- Mercapto-amide boronic acid derivative and application thereof as MBL (metal beta-lactamase) and/or SBL (serine beta-lactamase) inhibitor
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The invention provides a compound of a formula (I) shown in the specification, or a conformational isomer, or an optical isomer or a pharmaceutically acceptable salt thereof. The compound of the formula (I) shown in the specification has excellent broad-spectrum inhibitory activity on MBL (metal beta-lactamase) and/or SBL (serine beta-lactamase), and can be used for preparing MBL and/or SBL inhibitors. Moreover, the compound disclosed by the invention has excellent antibacterial activity on multiple drug-resistant bacteria and is capable of reversing drug resistance of carbapenem drug-resistant bacteria, and the antibacterial effect of the compound is prior to those of positive control products such as L-captopril and tazobactam. The compound disclosed by the invention has very great potential in preparation of MBL/SBL dual inhibitors and medicines reversing drug resistance of carbapenem drug-resistance bacteria.
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Paragraph 0090-0093
(2019/09/14)
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- Structure-based development of (1-(3′-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- And Serine-β-lactamases
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The emergence and spread of bacterial pathogens acquired metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) medicated β-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2′S)-(1-(3′-mercapto-2′-methylpropanamido)methyl)boronic acid (MS01) as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2:MS01 and KPC-2:MS01 complex structures, further structural optimization yielded new, more potent dual-action inhibitors. Selectivity studies indicated that the inhibitors had no apparent inhibition to human angiotensin-converting enzyme-2 and showed selectivity across serine hydrolyases in E. coli and human HEK293T cells labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors displayed potentiation of meropenem efficacy against MBL- or SBL-positive clinical isolates without apparent cytotoxicity. This work will aid efforts to develop new types of clinically useful dual-action inhibitors targeting MBL/SBL enzymes.
- Wang, Yao-Ling,Liu, Sha,Yu, Zhu-Jun,Lei, Yuan,Huang, Meng-Yi,Yan, Yu-Hang,Ma, Qiang,Zheng, Yang,Deng, Hui,Sun, Ying,Wu, Chengyong,Yu, Yamei,Chen, Qiang,Wang, Zhenling,Wu, Yong,Li, Guo-Bo
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supporting information
p. 7160 - 7184
(2019/08/28)
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- Cinnamoylated chloroquine analogues: A new structural class of antimalarial agents
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A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as antimalarial agents. The trans cinnamic acid derivatives (3–8) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine analogues (9–14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl2 as chlorinating agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in actonitrile in presence of K2CO3?as?base followed by basic hydrolysis. The preparation of amide based chloroquine-chalcone analogues (18–22), were obtained by the combination of amido chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25–28), by reacting the epoxide (24a, 24b and 24c) with 2 and methelenedioxy aniline. In?vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1 of P.?falciparum and in?vitro cytotoxicity of compounds using VERO cell line was carried out. The synthesized molecules showed significant in?vitro antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and 10 were found to be the most potent compounds of the series with IC50 value of 44.06, 48.04 and 59.37?nM against chloroquine resistant K1 strain.
- Gayam, Venkatareddy,Ravi, Subban
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p. 382 - 391
(2017/05/04)
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- Substrate-Tuned Catalysis of the Radical S-Adenosyl- L -Methionine Enzyme NosL Involved in Nosiheptide Biosynthesis
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NosL is a radical S-adenosyl-L-methionine (SAM) enzyme that converts L-Trp to 3-methyl-2-indolic acid, a key intermediate in the biosynthesis of a thiopeptide antibiotic nosiheptide. In this work we investigated NosL catalysis by using a series of Trp analogues as the molecular probes. Using a benzofuran substrate 2-amino-3-(benzofuran-3-yl)propanoic acid (ABPA), we clearly demonstrated that the 5′-deoxyadenosyl (dAdo) radical-mediated hydrogen abstraction in NosL catalysis is not from the indole nitrogen but likely from the amino group of L-Trp. Unexpectedly, the major product of ABPA is a decarboxylated compound, indicating that NosL was transformed to a novel decarboxylase by an unnatural substrate. Furthermore, we showed that, for the first time to our knowledge, the dAdo radical-mediated hydrogen abstraction can occur from an alcohol hydroxy group. Our study demonstrates the intriguing promiscuity of NosL catalysis and highlights the potential of engineering radical SAM enzymes for novel activities.
- Ji, Xinjian,Li, Yongzhen,Ding, Wei,Zhang, Qi
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supporting information
p. 9021 - 9024
(2015/08/03)
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- Finding new elicitors that induce resistance in rice to the white-backed planthopper Sogatella furcifera
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Herein we report a new way to identify chemical elicitors that induce resistance in rice to herbivores. Using this method, by quantifying the induction of chemicals for GUS activity in a specific screening system that we established previously, 5 candidate elicitors were selected from the 29 designed and synthesized phenoxyalkanoic acid derivatives. Bioassays confirmed that these candidate elicitors could induce plant defense and then repel feeding of white-backed planthopper Sogatella furcifera.
- He, Xingrui,Yu, Zhaonan,Jiang, Shaojie,Zhang, Peizhi,Shang, Zhicai,Lou, Yonggen,Wu, Jun
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supporting information
p. 5601 - 5603
(2015/11/17)
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- Ruthenium NHC catalyzed highly asymmetric hydrogenation of benzofurans
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H2-O-T! Aromatic O-heterocycles are a challenging substrates for asymmetric hydrogenation (H2). An in situ formed chiral N-heterocyclic carbene (NHC) ruthenium complex allows the high yielding, completely regioselective, and highly asymmetric hydrogenation of substituted benzofurans at room Temperature, giving valuable 2,3-dihydrobenzofurans (see scheme). Copyright
- Ortega, Nuria,Urban, Slawomir,Beiring, Bernhard,Glorius, Frank
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supporting information; experimental part
p. 1710 - 1713
(2012/04/05)
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- Highly asymmetric synthesis of (+)-corsifuran A. Elucidation of the electronic requirements in the Ruthenium-NHC catalyzed hydrogenation of benzofurans
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A short and efficient synthesis of ent-corsifuran A by a highly asymmetric hydrogenation of a benzofuran precursor is reported. In addition, the electronic influence of the substituents on the asymmetric hydrogenation of benzofurans is provided. Whereas the hydrogenation of electron-deficient benzofurans was achieved under very mild conditions, the presence of electron-donating groups in the benzofuran required harsher reaction conditions for achieving full conversion to the 2,3-dihydrobenzofuran.
- Ortega, Nuria,Beiring, Bernhard,Urban, Slawomir,Glorius, Frank
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supporting information; experimental part
p. 5185 - 5192
(2012/07/31)
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- ANTI-HIV COMPOUNDS
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Thiazole derivatives represented by Formula (I) are disclosed, where R1, R2, R3, A, X, Y, Z, R6 and R7 are disclosed herein. These thiazole derivatives and pharmaceutical compositions comprising these derivatives are useful in the treatment of HIV mediated diseases and conditions.
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Page/Page column 39; 49
(2009/08/14)
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- Chemoenzymatic preparation of enantiopure l-benzofuranyl- and l-benzo[b]thiophenyl alanines
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Lipase mediated DKR followed by a chemical and an enzymatic hydrolytic step were combined for the synthesis of enantiopure l-benzofuranyl- and l-benzothienyl alanines.
- Podea, Paula Veronica,Tosa, Monica Ioana,Paizs, Csaba,Irimie, Florin Dan
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p. 500 - 511
(2008/09/19)
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- Preparation of 2-, 3-, 4- and 7-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b] furans and their BLT1 and/or BLT2 inhibitory activities
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Several 2-alkylcarbamoyl-1-alkylvinylbenzo[b]furans were designed to find a selective leukotriene B4 (LTB4) receptor antagonist. 2-(2-Alkylcarbamoyl-1-alkylvinyl)benzo[b]furans having a substituent group at the 3-position, 4-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans having a substituent group at the 3-position, and 7-(2-alkylcarbamoyl-1-methylvinyl) benzo[b]furans and 3-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans were prepared and evaluated for LTB4 receptor (BLT1 and BLT 2) inhibitory activities. (E)-3-Amino-4-[2-[2-(3,4-dimethoxyphenyl) ethylcarbamoyl]-1-methylvinyl]benzo[b]furan ((E)-17c) showed potent and selective inhibitory activity for BLT2. On the other hand, (E)-7-(2-diethylcarbamoyl-1-methylvinyl)benzo[b]furan ((E)-27a) showed potent inhibitory activity for both BLT1 and BLT2. This journal is The Royal Society of Chemistry.
- Ando, Kumiko,Kawamura, Yoko,Akai, Yukiko,Kunitomo, Jun-Ichi,Yokomizo, Takehiko,Yamashita, Masayuki,Ohta, Shunsaku,Ohishi, Takahiro,Ohishi, Yoshitaka
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p. 296 - 307
(2008/09/21)
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- Structure-activity relationships for a novel series of dopamine D2-like receptor ligands based on N-substituted 3-aryl-8-azabicyclo[3.2.1]octan-3-ol
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Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K i(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2LR- or hD3R-transfected HEK 293 cells (31, Ki(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, Ki(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.
- Paul, Noel M.,Taylor, Michelle,Kumar, Rakesh,Deschamps, Jeffrey R.,Luedtke, Robert R.,Newman, Amy Hauck
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experimental part
p. 6095 - 6109
(2009/10/01)
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- The interaction of heteroaryl-acrylates and alanines with phenylalanine ammonia-lyase from parsley
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Acrylic acids and alanines substituted with heteroaryl groups at the β-position were synthesized and spectroscopically characterized (UV, HRMS, 1H NMR, and 13C NMR spectroscopy). The heteroaryl groups were furanyl, thiophenyl, benzofuranyl, and benzothiophenyl and contained the alanyl side chains either at the 2- or 3-positions. While the former are good substrates for phenylalanine ammonia lyase (PAL), the latter compounds are inhibitors. Exceptions are thiophen-3-yl-alanine, a moderate substrate and furan-3-yl-alanine, which is inert. Possible reasons for these exceptions are discussed. Starting from racemic het eroaryl-2-alanines their D-enantiomers were prepared by using a stereodestructive procedure. From the heteroaryl-2- acrylates, the L-enantiomers of the heteroaryl-2-alanines were prepared at high ammonia concentration. These results can be best explained by a Friedel - Crafts-type electrophilic attack at the aromatic part of the substrates as the initial step of the PAL reaction.
- Paizs, Csaba,Katona, Adrian,Retey, Janos
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p. 2739 - 2744
(2008/02/03)
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- Benzofuran Derivatives. Part 4. Synthesis of Benzofurans and 2,3,4,5-Tetrahydro-1-benzoxepin-3,5-diones
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By treatment of ethyl 4- or 5-substituted 2-acetylphenoxyacetates 1 with potassium hydroxide in dry dioxane, benzofurans 2-7 and 2,3,4,5-tetrahydro-1-benzoxepin-3,5-diones 8 were obtained.The relative yields of benzofurans 2-7 and 2,3,4,5-tetrahydro-1-benzoxepin-3,5-diones 8 varied with the types of 4- or 5-substituents.The electron-donating 4-methoxyl group favored the formation of benzoxepins.On the other hand, electron-withdrawing substituents such as the 4-nitro group favored the formation of benzofurans.When esters 1 were treated with sodium amide,2,3-dihydrobenzofurans 2 were obtained exclusively regardless of 4- or 5-substituents.
- Suzuki, Tsuneo,Tanemura, Kiyoshi,Horaguchi, Takaaki,Shimimizu, Takahachi,Sakakibara, Tohru
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p. 423 - 429
(2007/10/02)
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- Photocyclization Reactions. Part 1. Synthesis of Dihydrobenzofuranols Using Photocyclization of 2-Alkoxybenzaldehydes, 2'-Alkoxyacetophenones, 2-Formylphenoxyacetic Acids and 2-Acetylphenoxyacetic Acids
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Photocyclization reactions were carried out on 2-alkoxybenzaldehydes 1a-f, 2'-alkoxyacetophenones 2a-h, 2-formylphenoxyacetic acids 1i-l and 2-acetylphenoxyacetic acids 2i-m.Irradiation opf 1a-f and 2a-h in acetonitrile gave the corresponding dihydrobenzofuranols 3, 5 and dihydroisobenzofuranols 4, 6.Using carboxylic acids 1i-l, 2i-m as starting materials, decarboxylation occurred immediately to give the corresponding ethers 1a-d, 2a-e.Further irradiation of the solution afforded dihydrobenzofuranols 3,5 and dihydroisobenzofuranols 4, 6.Substituent effects on photocyclization and reaction pathways are discussed.
- Horaguchi, Takaaki,Tsukada, Chikara,Hasegawa, Eietsu,Shimizu, Takahachi,Suzuki, Tsuneo,Tanemura, Kiyoshi
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p. 1261 - 1272
(2007/10/02)
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- Chemistry of Thiazole, I. Synthesis and Properties of 2,3,5,6-Tetrahydro-6-(3-methyl-benzofuran-2-yl)imidazothiazole
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Die Titelverbindung 13 wird auf zwei Wegen ausgehend von 2-Hydroxyacetophenon (1) ueber das Benzofuran-Derivat 7 und die Thiazolidine 9 bzw. 10 erhalten.
- Nielek, Stefan,Lesiak, Tadeusz
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p. 1247 - 1251
(2007/10/02)
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