3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydropyran-2-yl]oxyphenyl]-N-[2-[2-[[3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]benzoyl]amino]ethoxy]ethyl]benzamide | 1231608-60-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydropyran-2-yl]oxyphenyl]-N-[2-[2-[[3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]benzoyl]amino]ethoxy]ethyl]benzamide
• 英文别名: 3-[4-[3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]-N-[2-[2-[[3-[4-[3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]benzoyl]amino]ethoxy]ethyl]benzamide；3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]-N-[2-[2-[[3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]benzoyl]amino]ethoxy]ethyl]benzamide
• CAS: 1231608-60-8
• 化学式: C₄₂H₄₈N₂O₁₅
• 分子量: 820.848
• InChiKey: RDGKSFSWSXSXST-GVLJZANCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  59
• 可旋转键数：
  16
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  266
• 氢给体数：
  10
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  2,2'-氧双(乙胺) 、 3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydropyran-2-yl]oxyphenyl]benzoic acid 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以76%的产率得到3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydropyran-2-yl]oxyphenyl]-N-[2-[2-[[3-[4-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]benzoyl]amino]ethoxy]ethyl]benzamide
  参考文献：
  名称：

  Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists

  摘要：

  FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on alpha-D-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biarylmannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and submicromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including pi-pi interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt bridge. Dimeric analogues linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections.

  DOI：

  10.1021/jm100438s

文献信息

• COMPOUNDS AND METHODS FOR TREATING BACTERIAL INFECTIONS
  申请人：Janetka James W.

  公开号：US20120309701A1

  公开（公告）日：2012-12-06

  The present invention encompasses compounds and methods for treating urinary tract infections.

  本发明涵盖了治疗尿路感染的化合物和方法。
• US8937167B2
  申请人：——

  公开号：US8937167B2

  公开（公告）日：2015-01-20
• US9567362B2
  申请人：——

  公开号：US9567362B2

  公开（公告）日：2017-02-14
• Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists
  作者：Zhenfu Han、Jerome S. Pinkner、Bradley Ford、Robert Obermann、William Nolan、Scott A. Wildman、Doug Hobbs、Tom Ellenberger、Corinne K. Cusumano、Scott J. Hultgren、James W. Janetka

  DOI：10.1021/jm100438s

  日期：2010.6.24

  FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on alpha-D-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biarylmannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and submicromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including pi-pi interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt bridge. Dimeric analogues linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections.