- Novel N-aryl Oxamic Acids
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The present disclosure relates to novel N-aryl oxamic acid based inhibitors for Mycobacterium tuberculosis protein tyrosine phosphatase B (mPTPB), and to the method of making and using the novel N-aryl oxamic acid based inhibitors. More specifically, compounds provided in this disclosure can be used to inhibit Mycobacterium tuberculosis protein tyrosine phosphatase B (mPTPB) and to treat a patient having a Tuberculosis disease.
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Paragraph 0045
(2021/10/11)
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- Direct C3 Carbamoylation of 2H-Indazoles
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We developed a novel method for direct C3 carbamoylation of 2H-indazoles using oxamic acids as carbamoyl radical sources. In the presence of ammonium persulfate, carbamoyl radicals were generated from oxamic acids, then used for further reactions with 2H-indazoles to afford the desired products. The reaction proceeds under metal- and catalyst-free conditions. This simple process allows for the efficient synthesis of C3 carbamoylated 2H-indazoles, which are important scaffolds in organic synthesis.
- Bhat, Vighneshwar Shridhar,Lee, Anna
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supporting information
p. 3382 - 3385
(2021/06/28)
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- Application of High-Throughput Competition Experiments in the Development of Aspartate-Directed Site-Selective Modification of Tyrosine Residues in Peptides
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Herein we report a Cu-catalyzed, site-selective functionalization of peptides that employs an aspartic acid (Asp) as a native directing motif, which directs the site of O-arylation at a proximal tyrosine (Tyr) residue. Through a series of competition studies conducted in high-throughput reaction arrays, effective conditions were identified that gave high selectivity for the proximal Tyr in Asp-directed Tyr modification. Good levels of site-selectivity were achieved in the O-arylation at a proximal Tyr residue in a number of cases, including a peptide-small molecule hybrid.
- Chinn, Alex J.,Hwang, Jaeyeon,Kim, Byoungmoo,Parish, Craig A.,Krska, Shane W.,Miller, Scott J.
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supporting information
p. 9424 - 9433
(2020/08/14)
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- Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B
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Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Mtb protein tyrosine phosphatase B (mPTPB) is a virulence factor required for Mtb survival in host macrophages. Consequently, mPTPB represents an exciting target for tuberculosis treatment. Here, we identified N-phenyl oxamic acid as a highly potent and selective monoacid-based phosphotyrosine mimetic for mPTPB inhibition. SAR studies on the initial hit, compound 4 (IC50 = 257 nM), resulted in several highly potent inhibitors with IC50 values lower than 20 nM for mPTPB. Among them, compound 4t showed a Ki of 2.7 nM for mPTPB with over 4500-fold preference over 25 mammalian PTPs. Kinetic, molecular docking, and site-directed mutagenesis analyses confirmed these compounds as active site-directed reversible inhibitors of mPTPB. These inhibitors can reverse the altered host cell immune responses induced by the bacterial phosphatase. Furthermore, the inhibitors possess molecular weights 0.43, and good aqueous solubility and metabolic stability, thus offering excellent starting points for further therapeutic development.
- Ruddraraju, Kasi Viswanatharaju,Aggarwal, Devesh,Niu, Congwei,Baker, Erica Anne,Zhang, Ruo-Yu,Wu, Li,Zhang, Zhong-Yin
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p. 9212 - 9227
(2020/10/19)
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- ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase
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The serine hydrolase monoacylglycerol lipase (MAGL) is involved in a plethora of pathological conditions, in particular pain and inflammation, various types of cancer, metabolic, neurological and cardiovascular disorders, and is therefore a promising target for drug development. Although a large number of irreversible-acting MAGL inhibitors have been discovered over the past years, there are only few compounds known so far which inhibit the enzyme in a reversible manner. Therefore, much effort is put into the development of novel chemical entities showing reversible inhibitory behavior, which is thought to cause less undesired side effects. To explore a wide range of chemical structures as MAGL binders, we have applied a virtual screening approach by docking small molecules into the crystal structure of human MAGL (hMAGL) and envisaged a library of 45 selected compounds which were then synthesized. Biochemical investigations included the determination of the inhibitory potency on hMAGL and two related hydrolases, i.e. human fatty acid amide hydrolase (hFAAH) and murine cholesterol esterase (mCEase). The most promising candidates from theses analyses, i.e. three ω-quinazolinonylalkyl aryl ureas bearing alkyl spacers of three to five methylene groups, exhibited IC50 values of 20–41 μM and reversible, detergent-insensitive behavior towards hMAGL. Among these compounds, the inhibitor 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyl)urea (96) was selected for further kinetic characterization, yielding a dissociation constant Ki = 15.4 μM and a mixed-type inhibition with a pronounced competitive component (α = 8.94). This mode of inhibition was further supported by a docking experiment, which suggested that the inhibitor occupies the substrate binding pocket of hMAGL.
- Dato, Florian M.,Neud?rfl, J?rg-Martin,Gütschow, Michael,Goldfuss, Bernd,Pietsch, Markus
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supporting information
(2019/11/13)
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- CASPASE INHIBITOR AND PHARMACEUTICAL COMPOSITION, USE AND THERAPEUTIC METHOD THEREOF
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Disclosed are a class of compounds as a caspase inhibitor, and in particular the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound in treating caspase-related diseases.
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Paragraph 0585; 0587
(2019/04/05)
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- Metal-, Photocatalyst-, and Light-Free Direct C-H Acylation and Carbamoylation of Heterocycles
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Direct C-H acylations and carbamoylations of heterocycles can now be readily achieved without requiring any conventional metal, photocatalyst, electrocatalysis, or light activation, thus significantly improving on sustainability, costs, toxicity, waste, and simplicity of the operational procedure. These mild conditions are also suitable for gram-scale reactions and late-stage functionalizations of complex molecules, including pharmaceuticals, N,N-ligands, and light-sensitive molecules.
- Westwood, Matthew T.,Lamb, Claire J. C.,Sutherland, Daniel R.,Lee, Ai-Lan
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supporting information
p. 7119 - 7123
(2019/09/03)
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- Structure-activity relationship study of a series of caspase inhibitors containing γ-amino acid moiety for treatment of cholestatic liver disease
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A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. A systemic study on their structure-activity relationship of anti-apoptotic cellular activity is presented. These efforts led to the discovery of compound 20o as a potent caspase inhibitor, which demonstrated preclinical ameliorating total bilirubin efficacy with a significantly improved pharmacokinetic profile.
- Mou, Jianfeng,Wu, Songliang,Luo, Zhi,Guo, Fengying,He, Haiying,Wang, Jianhua,Lin, Fusen,Guo, Fengxun,Sun, Jianping,Shen, Liang,Zeng, Minggao,Wang, Chuan,Xu, Deming,Gu, Zhengxian,Tian, Xin,Zhang, Aiming,Xu, Hongjiang,Yang, Ling,Zhang, Xiquan,Li, Jian,Chen, Shuhui
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supporting information
p. 1874 - 1878
(2018/04/12)
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- Mild Access to N-Formylation of Primary Amines using Ethers as C1 Synthons under Metal-Free Conditions
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A new synthetic protocol has been developed for the synthesis of N-formamide derivatives using ethers as a C1 synthon under metal-free reaction conditions. The reaction is proposed to proceed through C?H functionalization, C?O cleavage, and C?N bond formation. This protocol is applicable to a variety of primary amines resulting in N-formamides in moderate to good yields. 1,4-dioxane was chosen as best C1 synthon after screening with various ethers. Mechanistic studies disclosed that the reaction proceeds through a radical pathway. While using α-amino ketones a α-alkylation product was formed rather than formylation. By replacing dioxane with Tetramethylethylenediamine (TMEDA) under standard conditions also gave the N-formamide derivatives in moderate yields. (Figure presented.).
- Mutra, Mohana Reddy,Dhandabani, Ganesh Kumar,Wang, Jeh-Jeng
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p. 3960 - 3968
(2018/09/10)
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- Visible-light photocatalyzed oxidative decarboxylation of oxamic acids: a green route to urethanes and ureas
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A sustainable metal-free route to urethanes and ureas based on a photocatalyzed oxidative decarboxylation of oxamic acids is described. The reaction includes in situ generation of an isocyanate from the oxamic acid, using an organic dye as a photocatalyst, a hypervalent iodine reagent as an oxidant and a light source, which trigger the free-radical decarboxylation. This protocol successfully avoids the isolation, purification and storage of carcinogenic isocyanates and allows elaboration of urethanes and ureas in a one-pot process from commercially available sources.
- Pawar, Govind Goroba,Robert, Frédéric,Grau, Etienne,Cramail, Henri,Landais, Yannick
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supporting information
p. 9337 - 9340
(2018/08/31)
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- Improved microwave synthesis of unsymmetrical N,N'-diaryl-1,2-aminoethane and imidazolidinium salts as precursors of N-heterocyclic carbenes
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Lithium aluminium hydride reduction of bis-unsymmetric-diaryloxamides 3 is difficult to accomplish especially for the sterically hindered mesityl derivative. Using microwaves LAH reduction of 3a,d was successful in a short time, however, with cleavage of the ether linkage to give compounds 11a,d. Extension of this method enabled the reduction of bis-oxamide derivatives 13 to the corresponding tetraamine derivative 14 which was then converted to the bis-imidazolidinium salt 15. Application of this method led to rapid reduction of unsymmetric N,N'-diaryloxamides 16 to the corresponding N,N'- diarylethylenediamines 17 which were converted to their corresponding imidazolidinium salts 18. the Partner Organisations 2014.
- Ibrahim, Yehia A.,Al-Awadi, Nouria A.,Al-Azemi, Talal F.,John, Elizabeth
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p. 38869 - 38876
(2014/11/08)
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- CD4 mimics targeting the mechanism of HIV entry
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A structure-activity relationship study was conducted of several CD4 mimicking small molecules which block the interaction between HIV-1 gp120 and CD4. These CD4 mimics induce a conformational change in gp120, exposing its co-receptor-binding site. This induces a highly synergistic interaction in the use in combination with a co-receptor CXCR4 antagonist and reveals a pronounced effect on the dynamic supramolecular mechanism of HIV-1 entry.
- Yamada, Yuko,Ochiai, Chihiro,Yoshimura, Kazuhisa,Tanaka, Tomohiro,Ohashi, Nami,Narumi, Tetsuo,Nomura, Wataru,Harada, Shigeyoshi,Matsushita, Shuzo,Tamamura, Hirokazu
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experimental part
p. 354 - 358
(2010/04/05)
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- Synthesis, crystal structure, and insecticidal activity of novel N-alkyloxyoxalyl derivatives of 2-arylpyrrole
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Two series of novel N-alkyloxyoxalyl derivatives of 2-arylpyrrole were synthesized, and their structures were characterized by 1H NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays indicated that some of these title compounds exhibited excellent insecticidal activities, and their insecticidal activities against oriental armyworm, mosquito, and spider mite are comparable to those of the commercialized Chlorfenapyr.
- Zhao, Yu,Mao, Chunhui,Li, Yongqiang,Zhang, Pengxiang,Huang, Zhiqiang,Bi, Fuchun,Huang, Runqiu,Wang, Qingmin
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experimental part
p. 7326 - 7332
(2010/06/11)
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- Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors
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Inhibitors of histone deacetylases (HDAC) are emerging as a promising class of anti-cancer agents. A mercaptoamide functionality was designed as a bidentate zinc chelator and incorporated into the hydroxamic acid based SAHA (1) scaffold in order to identify non-hydroxamate compounds as potential inhibitors of histone deacetylases. Two sets of mercaptoamides 2 and 3 with varying spacer length were synthesized and their HDAC inhibitory activity was evaluated. Low micromolar inhibition was observed for mercaptoamides 2e, 3b, and 3d.
- Anandan, Sampath-Kumar,Ward, John S.,Brokx, Richard D.,Bray, Mark R.,Patel, Dinesh V.,Xiao, Xiao-Xi
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p. 1969 - 1972
(2007/10/03)
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- First-in-class pan caspase inhibitor developed for the treatment of liver disease
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A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of α-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.
- Linton, Steven D.,Aja, Teresa,Armstrong, Robert A.,Bai, Xu,Chen, Long-Shiuh,Chen, Ning,Ching, Brett,Contreras, Patricia,Diaz, Jose-Luis,Fisher, Craig D.,Fritz, Lawrence C.,Gladstone, Patricia,Groessl, Todd,Gu, Xin,Herrmann, Julia,Hirakawa, Brad P.,Hoglen, Niel C.,Jahangiri, Kathy G.,Kalish, Vincent J.,Karanewsky, Donald S.,Kodandapani, Lalitha,Krebs, Joseph,McQuiston, Jeff,Meduna, Steven P.,Nalley, Kip,Robinson, Edward D.,Sayers, Robert O.,Sebring, Kristen,Spada, Alfred P.,Ternansky, Robert J.,Tomaselli, Kevin J.,Ullman, Brett R.,Valentino, Karen L.,Weeks, Suzanne,Winn, David,Wu, Joe C.,Yeo, Pauline,Zhang, Cheng-Zhi
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p. 6779 - 6782
(2007/10/03)
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- Phototransformation of carboxin in water. Toxicity of the pesticide and its sulfoxide to aquatic organisms
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Sunlight exposure of aqueous suspensions of carboxin (1) causes its phototransformation to sulfoxide 2 and minor components. Similar effects are observed in the presence of humic acid or nitrate or at different pH values. Photoproducts 2-9 were isolated by Chromatographic techniques and/or identified by spectroscopic means. Carboxin 1 and its main photoproduct sulfoxide 2 were tested to evaluate acute toxicity to primary consumers typical of the aquatic environment: the rotifer Brachionus calyciflorus and two crustaceans, Daphnia magna and Thamnocephalus platyurus. Chronic tests comprised a producer, the alga Pseudokirchneriella subcapitata, and a consumer, the crustacean Ceriodaphnia dubia.
- Dellagreca, Marina,Iesce, Maria Rosaria,Cermola, Flavio,Rubino, Maria,Isidori, Marina
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p. 6228 - 6232
(2007/10/03)
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- Oxamyl dipeptide caspase inhibitors developed for the treatment of stroke
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Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.
- Linton, Steven D.,Aja, Teresa,Allegrini, Peter R.,Deckwerth, Thomas L.,Diaz, Jose-Luis,Hengerer, Bastian,Herrmann, Julia,Jahangiri, Kathy G.,Kallen, Joerg,Karanewsky, Donald S.,Meduna, Steven P.,Nalley, Kip,Robinson, Edward D.,Roggo, Silvio,Rovelli, Giorgio,Sauter, Andre,Sayers, Robert O.,Schmitz, Albert,Smidt, Robert,Ternansky, Robert J.,Tomaselli, Kevin J.,Ullman, Brett R.,Wiessner, Christoph,Wu, Joe C.
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p. 2685 - 2691
(2007/10/03)
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- 3-Hydroxy-quinolin-2-ones: Inhibitors of [3H]-glycine binding to the site associated with the NMDA receptor
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A series of substituted 3-hydroxy-quinolin-2-one derivatives 6 was synthesized and evaluated as inhibitors of [3H]-glycine and [3H]-AMPA binding to rat cortical membranes. These compounds were generally found to be more potent ligands for the NMDA-associated glycine binding site than the AMPA receptor. Affinity for the glycine site was found to be influenced by both the electronic and steric properties associated with the C-4 substituent and the nature and pattern of substitution of the aromatic ring. The most active compound in this series, 6y, displaces [3H]-glycine with an IC50 of 29 nM.
- Sit, Sing-Yuen,Ehrgott, Frederick J.,Gao, Jinnian,Meanwell, Nicholas A.
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p. 499 - 504
(2007/10/03)
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- Reactivity of Carbamoyl Radicals. A New, General, Convenient Free-Radical Synthesis of Isocyanates from Monoamides of Oxalic Acid
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A new, general, simple synthesis of isocyanates was developed by oxidation of monoamides of oxalix acid with peroxydisulfate catalyzed by Ag and Cu salts.The reaction was carried out in a two-phase system (water and an organic solvent), and it is suitable also for practical applications, due to the simple experimental conditions and the inexpensive as well as nontoxic reagents.The first example of homolytic intramolecular aromatic carbamoylation is also reported.
- Minisci, Francesco,Fontana, Francesca,Coppa, Fausta,Yan, Yong Ming
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p. 5430 - 5433
(2007/10/02)
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- 7-Oxabicycloheptyl Carboxylic Acids as Thromboxane A2 Antagonists: Aza ω-Chain Analogues
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A novel bicyclic prostaglandin analogue, >-7-acetyl>amino>methyl>-7-oxabicyclohept-2-yl>-5-heptenoic acid ((-)-7) was found to be a potent and selective thromboxane A2 (TxA2) receptor antagonist.Unlike the related series of ω-chain allylic alcohols, amide 7 and its congeners were uniformly free of direct contractile activity in vitro (bovine coronary) and in vivo (anesthetized guinea pig).Amide 7 was effective in the inhibition of (a) arachidonic acid induced platelet aggregation of human platelet-richplasma (I50 = 0.18 +/- 0.006 μM), (b) 11,9-epoxymethano-PGH2 induced platelet aggregation of human platelet-rich plasma (I50 = 0.24 μM), (c) 11,9-epoxymethano-PGH2 induced contraction of guinea pig trachea (Kb = 3.0 +/- 0.3 nM) or rat aorta (Kb = 8.8 +/- 1.1 nM), and (d) arachidonic acid induced bronchoconstriction in the anesthetized guinea pig (0.1-1.0 mg/kg iv).Amide 7 inhibited the binding of ->-7-hydrazino>methyl>-7-oxabicyclohept-2-yl>-5-heptenoic acid to human platelet membranes in a specific and saturable manner with a Kd = 49.6 +/- 1.4 nM.
- Nakane, Masami,Reid, Joyce A.,Han, Wen-Ching,Das, Jagabandhu,Truc, Vu Chi,et al.
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p. 2465 - 2476
(2007/10/02)
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- The Interaction of Chlorinated 6-Spiroepoxypenicillins with Bacillus cereus &β-Lactamase I: Irreversible Inhibition and Turnover
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The chlorinated 6-spiroepoxypenicillin anilides (1a) and (1b) are irreversible inhibitors of β-lactamase I from Bacillus cereus, but they are also turned over by this enzyme to yield the same hydrolysis product, whose structure has been revealed to be an unusual 6-substituted-1,4-dihydrothiazine-3-carboxylate, α-ketoamide; a possible pathway for the turnover and inhibitory processes associated with these interactions is presented.
- Bycroft, Barrie W.,Gledhill, Linden,Shute, Richard E.,Williams, Paul
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p. 1610 - 1612
(2007/10/02)
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- 7-Oxabicycloheptane substituted oxamide prostaglandin analogs and their use in treating thrombolytic disease
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7-Oxabicycloheptane substituted oxamide prostaglandin analogs are provided having the structural formula STR1 and including all stereoisomers thereof. The compounds are cardiovascular agents useful, for example, in the treatment of thrombolytic disease.
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- Pyridinethiones. IX Preparation of Ricinidine, Thioricinidine and Other 2(1H)-Pyridones and -thiones Related to Nicotinic acid
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1(1H)-Pyridones and -thiones related to 1-substituted nicotinic acid derivatives have been prepared via the corresponding 1-substituted-3-formyl-2(1H)-pyridones and -thiones.A number of synthetic procedures for the interconversion of functional groups in these nicotinic acid derivatives are given i.e. preparation of the aldoximes, nitriles, carboxamides and carboxylic acids as well as the 3-hydroxyalkyl derivatives.The course of the basic peroxide oxidation of the 1-substituted-3-formyl-2(1H)-pyridinethiones is found to be very dependent upon the electronegativity ofthe 1-substituent.A preparation of ricinidine is also described.
- Becher, Jan,Johansen, Tea,Michael, Maged Aziz
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- SYNTHESIS OF ETHOXALYL CYANIDE. A NOVEL HETERODIENO- AND HETEROENOPHILE
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The action of di-n-heptylsulphide on diethyl 2,3-dicyanooxiran-2,3-dicarboxylate yields ethoxalyl cyanide, a new dieno- and enophile with active CO group.
- Achmatowicz, O. Jr.,Szymoniak, J.
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p. 1299 - 1302
(2007/10/02)
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