- Uptake and transformation of pesticide metabolites by duckweed (Lemna gibba)
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Uptake and transformation of 14C-labeled metabolites from several pesticides, 3-methyl-4-nitrophenol (1), 3,5-dichloroaniline (2), 3-phenoxybenzoic acid (3), (R,S)-2-(4-chlorophenyl)-3-methylbutanoic acid (4), and (1RS)-trans-3-(2,2-dichlorovin
- Fujisawa, Takuo,Kurosawa, Motohiro,Katagi, Toshiyuki
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Read Online
- Design and synthesis of N-(3-sulfamoylphenyl)amides as Trypanosoma brucei leucyl-tRNA synthetase inhibitors
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The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (TbLeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC50 of 0.24 and 0.25 μM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents.
- Li, Zezhong,Xin, Weixiang,Wang, Qing,Zhu, Mingyan,Zhou, Huchen
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- Decarbonylative Methylation of Aromatic Esters by a Nickel Catalyst
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A Ni-catalyzed decarbonylative methylation of aromatic esters was achieved using methylaluminums as methylating agents. Dimethylaluminum chlorides uniquely worked as the methyl source. Because of the Lewis acidity of aluminum reagents, less reactive alkyl esters could also undergo the present methylation. By controlling the Lewis acidity of aluminum reagents, a chemoselective decarbonylative cross-coupling between alkyl esters and phenyl esters was successful.
- Okita, Toshimasa,Muto, Kei,Yamaguchi, Junichiro
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supporting information
p. 3132 - 3135
(2018/05/28)
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- Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne
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The use of an interleukin β antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1β into active IL-1β, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.
- Fournier, Jean-Fran?ois,Clary, Laurence,Chambon, Sandrine,Dumais, Laurence,Harris, Craig Steven,Millois, Corinne,Pierre, Romain,Talano, Sandrine,Thoreau, étienne,Aubert, Jérome,Aurelly, Michèle,Bouix-Peter, Claire,Brethon, Anne,Chantalat, Laurent,Christin, Olivier,Comino, Catherine,El-Bazbouz, Ghizlane,Ghilini, Anne-Laurence,Isabet, Tatiana,Lardy, Claude,Luzy, Anne-Pascale,Mathieu, Céline,Mebrouk, Kenny,Orfila, Danielle,Pascau, Jonathan,Reverse, Kevin,Roche, Didier,Rodeschini, Vincent,Hennequin, Laurent Fran?ois
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supporting information
p. 4030 - 4051
(2018/05/23)
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- REDUCTION OF PRO-INFLAMMATORY HDL USING A LEUKOTRIENE INHIBITOR
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A method involving the administration of a therapeutically effective amount of a leukotriene inhibitor, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof to a human for reducing a level of pro-inflammatory HDL in the human. Various examples of leukotriene inhibitors, including 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin- 3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2, 2-dimethyl-propionic acid, are disclosed for administration for the reduction of pro-inflammatory HDL in a human. Reduction of pro-inflammatory HDL by the leukotriene inhibitor may include conversion of at least a portion of pro-inflammatory HDL to anti-inflammatory HDL.
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Paragraph 00207
(2018/09/12)
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- Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus
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A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in?vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.
- Eissa, Ibrahim H.,Mohammad, Haroon,Qassem, Omar A.,Younis, Waleed,Abdelghany, Tamer M.,Elshafeey, Ahmed,Abd Rabo Moustafa, Mahmoud M.,Seleem, Mohamed N.,Mayhoub, Abdelrahman S.
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- Design, synthesis, and biological evaluation of oxazolidone derivatives as highly potent N-acylethanolamine acid amidase (NAAA) inhibitors
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N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme that catalyzes the hydrolysis of endogenous fatty acid ethanolamides (FAEs), such as N-palmitoylethanolamide (PEA). PEA exhibits anti-inflammatory and analgesic activities by engaging peroxisome proliferator-activated receptor α (PPAR-α). Preventing PEA degradation by inhibition of NAAA has been proposed as a novel strategy for the treatment of inflammation and pain. In the present study, we reported the discovery of the oxazolidone derivative as a novel scaffold for NAAA inhibitors, and studied the structure-activity relationship (SAR) by modification of the side chain and terminal lipophilic substituents. The results showed that the link chain length of C5, straight and saturated linkages were the preferred shape patterns for NAAA inhibition. Several nanomolar NAAA inhibitors were described, including 2f, 3h, 3i and 3j with IC50 values of 270 nM, 150 nM, 100 nM and 190 nM, respectively. Enzymatic degradation studies suggested that 2f inhibited NAAA in a selective, noncompetitive and reversible pattern. Moreover, 2f showed high anti-inflammatory and analgesic activities after systemic and oral administration.
- Ren, Jie,Li, Yuhang,Ke, Hongwei,Li, Yanting,Yang, Longhe,Yu, Helin,Huang, Rui,Lu, Canzhong,Qiu, Yan
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p. 12455 - 12463
(2017/03/11)
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- RhIII-Catalyzed C-H Allylation of Amides and Domino Cycling Synthesis of 3,4-Dihydroisoquinolin-1(2H)-ones with N-Bromosuccinimide
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A RhIII-catalyzed C-H allylation of electron-deficient arenes, heteroarenes, and alkenes at room temperature was developed with allyl bromide. The reaction was carried out in diethyl ether without dehydration, and C-H activation was assisted by the directing anionic nitrogen of the aniline-derived amide. Following the allylation, a domino cycling synthesis of 3,4-dihydroisoquinolin-1(2H)-ones with N-bromosuccinimide (NBS) through intramolecular aminobromination of the introduced double bond was achieved. A C-H allylation of amides with allyl halides at room temperature and a tandem synthesis of 3,4-dihydroisoquinolin-1(2H)-ones with N-bromosuccinimide (NBS) are reported.
- Dai, Huimin,Yu, Chao,Lu, Changsheng,Yan, Hong
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supporting information
p. 1255 - 1259
(2016/03/16)
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- An efficient method for the preparation of hydroxamic acids
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Reactions of acyl chlorides with hydroxylamine hydrochloride and NaHCO 3 generate the corresponding hydroxamic acid products in ethyl acetate and water at room temperature for 5 min. This is a simple and efficient method to synthesize a wide range of hydroxamic acids from carboxylic acids in excellent yield and high purity after simple post-treatment without chromatographic purification. In this process, the highlights are the simple separation of products and cheaply available reagents.
- Gao, Xi-Ai,Wang, Xian-Xue,Yan, Hao,Li, Jian,Yan, Ru-Long,Huang, Guo-Sheng
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p. 381 - 385
(2013/05/22)
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- Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by toxoplasma gondii
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Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a number of new derivatives of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogues in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low μM EC 50 values) were highly correlated and occurred in a CDPK1-specific manner. Chemical modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compounds with enhanced stability while retaining activity. Several of these more potent compounds were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compounds for treatment of toxoplasmosis and perhaps related parasitic diseases.
- Lourido, Sebastian,Zhang, Chao,Lopez, Michael S.,Tang, Keliang,Barks, Jennifer,Wang, Qiuling,Wildman, Scott A.,Shokat, Kevan M.,Sibley, L. David
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p. 3068 - 3077
(2013/06/05)
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- Discovery of novel bacterial RNA polymerase inhibitors: Pharmacophore-based virtual screening and hit optimization
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The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ70 and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
- Hinsberger, Stefan,Hüsecken, Kristina,Groh, Matthias,Negri, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
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p. 8332 - 8338
(2013/12/04)
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- Design, synthesis and evaluation of novel molecules with a diphenyl ether nucleus as potential antitubercular agents
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A series of compounds with a diphenyl ether nucleus were synthesized by incorporating various amines into the diphenyl ether scaffold with an amide bond. Their antitubercular activities were evaluated against Mycobacterium tuberculosis H37Rv by a microdilution method, with MIC values ranging from 4 to 64 μg/mL. Through structure-activity relationship studies, the two chlorine atoms at 3 and 4 positions in the phenyl ring of R2 group were found to play a significant role in the antitubercular activity. The most potent compound 6c showed an MIC value of 4 μg/mL and a good safety profile in HepG2 cell line by the MTT assay. Compound 6c was further found to be effective in a murine model of BCG infection, providing a good lead for subsequent optimization.
- Yang, Yinghong,Wang, Zhenling,Yang, Jianzhong,Yang, Tao,Pi, Weiyi,Ang, Wei,Lin, Yanni,Liu, Yuanyuan,Li, Zicheng,Luo, Youfu,Wei, Yuquan
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p. 954 - 957
(2012/03/11)
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- BRONCHORELAXING ARYLAMIDES
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The invention relates to novel molecules having the general formula (I), and which molecules are useful to manufacture a medicament to treat a disorder or disease characterized by bronchoconstriction.
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Page/Page column 33; 35
(2008/12/08)
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- Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors
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In this report, we describe new HDAC inhibitors designed to exploit a unique sub-pocket in the HDAC8 active site. These compounds were based on inspection of the available HDAC8 crystal structures bound to various inhibitors, which collectively show that the HDAC8 active site is unusually malleable and can accommodate inhibitor structures that are distinct from the canonical 'zinc binding group-linker-cap group' structures of SAHA, TSA, and similar HDAC inhibitors. Some inhibitors based on this new scaffold are >100-fold selective for HDAC8 over other class I and class II HDACs with IC50 values 1 μM against HDAC8. Furthermore, treatment of human cells with the inhibitors described here shows a unique pattern of hyperacetylated proteins compared with the broad-spectrum HDAC inhibitor TSA.
- KrennHrubec, Keris,Marshall, Brett L.,Hedglin, Mark,Verdin, Eric,Ulrich, Scott M.
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p. 2874 - 2878
(2008/02/03)
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- 5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS
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Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.
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Page/Page column 65
(2008/06/13)
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- NOVEL MCH RECEPTOR ANTAGONISTS
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The present invention relates to a melanin concentrating hormone antagonist compound of formula (I); wherein Ar1, L1, R1, q, X, R2, R3, R4, and R5 are as defined, or a pharmaceutically acceptable salt, solvate, or enantiomer thereof useful in the treatment, prevention or amelioration of symptoms associated with obesity and related diseases.
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Page/Page column 63
(2008/06/13)
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- Structure-based design, synthesis, and study of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents
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Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, β-ketoacyl-ACP synthase III, is a particularly attractiv
- Nie, Zhe,Perretta, Carin,Lu, Jia,Su, Ying,Margosiak, Stephen,Gajiwala, Ketan S.,Cortez, Joseph,Nikulin, Victor,Yager, Kraig M.,Appelt, Krzysztof,Chu, Shaosong
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p. 1596 - 1609
(2007/10/03)
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- Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
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The present invention provides compounds and pharmaceutical compositions that act as antagonists at metabotropic glutamate receptors, and that are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.
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- BEZAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY CYTOKINES
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The invention concerns the use of amide derivatives of formula (I) wherein: R1 and R2 are substituents such as hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino, C1-6alkylamino and di-(C1-6alkyl)amino; m and p are independently 0-3; R3 is C1-4alkyl; q is 0-4; and R4 is aryl or cycloalkyl; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines
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- Tricyclic inhibitors of poly(ADP-ribose) polymerases
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Compounds of the formula shown below are poly(ADP-ribosyl)transferase inhibitors: Such compounds are useful as therapeutics in treating cancers and in ameliorating the effects of stroke, head trauma, and neurodegenerative disease.
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- Synthesis of m-phenoxybenzaldehyde starting from chlorobenzene and m-cresol: Some aspects of process development
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m-Phenoxybenzaldehyde (MPB) is an important intermediate for synthetic pyrethroids. In the present paper, an economic process scheme was developed to synthesize MPB starting from cheaper reactants. The process scheme was started with the synthesis of m-phenoxytoluene (MPT). Oxidation of MPT by air gave MPB, but the selectivity was found to be high at low conversions of about 10%, and if the conversion level was increased, then large amounts of the undesired m-phenoxybenzoic acid (MPBA) was formed. To obtain the desired aldehyde, Rosenmund reduction of MPBA was carried out to give high yields of the MPB. The effects of different parameters such as catalyst, substrate concentration, temperature, etc., were studied for all three of the reactions, viz., Ullmann ether synthesis, oxidation, and Rosenmund reduction. MPT was prepared from chlorobenzene, a relatively cheaper starting material, in the presence of polyethylene glycol) as cosolvent and cuprous chloride as the catalyst. A selectivity of 97% was obtained with 86% conversion to the product. Oxidation of MPT was carried out by air in the presence of cobalt acetate as catalyst and sodium bromide as catalyst promoter. The selectivity with respect to the aldehyde and the ester was 37.4 and 30.6%, respectively, at a restricted overall conversion of 24%. The process parameters were controlled to achieve high selectivity towards the aldehyde. The acid, formed as the side product, was reduced to the aldehyde by Rosenmund reduction via the acyl chloride. At a conversion level of 85%, a selectivity of 87% to MPB was obtained using Pd/C.
- Chandnani, Kavita H.,Chandalia, Sampatraj B.
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p. 416 - 424
(2013/09/08)
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- Generation of monospecific nanomolar tyrosine kinase inhibitors via a chemical genetic approach
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Selective protein kinase inhibitors are highly sought after as tools for studying cellular signal transduction cascades, yet few have been discovered due to the highly conserved fold of kinase catalytic domains. Through a combination of small molecule syn
- Bishop, Anthony C.,Kung, Chi-Yun,Shah, Kavita,Witucki, Laurie,Shokat, Kevan M.,Liu, Yi
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p. 627 - 631
(2007/10/03)
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- An enzyme-linked immunosorbent assay for the detection of esfenvalerate metabolites in human urine
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The pyrethroids are one of the most heavily used insecticide classes in the world. Sensitive and rapid analytical techniques are needed for assessments of human exposure to these compounds. Highly sensitive and selective ELISAs for glycine conjugates of e
- Shan, Guomin,Wengatz, Ingrid,Stoutamire, Donald W.,Gee, Shirley J.,Hammock, Bruce D.
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p. 1033 - 1041
(2007/10/03)
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- Reactions of cesium perfluorotertiary alkoxides and perfluorotertiary alcohols with reactive halides
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Reactions of cesium perfluorotertiary alkoxides and perfluorotertiary alcohols with chlorotrimethylsilane, benzoyl chloride, perfluoroacyl halides and 3-phenoxybenzoyl chloride gave the compounds Me3SiORf1 (3), C6/su
- Chen, Grace J.,Chen, Loomis S.
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p. 125 - 131
(2007/10/03)
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- INFLUENCE OF THE ANGULAR LINKAGE ON THE MESOMORPHIC PROPERTIES OF CHOLESTERYL ARYLBENZOATES.
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Some cholesteryl esters of arylbenzoic acids incorporating angular linkage such as -Co-, -O-, -S-, and -CH//2-, were prepared, and the transition temperatures and heats determined. The cholesteric-isotropic transition temperatures are likely to correlate with the angular correlation parameters of these carboxylic acid moieties. The mesomorphic phenomena are discussed in terms of the molecular structure and electronic effect of these linkages.
- Koden,Takenaka,Kusabayashi
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p. 137 - 150
(2007/10/02)
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- N-[Diaminophosphinyl]arylcarboxamides
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A series of N-[diaminophosphinyl]arylcarboxamides are useful as inhibitors of the enzyme urease.
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