(3R,4S,5R)-5-(4-phenoxymethyl-1H-1,2,3-triazol-1-yl)-3,4-dihydroxycyclohex-1-ene-1-carboxylic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (3R,4S,5R)-5-(4-phenoxymethyl-1H-1,2,3-triazol-1-yl)-3,4-dihydroxycyclohex-1-ene-1-carboxylic acid
• 英文别名: (3R,4S,5R)-3,4-dihydroxy-5-[4-(phenoxymethyl)triazol-1-yl]cyclohexene-1-carboxylic acid
• 化学式: C₁₆H₁₇N₃O₅
• 分子量: 331.328
• InChiKey: DQILQRGUJCOKQW-KFWWJZLASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  118
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  Methyl (3R,4S,5R)-5-Hydroxy-3,4-<(methoxymethylene)dioxy>cyclohex-1-ene-1-carboxylate 在 盐酸 、 sodium azide 、 水 、 sodium methylate 、 copper(II) sulfate 、 溶剂黄146 、 sodium ascorbate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 叔丁醇 为溶剂， 反应 48.75h， 生成 (3R,4S,5R)-5-(4-phenoxymethyl-1H-1,2,3-triazol-1-yl)-3,4-dihydroxycyclohex-1-ene-1-carboxylic acid
  参考文献：
  名称：

  Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme

  摘要：

  The large conformational changes observed by Molecular Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogues interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivatives 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient derivative in achieving good in vitro activity against H. pylori, having a MIC value of 4 mu g/mL.

  DOI：

  10.1021/acs.jmedchem.6b00483

文献信息

• Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme
  作者：Verónica Prado、Emilio Lence、María Maneiro、Juan C. Vázquez-Ucha、Alejandro Beceiro、Paul Thompson、Alastair R. Hawkins、Concepción González-Bello

  DOI：10.1021/acs.jmedchem.6b00483

  日期：2016.6.9

  The large conformational changes observed by Molecular Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogues interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivatives 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient derivative in achieving good in vitro activity against H. pylori, having a MIC value of 4 mu g/mL.