ying,Liu, Zhen,Liu, Xing-Hai,Liu, Zhuo,Wang, Gang,Li, Zheng-Ming,Wang, Di
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scheme or table
p. 18 - 26
(2012/07/01)
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- Synthesis and Preliminary Biologic Evaluation of 5-Substituted-2-(4-substituted phenyl)-1,3-Benzoxazoles as A Novel Class of Influenza Virus A Inhibitors
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The diversity-oriented chemistry synthesis together with the random screening approach has permitted the discovery and optimization of novel antiviral lead compounds. In this paper, a series of novel 5-substituted-2-(4-substituted phenyl)-1,3-benzoxazoles was synthesized and evaluated for their in vitro anti-influenza A virus and anti-influenza B virus activity. The activity was monitored by the MTS assay in the Madin-Darby canine kidney cells. Compound 7h showed excellent inhibitory activity and selective index against A/H3N2 (EC50=37.03μm, SI>5), which were all higher than that of the reference drug oseltamivir (EC50>59.00μm, SI>1). However, no compound displays inhibitory activity against influenza B virus.
- Li, Zhenyu,Zhan, Peng,Naesens, Lieve,Vanderlinden, Evelien,Liu, Ailin,Du, Guanhua,De Clercq, Erik,Liu, Xinyong
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experimental part
p. 1018 - 1024
(2012/07/30)
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- Synthesis, antimicrobial evaluation, and QSAR analysis of 2-isopropyl-5-methylcyclohexanol derivatives
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A series of 2-isopropyl-5-methylcyclohexanol derivatives were synthesized and evaluated for their antibacterial activity against Gram-positive Staphylococcus aureus and Bacillus subtilis and Gram-negative Escherichia coli and in vitro antifungal activity against Candida albicans and Aspergillus niger. The results of antimicrobial activity demonstrated that the compounds 10, 20, and 21 were the most active ones among the synthesized compounds. The QSAR studies revealed the importance of dipole moment (μ), total energy (Te), and topological parameters (κ1 and κ3) in describing the antimicrobial activity of 2-isopropyl-5-methylcyclohexanol derivatives. Springer Science+Business Media, LLC 2011.
- Singh, Manjeet,Kumar, Sunil,Kumar, Ashwani,Kumar, Pradeep,Narasimhan, Balasubramanian
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experimental part
p. 511 - 522
(2012/08/07)
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- URACIL-BASED COMPOUNDS, AND HERBICIDES COMPRISING SAME
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Disclosed are uracil compounds represented by Formula 1, a method for preparing the compounds, and a herbicide including the same as an active ingredient: wherein R1, R2, R3, R4, R5, X, Y, Z and W are the same as defined in the detailed description.
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Page/Page column 28
(2011/08/03)
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- URACIL COMPOUNDS AND A HERBICIDE COMPRISING THE SAME
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Disclosed are uracil compounds represented by Formula 1, a method for preparing the compounds, and a herbicide including the same as an active ingredient: wherein R1, R2, R3, R4, R5, X, Y, Z and W are the same as defined in the detailed description.
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Page/Page column 10
(2011/10/04)
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- METHOD FOR PRODUCING 3,3,3-TRIFLUOROPROPIONIC ACID CHLORIDE
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There is provided a process for producing 3,3,3-trifluoropropionyl chloride, which is characterized in that 3,3,3-trifluoropropionaldehyde is chlorinated by a chlorinating agent selected from the group consisting of chlorine (Cl2), sulfuryl chloride (SO2Cl2) and organic N-chloro compounds.
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Page/Page column 13
(2009/01/24)
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- pH-independent hydrolysis of 4-nitrophenyl 2,2-dichloropropionate in aqueous micellar solutions: Relative contributions of hydrophobic and electrostatic interactions
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The pH-independent hydrolysis of 4-nitrophenyl 2,2-dichloropropionate (NPDCP) in the presence of aqueous micelles of sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, alkyltrimethylammonium chlorides, alkyldimethylbenzylammonium chlorides (alkyl = cetyl and dodecyl) and polyoxyethylene(9) nonylphenyl ether was studied spectrophotometrically. The observed rate constants, kobs, decrease in the following order: bulk water >cationic micelles >anionic micelles >non-ionic micelles. This order is different from that observed for pH-independent hydrolysis of 4-nitrophenyl chloroformate (NPCF), whose reaction is faster in cationic micelles than in bulk water. A proton NMR study on solubilization of a model ester, 4-nitrophenyl 2-chloropropionate, showed that the methylene groups in the middle of the surfactant hydrophobic chain are most affected by the solubilizate. Lower polarity and high ionic strength of interfacial water decrease the rates of hydrolysis of both NPCF and NPDCP, but t he fraction of the former ester that diffuses to the interface is probably higher than that of the latter. Therefore, whereas the (negatively charged) transition state of NPCF is stabilized by cationic interfaces and destabilized by anionic interfaces, that of NPDCP is negligibly affected by ionic interfaces, which explains the observed rate retardation by all ionic micelles. Calculated activation parameters corroborate our explanation.
- Seoud, Omar A. E.I.,Ruasse, Marie-Francoise,Possidonio, Shirley
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p. 526 - 532
(2007/10/03)
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- Dynamic enzymatic resolution of thioesters
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A detailed investigation of several issues related to the enzymatic resolution of thioesters under conditions of continuous racemization of substrate was conducted. The kinetic acidity of the α-protons of a series of α-substituted propionate thioesters was studied. It was found that the rate of α-proton exchange could be enhanced as much as 20-fold by variation of the thiol moiety, increasing the range of compounds to which enzymatic dynamic resolution may be applied. The relative rates of hydrolysis of ethyl butyrate and ethyl thiobutyrate by several enzymes commonly used in enzymatic resolution were determined. All of the enzymes studied exhibited similar rates of thioester and oxoester hydrolysis except for the esterase from pig liver, which showed very low activity in thioester hydrolysis. Dynamic resolution of the propargyl and trifluoroethyl thioesters of α- phenylpropionate was conducted using subtilisin Carlsberg as a catalyst. These examples demonstrated that enzymatic dynamic resolution can be applied even when the rate of α-proton exchange and the enantioselectivity of the enzyme are fairly low. A dynamic enzymatic transesterification procedure was demonstrated in the resolution of the trifluoroethyl thioester of α-(2,4- dichlorophenoxy)propionate, and product was obtained in 93% ee. This work helps expand and define the scope of enzymatic dynamic resolution of thioesters.
- Um, Pil-Je,Drueckhammer, Dale G.
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p. 5605 - 5610
(2007/10/03)
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- A Simple Synthesis of a cis-anti-cis Linear Triquinane Framework
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A simple approach to the synthesis of a key intermediate containing the cis-anti-cis linear triquinane framework starting from readily available indene is described.
- Chidambaram,Chandrasekaran
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p. 926 - 929
(2007/10/03)
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- Pyridazinone derivatives and processes for preparing the same
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Disclosed is a pyridazinone compound represented by the formula (I): STR1 wherein X represents hydrogen atom or the like; Y represents a single bonding arm, oxygen atom or sulfur atom; A represents a straight or branched alkylene group which may have a double bond; B represents carbonyl group or thiocarbonyl group; and R2 represents an alkyl group having 1 to 10 carbon atoms which may be substituted or the like; or B represents sulfonyl group; and R2 represents a lower alkenyl group or the like; R1 represents hydrogen atom or the like; R3 represents hydrogen atom or the like; R4 represents hydrogen atom or the like; and R5 represents hydrogen atom or the like, or a pharmaceutically acceptable salt thereof.
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- Rhenium(V) Complexes of N,N'-Ethylenebis(2-mercaptopropanamide). Synthesis, Characterization, and X-ray Crystal Structures
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The preparation of benzoyl-protected N,N'-ethylenebis(2-mercaptopropanamide) (H4emp) and its ligand-exchange reaction with ReO2(en)2Cl are described.Three diastereomers, -, -, and a pair of enantiomers, -, were formed due to syn and anti orientation of the two methyl groups of the ligand relative to the ReO core.The diastereomers were separated by reverse phase C18 semipreparative HPLC and isolated as salts of .The structures of were determined by single-crystal X-ray analyses. *H2O crystallizes in triclinic space group P with a=10.326(3) Angstroem, b=13.672(4) Angstroem, c=14.023(5) Angstroem, α=61.20(2)deg, β=74.74(3)deg, γ=75.68(2)deg, V=1656.6(8) Angstroem3, Z=2, Dc=1.676 gmL-1, F(000)=824 and R=0.0329 for 5877 unique reflections.For the complex , the crystal data are: monoclinic, space group P21/n, a= 9.128(2) Angstroem, b=24.284(7) Angstroem, c=14.112(4) Angstroem, β=93.41(2) deg, V=3122.5(15) Angstroem3, Z=4, Dc=1.74O gmL-1, F(000)=1608 and R=0.0361 for 5487 unique reflections.In both structures the rhenium atom is penta-coordinated and in an approximately square pyramidal environment. - Key Words Diamine-dithiol; N2S2 donor set; ReO(N2S2) anion.
- Liao, Fen-Ling,Wang, Sue-Lein,Lin, Cheng-Hsien,Huang, Shih-Tsorng
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p. 557 - 564
(2007/10/03)
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- α-FLUOROACRYLIC ACID CHLORANHYDRIDE
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Kinetic studies were carried out on the reaction of 2-fluoro-3-chloropropanoic acid and other halo- and methoxy-substituted propanoic acids with thionyl chloride at 50-110 deg C.The catalytic dehydro-chlorination of 2-fluoro-3-chloropropanoic acid chloranhydride by tertiary amines and their salts was investigated.Dimethylaniline chlorohydrate was shown to be an effective catalyst, providing maximum dehydrochlorination at a concentration of 20percent.A mechanism for the reaction was proposed.
- Boguslavskaya, L. S.,Morozova, T. V.
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p. 716 - 720
(2007/10/02)
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- Synthesis and some reactions of 2-(1-chloroethyl)-3,1-benzoxazin-4(H)-one
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2-(1-Chloroethyl)-3,1-benzoxazin-4(H)-one (II) reacts with ammonia to give the corresponding quinazolone (III) which on alkylation provides 3-N-alkyl quinazolones (IVa,b).Quinazolone III undergoes Mannich reaction with formaldehyde to give the Mannich base (V).It also reacts with P2S5 to give quinazole-4-thione (VI).The benzoxazinone II also reacts with hydrazines to give 3-aminoquinazolones (VIIa,b) which undergo condensation with p-chlorobenzaldehyde to afford the schiff base (VIII).Amonolysis of II gives the anilides (XIa,b) which undergo ring closure with Ac2O to give the quinazolone IVb.Reaction of II with P2S5 gives the benzothiazinone (XII) which reacts with benzylamine to give IVb.Reaction of II with hydrocarbons under Friedel Crafts conditions furnishes the phenyl aryl ketone derivatives (XIIIa,b).
- Sayed, M A,El-Kafrawy, A F,Soliman, A Y,El-Bassiouny, F A
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p. 980 - 983
(2007/10/02)
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- 4-hydroxy-3-quinolinecarboxamides with antiarthritic and analgesic activities
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A series of 4-hydroxy-3-quinolinecarboxamides has been synthesized and evaluated by the oral route as antiinflammatory agents in carrageenin-induced foot edema and adjuvant-induced arthritis and as analgesic agents in the acetic acid induced writhing test. Among the most active molecules, some have shown both analgesic and acute antiinflammatory activities. Others, such as compounds 24, 37, and 52, were only powerful peripherally acting analgesics. Compound 52, being active at 1 mg/kg (ED50), is the most potent compound in the series. Some analogues, substituted in the 2-position by an alcohol, ester, or amine function, displayed potent antiarthritic activity in the same range as that of piroxicam and were also active in acute tests of inflammation and nociception. They inhibited the activity of both cyclooxygenase and 5-lipoxygenase at micromolar concentrations. Compound 102 (RU 43526) showed potent antiarthritic activity (adjuvant-induced arthritis, ED50 = 0.7 mg/kg, po), and gastrointestinal tolerance (ED100 250 mg/kg, po) and thus it is presently undergoing an extensive pharmacological evaluation.
- Clemence,Le Martret,Delevallee,Benzoni,Jouanen,Jouquey,Mouren,Deraedt
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p. 1453 - 1462
(2007/10/02)
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- NUCLEOPHILIC REACTIONS AT VINYL CENTER. V. SYNTHESIS OF α-METHYL-β,β-DICHLOROVINYL PHENYL SULFONE
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α-Methyl-β,β-dichlorovinyl phenyl sulfone was synthesized by the reaction of 1,1,2-trichloropropene with sodium thiophenolate in dimethylformamide and subsequent oxidation with hydrogen peroxide.The side reactions accompanying the formation of 1,1,2-trichloropropene during dehydration of 1,1,1-trichloro-2-propanol over phosphorus pentoxide were examined in detail.
- Shainyan, B. A.,Mirskova, A. N.
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