- Catalytic Detoxification of Organophosphorus Nerve Agents by Butyrylcholinesterase-Polymer-Oxime Bioscavengers
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Organophosphorus nerve agents (OPNAs), used in chemical warfare, irreversibly inhibit essential cholinesterases (ChEs) in the cholinergic neurotransmission system. Several potent nucleophilic oximes have been approved for the treatment of acute poisoning by OPNAs, but they are rapidly cleared from blood circulation. Butyrylcholinesterase (BChE) stoichiometrically binds nerve agents, but because the molecular weight of a nerve agent is about 500-fold less than the enzyme, the bioscavenger has had limited utility. We synthesized BChE-polymer-oxime conjugates using atom transfer radical polymerization (ATRP) and azide-alkyne "click"chemistry. The activity of the BChE-polymer-oxime conjugates was dependent on the degree of oxime loading within the copolymer side chains. The covalent modification of oxime-containing copolymers prolonged the activity of BChE in the presence of the VX-and cyclosarin-fluorogenic analogues EMP-MeCyC and CMP-MeCyC, respectively. After complete inactivation by VX and cyclosarin fluorogenic analogues, the conjugates demonstrated efficient self-reactivation of up to 80% within 3-6 h. Repeated inhibition and high-level self-reactivation assays revealed that the BChE-polymer-oxime conjugates were excellent reactivators of OPNA-inhibited BChE. Recurring self-reactivation of BChE-polymer-oxime conjugates following repeated BChE inhibition by fluorogenic OPNAs (Flu-OPNAs) opens the door to developing the next generation of nerve agent "catalytic"bioscavengers.
- Zhang, Libin,Murata, Hironobu,Amitai, Gabriel,Smith, Paige N.,Matyjaszewski, Krzysztof,Russell, Alan J.
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- Novel pyridinium oximes: Synthesis, molecular docking and in vitro reactivation studies
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A computational approach has been attempted for the screening of 4-pyridoxinium (4P) ring based reactivators for paraoxon inhibited AChE. The oxime molecules were designed with the common 4P skeleton and varying the carbon linkers. Initially, the AChE binding capability was assessed by molecular docking with PDB:2WHP and 3ZLV, which showed important interactions with Ser298, Try124 and Trp286. These computational results were validated by an in vitro AChE binding assay, which showed binding affinities in the range of 10-90%. Finally, reactivation potency was calculated as % reactivation on paraoxon inhibited eelAChE in the concentration range of 10-5 to 10-7 M. It was observed that introduction of an aliphatic linker attached to 4-pyridoxime has a high binding affinity and hence, may act as a good reactivator as compared to the aromatic pyridoximes.
- Pooja,Aggarwal,Tiwari,Kumar,Pratap,Singh,Mishra
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- Synthesis and SAR study of simple aryl oximes and nitrofuranyl derivatives with potent activity against Mycobacterium tuberculosis
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Background: Oximes and nitrofuranyl derivatives are particularly important compounds in medicinal chemistry. Thus, many researchers have been reported to possess antibacterial, antiparasitic, insecticidal and fungicidal activities. Methods: In this work, we report the synthesis and the biological activity against Mycobacterium tuberculosis H37RV of a series of fifty aryl oximes, ArCH=N-OH, I, and eight nitrofuranyl compounds, 2-nitrofuranyl-X, II. Results: Among the oximes, I: Ar = 2-OH-4-OH, 42, and I: Ar = 5-nitrofuranyl, 46, possessed the best activity at 3.74 and 32.0 μM, respectively. Also, 46, the nitrofuran compounds, II; X = MeO, 55, and II: X = NHCH2Ph, 58, (14.6 and 12.6 μM, respectively), exhibited excellent biological activities and were non-cytotoxic. Conclusion: The compound 55 showed a selectivity index of 9.85. Further antibacterial tests were performed with compound 55 which was inactive against Enterococcus faecalis, Klebisiella pneumonae, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhymurium and Shigel-la flexneri. This study adds important information to the rational design of new lead anti-TB drugs. Structure-activity Relationship (SAR) is reported.
- Calixto, Stephane Lima,Carvalho, Guilherme da Silva Louren?o,Coimbra, Elaine Soares,Granato, Juliana da Trindade,Louren?o, Maria Cristina da Silva,Wardell, James,da Costa, Cristiane Fran?a,de Souza, Marcus Vinicius Nora
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- Synthesis and in vitro evaluation of neutral aryloximes as reactivators of Electrophorus eel acetylcholinesterase inhibited by NEMP, a VX surrogate
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Casualties caused by nerve agents, potent acetylcholinesterase inhibitors, have attracted attention from media recently. Poisoning with these chemicals may be fatal if not correctly addressed. Therefore, research on novel antidotes is clearly warranted. Pyridinium oximes are the only clinically available compounds, but poor penetration into the blood-brain barrier hampers efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in SAR studies, we synthesized and evaluated neutral aryloximes as reactivators for acetylcholinesterase inhibited by NEMP, a VX surrogate. Although few tested compounds reached comparable reactivation results with clinical standards, they may be considered as leads for further optimization.
- Cavalcante, Samir F. de A.,Kitagawa, Daniel A.S.,Rodrigues, Rafael B.,Bernardo, Leandro B.,da Silva, Thiago N.,dos Santos, Wellington V.,Correa, Ana Beatriz de A.,de Almeida, Joyce S.F.D.,Fran?a, Tanos C.C.,Ku?a, Kamil,Simas, Alessandro B.C.
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- Novel design of recyclable copper(II) complex supported on magnetic nanoparticles as active catalyst for Beckmann rearrangement in poly(ethylene glycol)
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Copper complex-functionalized magnetic core–shell nanoparticles (Fe3O4@SiO2-Lig-Cu) were prepared and characterized using various techniques. The activity of the new catalyst was tested for the Beckmann rearrangement. The reaction conditions allow for the conversion of a wide variety of aldoximes, including aromatic and heterocyclic ones, to amides in good to excellent yields. High efficiency, mild reaction conditions, easy work-up, use of poly(ethylene glycol) as a green medium and simple purification of products are important advantages of this system. Moreover, the eco-friendly heterogeneous nanocatalyst could be easily recovered from the reaction mixture using an external magnet and reused several times.
- Keyhaniyan, Mahdi,Shiri, Ali,Eshghi, Hossein,Khojastehnezhad, Amir
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- Asymmetric Nitrone Synthesis via Ligand-Enabled Copper-Catalyzed Cope-Type Hydroamination of Cyclopropene with Oxime
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We report realization of the first enantioselective Cope-type hydroamination of oximes for asymmetric nitrone synthesis. The ligand promoted asymmetric cyclopropene "hydronitronylation" process employs a Cu-based catalytic system and readily available starting materials, operates under mild conditions and displays broad scope and exceptionally high enantio- and diastereocontrol. Preliminary mechanistic studies corroborate a CuI-catalytic profile featuring an olefin metalla-retro-Cope aminocupration process as the key C-N bond forming event. This conceptually novel reactivity enables the first example of highly enantioselective catalytic nitrone formation process and will likely spur further developments that may significantly expedite chiral nitrone synthesis.
- Li, Zhanyu,Zhao, Jinbo,Sun, Baozhen,Zhou, Tingting,Liu, Mingzhu,Liu, Shuang,Zhang, Mengru,Zhang, Qian
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supporting information
p. 11702 - 11705
(2017/09/07)
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- Five-membered azole heterocyclic compound and its preparation method, pharmaceutical composition and use thereof
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The present invention relates to a five-membered azole heterocycle compound represented by the following general formula (I), a preparation method of the five-membered azole heterocycle compound, a drug composition of the five-membered azole heterocycle compound, and a use of the five-membered azole heterocycle compound in preparation of drugs for prevention or treatment of TGR5-mediated diseases. The formula (I) is represented by the instruction.
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Paragraph 0364; 0365
(2017/02/28)
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- Copper(ii)-promoted direct conversion of methylarenes into aromatic oximes
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A simple and efficient catalytic system for direct conversion of methylarenes into aromatic oximes has been developed, with Cu(OAc)2 as catalyst, NHPI (N-Hydroxyphthalimide) as additive, TBN (tert-butyl nitrite) as both the nitrogen source and the oxidant. This process proceeds under mild conditions, tolerates a wide range of substrates, affording the targeted aromatic oximes in 63-86% yields.
- Yu, Jiatao,Lu, Ming
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supporting information
p. 7397 - 7401
(2015/07/15)
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- Copper(II)-promoted direct conversion of methylarenes into aromatic oximes
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A simple and efficient catalytic system for direct conversion of methylarenes into aromatic oximes has been developed, with Cu(OAc)2 as catalyst, NHPI (N-Hydroxyphthalimide) as additive, TBN (tert-butyl nitrite) as both the nitrogen source and the oxidant. This process proceeds under mild conditions, tolerates a wide range of substrates, affording the targeted aromatic oximes in 63-86% yields.
- Yu, Jiatao,Lu, Ming
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supporting information
p. 7397 - 7401
(2015/11/27)
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- Effective conversion of heteroaromatic ketones into primary amines via hydrogenation of intermediate ketoximes
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A process to access heteroaromatic primary amines from the corresponding heteroaromatic ketones has been developed. A broad range of previously reported methods to convert ketones to primary amines was examined on heterocyclic ketones without success, including Leuckart-Wallach conditions, borane reductions, and transition-metal-catalyzed hydrogenations. Unique among the catalysts examined, Raney cobalt produced the desired primary heterocyclic amine. Raney cobalt hydrogenation of structurally varied heterocyclic ketoximes was demonstrated to form primary amines in good selectivity under mild conditions, and the products are easily isolated in high yield. Additionally, this is the first report of a systematic evaluation of the capabilities of Raney cobalt as an oxime hydrogenation catalyst.
- Baucom, Kyle D.,Guram, Anil S.,Borths, Christopher J.
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supporting information
p. 201 - 204
(2015/03/03)
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- A value-added use of volatile turpentine: antifungal activity and QSAR study of β-pinene derivatives against three agricultural fungi
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In consideration of turpentine and its analogues possessing some agricultural biological activity, persistent efforts to take advantage of renewable, abundant natural resources have been made. Three series of derivatives from β-pinene were synthesized and their fungicidal activities against Rhizoctonia solani, Fusarium graminearum, and Botrytis cinerea were investigated. Most of the synthesized compounds exhibited moderate to significant fungicidal activity. Among them, the acylthiourea derivatives from β-pinene showed more promising results than the other compounds. It was worth noting that compounds 7b and 7d displayed excellent fungicidal activity against Rhizoctonia solani, with IC50 values of 2.439 and 1.857 μg mL-1, which was close to or even better than the control triadimenol (1.945 μg mL-1, a commercial fungicide). The structure-activity relationship (SAR) analysis indicated that the compounds with more net positive charge possessed better fungicidal activity. The quantitative structure-activity relationship (QSAR) model (R2 = 0.9879, F = 348.41, S2 = 0.0047) was obtained through the best multi-linear regression. The built model revealed a strong correlation of fungicidal activity against Rhizoctonia solani with the molecular features of the title compounds. Additionally, the SAR and QSAR studies showed that the introduction of an electron-withdrawing group, which can increase the positive charge, was favorable towards the fungicidal activity. These encouraging results may provide an alternative, promising use of β-pinene through the design and exploration of eco-friendly fungicides with low toxicity and high efficiency.
- Li, Jian,Tian, Xiangrong,Gao, Yanqing,Shang, Shibin,Feng, Juntao,Zhang, Xing
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p. 66947 - 66955
(2015/08/24)
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- Metal-Free: A novel and efficient aerobic oxidation of primary amines to oximes using N, N', N''-trihydroxyisocyanuric acid and acetaldoxime as catalysts in water
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A general, efficient, and metal-free method for aerobic oxidation of aromatic primary amines to the corresponding oximes catalyzed by N,N',N''-trihydroxyisocyanuric acid and acetaldoxime with water as solvent is described. This practical method can use air as economic and green oxidant, water as green solvent, and tolerates a wide range of substrates, which can afford the target oximes in moderate to good yields. Georg Thieme Verlag Stuttgart. New York.
- Yu, Jiatao,Lu, Ming
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p. 1873 - 1878
(2014/08/18)
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- Iodine(III)-Mediated [3 + 2] cyclization for one-pot synthesis of benzo[ d ]isoxazole-4,7-diols in aqueous medium
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A one-pot [3 + 2] cycloadditive synthesis of benzo[d]isoxazole-4,7-diols in aqueous medium was carried out via nitrile oxides and benzoquinone intermediates by taking advantage of iodobenzene diacetate as an oxidant. This method can also be used to synthesize benzodiisoxazole-4,8-diols, isoxazolo[5,4-a]phenazines, and indazole-4,7-diols, which are difficult to obtain by classical methods.
- Hou, Yingwei,Lu, Shichao,Liu, Gang
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p. 8386 - 8395
(2013/09/24)
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- Isoxazoles: Synthesis, evaluation and bioinformatic design as acetylcholinesterase inhibitors
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Objectives Inhibition of acetylcholinesterase (AChE) is a common treatment for early stages of Alzheimer's disease. In this study, nine isoxazoles derivatives were tested for their in-vitro AChE activity. The molecular docking showed the interaction of the compounds with the active site. Methods The isoxazoles were synthesized using 1,3-dipolar cycloaddition in the presence of sodium hypochlorite. They were also isolated and characterized by spectroscopic methods. The in-vitro activity was measured by an adapted version of Ellman's assay. Key findings The isoxazoles are described as inhibitors of AChE. The most potent compound in the series exhibited a moderate inhibitory activity (50% inhibitory concentration = 134.87 μm). The design of new compounds was created by using the RACHEL module of the SYBYL software. Conclusions Our research provided enough evidence of the efficacy of isoxazoles as AChE inhibitors. The isoxazoles were synthesized and evaluated as inhibitors of AChE. The docking study based on a novel series of complexes isoxazole with AChE from Electroporus electricus has demonstrated that the ligand bind is similar to the compounds used as reference. To find new candidates with the isoxazole core that act as inhibitors of AChE, part of the structure of the compound 9 was used for de-novo design. Molecular docking models of the ligand-AChE complexes suggest that the compound 10 is located on the periphery of the AChE active site.
- Gutiérrez, Margarita,Matus, María Francisca,Poblete, Tomas,Amigo, Jessica,Vallejos, Gabriel,Astudillo, Luis
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p. 1796 - 1804
(2013/12/04)
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- A versatile and green mechanochemical route for aldehyde-oxime conversions
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A robust, facile and solvent-free mechanochemical path for aldehyde-oxime transformations using hydroxylamine and NaOH is explored; the method is suitable for aromatic and aliphatic aldehydes decorated with a range of substituents. This journal is
- Aakeroey, Christer B.,Sinha, Abhijeet S.,Epa, Kanishka N.,Spartz, Christine L.,Desper, John
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supporting information
p. 11289 - 11291,3
(2012/12/12)
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- Acetohydroxamic acid: A new reagent for efficient synthesis of nitriles directly from aldehydes using Bi(OTf)3 as the catalyst
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An efficient method for the preparation of nitriles directly from aldehydes by reaction with AHA using Bi(OTf)3 as the catalyst is described. Bi(OTf)3 is shown to be an efficient catalyst also for the conversion of aldoximes into nitriles.
- Sridhar, Madabhushi,Reddy, Mallu Kishore Kumar,Sairam, Vangipuram Venkata,Raveendra, Jillella,Godala, Kondal Reddy,Narsaiah, Chinthala,Ramanaiah, Beeram China,Reddy, Cirandur Suresh
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scheme or table
p. 3421 - 3424
(2012/08/08)
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- Efficient microwave-assisted synthesis of oximes from acetohydroxamic acid and carbonyl compounds using BF3·OEt2 as the catalyst
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An efficient synthesis of oximes by reaction of carbonyls with acetohydroxamic acid using BF3·OEt2 as a catalyst is described.
- Sridhar, Madabhushi,Narsaiah, Chinthala,Raveendra, Jillella,Kondal Reddy, Godala,Kishore Kumar Reddy, Mallu,China Ramanaiah, Beeram
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experimental part
p. 4701 - 4704
(2011/09/20)
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- Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent
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The potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the β-cyclodextrin cavity was synthesized, and the ability of these compounds to reduce the inhibitory effect of the neurotoxic organophosphonate cyclosarin on its key target, acetylcholinesterase, was assessed in vitro. All compounds exhibited a larger effect than native β-cyclodextrin, and characteristic differences were noted. These differences in activity were correlated with the structural and electronic parameters of the substituents. In addition, the relatively strong effect of the cyclodextrin derivatives on cyclosarin degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among the nine compounds investigated, one exhibited remarkable activity, completely preventing acetylcholinesterase inhibition by the (-)-enantiomer of cyclosarin within seconds under the conditions of the assay. Thus, these investigations demonstrate that decoration of cyclodextrins with appropriate substituents represents a promising approach for the development of scavengers able to detoxify highly toxic nerve agents.
- Zengerle, Michael,Brandhuber, Florian,Schneider, Christian,Worek, Franz,Reiter, Georg,Kubik, Stefan
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supporting information; experimental part
p. 1543 - 1554
(2012/01/30)
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- Isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists
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This Letter describes the synthesis and evaluation of mGluR7 antagonists in the isoxazolopyridone series. In the course of modification in this class, novel solid support synthesis of the isoxazolopyridone scaffold was developed. Subsequent chemical modification led to the identification of several potent derivatives with improved physicochemical properties compared to a hit compound 1. Among these, 2 showed good oral bioavailability and brain penetrability, suggesting that 2 may be useful for in vivo study to elucidate the role of mGluR7.
- Nakamura, Masayuki,Kurihara, Hideki,Suzuki, Gentaroh,Mitsuya, Morihiro,Ohkubo, Mitsuru,Ohta, Hisashi
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scheme or table
p. 726 - 729
(2010/05/18)
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- Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases
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We describe here the identification of non-peptidic vinylsulfones that inhibit parasite cysteine proteases in vitro and inhibit the growth of Trypanosoma brucei brucei parasites in culture. A high resolution (1.75 A) co-crystal structure of 8a bound to cruzain reveals how the non-peptidic P2/P3 moiety in such analogs bind the S2 and S3 subsites of the protease, effectively recapitulating important binding interactions present in more traditional peptide-based protease inhibitors and natural substrates.
- Bryant, Clifford,Kerr, Iain D.,Debnath, Moumita,Ang, Kenny K.H.,Ratnam, Joseline,Ferreira, Rafaela S.,Jaishankar, Priyadarshini,Zhao, DongMei,Arkin, Michelle R.,McKerrow, James H.,Brinen, Linda S.,Renslo, Adam R.
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scheme or table
p. 6218 - 6221
(2010/06/19)
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- Concise synthesis and antimicrobial activities of new substituted 5-isoxazolpenicillins
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The synthesis of a series of new 5-isoxazolpenicillins is described, which were obtained by coupling substituted isoxazoles with 6-APA. Concise large-scale synthesis of 3,5-disubstituted isoxazoles by 1,3-dipolar cycloaddition using copper(I) as catalyst was also investigated. Representative compounds were assayed for antimicrobial activities, showing satisfactory antimicrobial activities against Gram-negative bacteria.
- Wang, Xi-Zhao,Jia, Jiong,Zhang, Yan,Xu, Wei-Ren,Liu, Wei,Shi, Fang-Niu,Wang, Jian-Wu
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p. 643 - 652
(2008/03/11)
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- PROCESS FOR PRODUCTION OF 2-HYDROXY-4-SUBSTITUTED PYRIDINES
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A process for preparing a 2-hydroxy-4-substituted pyridine compound using a microbiological method, a novel microorganism, and a novel compound are provided. According to the process, a function of a microorganism or a product obtained therefrom is exerted on a 4-substituted pyridine of the general formula (1): wherein R is a methyl group, a carboxyl group, a carbamoyl group, a hydroxyiminomethyl group or a cyano group, to obtain the corresponding 2-hydroxy-4-substituted pyridine compound. The novel microorganisms are the Delftia species YGK-A649 (FERM BP-10389), Delftia species YGK-C217 (FERM BP-10388), or Acidovorax species YGK-A854 (FERM BP-10387) and the novel compound is a 2-hydroxy-4-pyridinaldoxime.
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Page/Page column 11-12
(2008/06/13)
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- Rh-catalyzed one-pot and practical transformation of aldoximes to amides
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Wilkinson's complex has been found to catalyze the one-pot transformation of aldoximes to the corresponding amides with high selectivity and efficiency under essentially neutral conditions.
- Park, Soyoung,Choi, Yoon-aa,Han, Hoon,Yang, Soon Ha,Chang, Sukbok
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p. 1936 - 1937
(2007/10/03)
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- Kinetics and Mechanism for Oxime Formation from Pyridine-2-, -3-, and -4-carboxaldehydes
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Oxime formation from pyridine-2-, -3-, and -4-carboxaldehydes occurs with rate-limiting carbinolamine dehydration under both acidic and neutral conditions.Carbinolamine dehydration of pyridine-2-carboxaldehyde occurs via a transition state bearing a single positive charge, unlike the corresponding reaction for formyl-1-methylpyridinium ion and the reaction under acidic conditions for pyridine-3- and -4-carboxaldehydes.
- Malpica, A.,Calzadilla, M.,Baumrucker, J.,Jimenez, J.,Lopez L.,et al.
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p. 3398 - 3401
(2007/10/02)
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- REINVESTIGATION OF NITROSATION OF METHYLPYRIDINES AND THEIR 1-OXIDES AND DEOXYGENATION OF 3-PYRIDINECARBALDEHYDE 1-OXIDE OXIME
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Treatment of methylpyridines and their 1-oxides with t-butyl nitrite in the presence of potassium t-butoxide in liquid ammonia afforded the corresponding aldoximes in good yields except for the case of 3-methylpyridine.The reaction of 3-methylpyridine with t-butyl nitrite in the presence of lithium 2,2,6,6-tetramethylpiperidide and N,N,N',N'-tetramethylethylenediamine in tetrahydrofuran at -78 deg C led to 3-(3-methyl-4-pyridyl)methylpyridine.Deoxygenation of 3-pyridinecarbaldehyde 1-oxide oxime was effected in 78percent yieldby the action of t-butyldimethylsilyl chloride-imidazolesodium iodide-zinc followed by desilylation with tetrabutylammonium fluoride to give 3-pyridinecarbaldehyde oxime.
- Tagawa, Yoshinobu,Hama, Kazuya,Goto, Yoshinobu
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p. 1605 - 1612
(2007/10/02)
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- Stability studies of bis(pyridiniumaldoxime) reactivators of organophosphate-inhibited acetylcholinesterase
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Relative stability studies of three organophosphate-inhibited acetylcholinesterase reactivators, 1-(2-hydroximinomethyl-1-pyridinium)-3-(4-carbamoyl-1-pyridi nium)-2-oxapropane dichloride (HI-6), 1,1'-methylenebis(4-hydroximinomethylpyridinium) dichloride (MMB-4), and 1,1'-trimethylenebis(4-hydroximinomethylpyridinium) dibromide (TMB-4) were carried out by semiquantitative TLC and NMR methods. TMB-4 appears to be the most, and HI-6 the least stable of the three compounds. The extent of hydrolysis of HI-6, MMB-4, and TMB-4 in 0.05 M, pH 7 phosphate buffer was ~50, 25, and 2O and of the protons at the 2- and 6-positions of the pyridinium ring of TMB-4 in NaOD/D2 were observed.
- Lin,Klayman
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p. 797 - 799
(2007/10/02)
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