共查询到20条相似文献,搜索用时 15 毫秒
1.
Yu XY Finn J Hill JM Wang ZG Keith D Silverman J Oliver N 《Bioorganic & medicinal chemistry letters》2004,14(5):1339-1342
We have identified a series of spirocyclic furan and pyrrolidine inhibitors of Enterococcus faecalis and Staphylococcus aureus phenylalanyl-tRNA synthetases. The most potent analogue 1b showed IC50=5 nM (E. faecalis PheRS) and IC50=2 nM (S. aureus PheRS) with high selectivity over the human enzyme. The crystal X-ray structure of analogue 1b was determined. 相似文献
2.
Barhate NB Reddy MC Reddy PS Wakharkar RD Reddanna P 《Indian journal of biochemistry & biophysics》2002,39(4):264-273
A series of benzyl propargyl ethers were synthesized and tested as inhibitors of 5-lipoxygenase, the key enzyme involved in leukotriene biosynthesis. Among these, optimum activity was displayed by 1-(2-heptynyloxymethyl) benzene 12 (IC50 1.2 microM). Addition of carboxyl group at the end of the alkyl side chain attached to the acetylenic group abolished the inhibition. Selective reduction of the acetylenic group to cis or trans double bond reduced the inhibitory potential, the cis isomer 24 showing more than 20-fold higher inhibition than the trans isomer 25. Introduction of sulphur in place of oxygen in the alkyl side chain attached to the (carboxyalkyl) benzyl group also reduced the inhibition. The IC50 value of 12, towards rabbit reticulocyte 15-LOX is > 50 fold higher than that of 5-LOX. These results indicate that compound 12 is a specific inhibitor of 5-LOX. 相似文献
3.
Finn J Mattia K Morytko M Ram S Yang Y Wu X Mak E Gallant P Keith D 《Bioorganic & medicinal chemistry letters》2003,13(13):2231-2234
Starting with a micromolar lead identified from high-throughput screening, a series of pyrazoles were discovered with significantly improved potency on bacterial methionyl-tRNA synthetase and selectivity over human methionyl-tRNA synthetase. 相似文献
4.
Kallan NC Spencer KL Blake JF Xu R Heizer J Bencsik JR Mitchell IS Gloor SL Martinson M Risom T Gross SD Morales TH Wu WI Vigers GP Brandhuber BJ Skelton NJ 《Bioorganic & medicinal chemistry letters》2011,21(8):2410-2414
A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA. 相似文献
5.
Wensheng Yu Zhuyan Guo Peter Orth Vincent Madison Lei Chen Chaoyang Dai Robert J. Feltz Vinay M. Girijavallabhan Seong Heon Kim Joseph A. Kozlowski Brian J. Lavey Dansu Li Daniel Lundell Xiaoda Niu John J. Piwinski Janeta Popovici-Muller Razia Rizvi Kristin E. Rosner Bandarpalle B. Shankar Neng-Yang Shih Guowei Zhou 《Bioorganic & medicinal chemistry letters》2010,20(6):1877-1880
We disclose inhibitors of TNF-α converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand. 相似文献
6.
In this study, a series of novel phenyl- and benzimidazole-substituted benzyl ethers were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Escherichia coli, Candida albicans, and Candida krusei. Compound 6g exhibited the most potent antibacterial activity with lowest MIC values of 3.12 and 6.25 microg/mL against S. aureus and MRSA, respectively. 相似文献
7.
Jarvest RL Erskine SG Forrest AK Fosberry AP Hibbs MJ Jones JJ O'Hanlon PJ Sheppard RJ Worby A 《Bioorganic & medicinal chemistry letters》2005,15(9):2305-2309
High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition. 相似文献
8.
Steven M. Ronkin Michael Badia Steve Bellon Anne-Laure Grillot Christian H. Gross Trudy H. Grossman Nagraj Mani Jonathan D. Parsons Dean Stamos Martin Trudeau Yunyi Wei Paul S. Charifson 《Bioorganic & medicinal chemistry letters》2010,20(9):2828-2831
Bacterial DNA gyrase is an attractive target for the investigation of new antibacterial agents. Inhibitors of the GyrB subunit, which contains the ATP-binding site, are described in this communication. Novel, substituted 5-(1H-pyrazol-3-yl)thiazole compounds were identified as inhibitors of bacterial gyrase. Structure-guided optimization led to greater enzymatic potency and moderate antibacterial potency. Data are presented for the demonstration of selective enzyme inhibition of Escherichia coli GyrB over Staphlococcus aureus GyrB. 相似文献
9.
Discovery of phenyl alanine derived ketoamides carrying benzoyl residues as novel calpain inhibitors
Novel calpain inhibitors derived from phenyl alanine aldehydes or ketoamides carrying a benzoyl residue were prepared and evaluated for their biological potency. A brief structure-activity relationship elucidated the importance of ortho-substitutents in the benzoyl moiety. The most potent derivative, the ketoamide 19c, exhibited a K(i) of 6nM and represents a novel class of reversible, highly potent and non-peptidic calpain inhibitors. 相似文献
10.
Walter MW Hoffman BJ Gordon K Johnson K Love P Jones M Man T Phebus L Reel JK Rudyk HC Shannon H Svensson K Yu H Valli MJ Porter WJ 《Bioorganic & medicinal chemistry letters》2007,17(18):5233-5238
Inhibition of the glycine transporter GlyT1 is a potential strategy for the treatment of schizophrenia. A novel series of GlyT1 inhibitors and their structure-activity relationships (SAR) are described. Members of this series are highly potent and selective transport inhibitors which are shown to elevate glycine levels in cerebrospinal fluid. 相似文献
11.
Patel JR Shuai Q Dinges J Winn M Pliushchev M Fung S Monzon K Chiou W Wang J Pan L Wagaw S Engstrom K Kerdesky FA Longenecker K Judge R Qin W Imade HM Stolarik D Beno DW Brune M Chovan LE Sham HL Jacobson P Link JT 《Bioorganic & medicinal chemistry letters》2007,17(3):750-755
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed. 相似文献
12.
Alice Lee-Dutra Danielle K. Wiener Kristen L. Arienti Jing Liu Neelakandha Mani Michael K. Ameriks Frank U. Axe Damara Gebauer Pragnya J. Desai Steven Nguyen Mike Randal Robin L. Thurmond Siquan Sun Lars Karlsson James P. Edwards Todd K. Jones Cheryl A. Grice 《Bioorganic & medicinal chemistry letters》2010,20(7):2370-2374
A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency. 相似文献
13.
Lin Zhang Yiming Chen Fahui Li Lihui Zhang Jinhong Feng Lei Zhang 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1918
Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound L20 exhibited class I selectivity with IC50 values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC50 value of >1000 µM), respectively. In the antiproliferative assay, compound L20 showed both hematological and solid cancer inhibitory activities. In the flow cytometry, L20 promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells. 相似文献
14.
Radi M Crespan E Botta G Falchi F Maga G Manetti F Corradi V Mancini M Santucci MA Schenone S Botta M 《Bioorganic & medicinal chemistry letters》2008,18(3):1207-1211
A series of substituted benzoylamino-2-[(4-benzyl)thio]-1,3,4-thiadiazoles has been discovered as potent Abl tyrosine kinase inhibitors. Molecular docking simulations on the Abl tyrosine kinase were conducted in order to rationalize the SAR of the synthesized inhibitors. The most active compound identified from the enzymatic screening (6a) showed interesting inhibitory activity on Imatinib-sensitive murine myeloid 3B clone and Bcr-Abl-independent Imatinib-resistant leukemia cells. Surprisingly, 6a was also proved to act as differentiating inducers in human promyelocytic leukemia cells (HL-60). 相似文献
15.
Tully DC Liu H Chatterjee AK Alper PB Epple R Williams JA Roberts MJ Woodmansee DH Masick BT Tumanut C Li J Spraggon G Hornsby M Chang J Tuntland T Hollenbeck T Gordon P Harris JL Karanewsky DS 《Bioorganic & medicinal chemistry letters》2006,16(19):5112-5117
The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported. 相似文献
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Cywin CL Zhao BP McNeil DW Hrapchak M Prokopowicz AS Goldberg DR Morwick TM Gao A Jakes S Kashem M Magolda RL Soll RM Player MR Bobko MA Rinker J DesJarlais RL Winters MP 《Bioorganic & medicinal chemistry letters》2003,13(8):1415-1418
The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail. 相似文献
19.
The biosynthesis of yeast mitochondrial Phe-tRNA synthetase is studied in vivo. Antibodies against the enzyme are raised in rabbits. They precipitate two proteins in the post-ribosomal supernatant of the yeast cell homogenate. Immunoprecipitate analysis on SDS - gel electrophoresis shows that the two types of mitochondrial enzyme subunits with molecular weights of 57,000 and 72,000, respectively, are cytoplasmically synthesized as larger, individual precursors. Terminal extensions of the precursors prevent enzyme activity. Mitochondrial membranes linked protease(s) play(s) an active role in maturation. 相似文献