(+)-pinanediol (1S)-1-chloro-1-[3-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)phenyl]methylboronate | 497258-61-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (+)-pinanediol (1S)-1-chloro-1-[3-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)phenyl]methylboronate
• CAS: 497258-61-4
• 化学式: C₂₂H₂₉BClNO₃
• 分子量: 401.741
• InChiKey: TYACSUXOXUGAKJ-YCGPWUDHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.79
• 重原子数：
  28.0
• 可旋转键数：
  3.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  40.05
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (+)-pinanediol (1S)-1-chloro-1-[3-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)phenyl]methylboronate 在 甲醇 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 1.17h， 生成 (+)-pinanediol (1R)-1-(2-thienylacetylamino)-1-[3-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)phenyl]methylboronate
  参考文献：
  名称：

  Nanomolar Inhibitors of AmpC β-Lactamase

  摘要：

  beta-lactamases are the most widespread resistance mechanism to beta-lactam antibiotics, such as the penicillins and the cephalosporins. In an effort to combat these enzymes, a combination of stereoselective organic synthesis, enzymology, microbiology, and X-ray crystallography was used to design and evaluate new carboxyphenyl-glycylboronic acid transition-state analogue inhibitors of the class C beta-lactamase AmpC. The new compounds improve inhibition by over 2 orders of magnitude compared to analogous glycylboronic acids, with K-1 values as low as 1 nM. On the basis of the differential binding of different analogues, the introduced carboxylate alone contributes about 2.1 kcal/mol in affinity. This carboxylate corresponds to the ubiquitous C3(4)'carboxylate of beta-lactams, and this energy represents the first thermodynamic measurement of the importance of this group in molecular recognition by class C beta-lactamases. The structures of AmpC in complex with two of these inhibitors were determined by X-ray crystallography at 1.72 and 1.83 Angstrom resolution. These structures suggest a structural basis for the high affinity of the new compounds and provide templates for further design. The highest affinity inhibitor was 5 orders of magnitude more selective for AmpC than for characteristic serine proteases, such as chymotrypsin. This inhibitor reversed the resistance of clinical pathogens to the third generation cephalosporin ceftazidime; it may serve as a lead compound for drug discovery to combat bacterial resistance to beta-lactam antibiotics.

  DOI：

  10.1021/ja0288338
• 作为产物：
  描述：

  2-(3-溴苯基)-4,4-二甲基-4,5-二氢-1,3-恶唑 在 正丁基锂 作用下， 以 四氢呋喃 、 乙醚 、 正己烷 为溶剂， 反应 2.5h， 生成 (+)-pinanediol (1S)-1-chloro-1-[3-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)phenyl]methylboronate
  参考文献：
  名称：

  Nanomolar Inhibitors of AmpC β-Lactamase

  摘要：

  beta-lactamases are the most widespread resistance mechanism to beta-lactam antibiotics, such as the penicillins and the cephalosporins. In an effort to combat these enzymes, a combination of stereoselective organic synthesis, enzymology, microbiology, and X-ray crystallography was used to design and evaluate new carboxyphenyl-glycylboronic acid transition-state analogue inhibitors of the class C beta-lactamase AmpC. The new compounds improve inhibition by over 2 orders of magnitude compared to analogous glycylboronic acids, with K-1 values as low as 1 nM. On the basis of the differential binding of different analogues, the introduced carboxylate alone contributes about 2.1 kcal/mol in affinity. This carboxylate corresponds to the ubiquitous C3(4)'carboxylate of beta-lactams, and this energy represents the first thermodynamic measurement of the importance of this group in molecular recognition by class C beta-lactamases. The structures of AmpC in complex with two of these inhibitors were determined by X-ray crystallography at 1.72 and 1.83 Angstrom resolution. These structures suggest a structural basis for the high affinity of the new compounds and provide templates for further design. The highest affinity inhibitor was 5 orders of magnitude more selective for AmpC than for characteristic serine proteases, such as chymotrypsin. This inhibitor reversed the resistance of clinical pathogens to the third generation cephalosporin ceftazidime; it may serve as a lead compound for drug discovery to combat bacterial resistance to beta-lactam antibiotics.

  DOI：

  10.1021/ja0288338

文献信息

• Nanomolar β-lactamase inhibitors
  申请人：Northwestern University

  公开号：US07271186B1

  公开（公告）日：2007-09-18

  New carboxyphenyl-glycylboronic acid transition-state analog inhibitors, representative of a class of compounds effective against class C β-lactamase AmpC. The new compounds improve inhibition by over two-orders of magnitude compared to analogous glycylboronic acids, with Ki values as low as 1 nM.

  新的羧基苯甘氨酰硼酸过渡态类似物抑制剂，代表了一类针对C类β-内酰胺酶AmpC有效的化合物。与类似的甘氨酰硼酸相比，这些新化合物的抑制效果提高了两个数量级，Ki值低至1纳摩尔。