2-(4-fluoro-3-trifluoromethyl-phenyl)-4,5-dihydro-oxazole-4-carboxylic acid hydroxyamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(4-fluoro-3-trifluoromethyl-phenyl)-4,5-dihydro-oxazole-4-carboxylic acid hydroxyamide
• 英文别名: (r)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-4,5-dihydrooxazole-4-carboxamide；(4R)-2-[4-fluoro-3-(trifluoromethyl)phenyl]-N-hydroxy-4,5-dihydro-1,3-oxazole-4-carboxamide
• 化学式: C₁₁H₈F₄N₂O₃
• 分子量: 292.19
• InChiKey: GXXKFVYNHMJXFV-MRVPVSSYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  70.9
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-[(R)-1-(2,4-Dimethoxy-benzyloxycarbamoyl)-2-hydroxy-ethyl]-4-fluoro-3-trifluoromethyl-benzamide 在 吡啶 、 二甲基乙基硅烷 、 polystyrene tosyl chloride resin 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 25.0h， 生成 2-(4-fluoro-3-trifluoromethyl-phenyl)-4,5-dihydro-oxazole-4-carboxylic acid hydroxyamide
  参考文献：
  名称：

  High-Throughput Catch-and-Release Synthesis of Oxazoline Hydroxamates. Structure−Activity Relationships in Novel Inhibitors of Escherichia coli LpxC:  In Vitro Enzyme Inhibition and Antibacterial Properties

  摘要：

  LpxC is a zinc amidase that catalyses the second step of lipid A biosynthesis in Gram-negative bacteria. Oxazolines incorporating a hydroxamic acid, which is believed to coordinate to the single essential zinc ion, at the 4-position are known inhibitors of this enzyme. Some of these enzyme inhibitors exhibit antibacterial activity through their inhibition of LpxC. We recently developed a method for the synthesis of oxazolines using resin capture and ring-forming release that eliminates traditional purification steps and can be used in high-throughput synthesis. Using our method, oxazoline hydroxamates with diverse 2-substituents were prepared in library form as candidate inhibitors for LpxC. Two conventional methods for oxazoline synthesis were also applied to generate more than 70 compounds. The groups at the 2-position included a wide variety of substituted aromatic rings and a limited selection of alkyl groups. These compounds were screened against wild-type and LpxC inhibitor-sensitive strains of Escherichia coli, as well as wildtype Pseudomonas aeruginosa. Inhibition of the E coli LpxC enzyme was also investigated. A broad correlation between enzyme inhibitory and antibacterial activity was observed, and novel compounds were discovered that exhibit antibacterial activity but fall outside earlier-known structural classes.

  DOI：

  10.1021/ja0209114

文献信息

• High-Throughput Catch-and-Release Synthesis of Oxazoline Hydroxamates. Structure−Activity Relationships in Novel Inhibitors of <i>Escherichia </i><i>c</i><i>oli</i> LpxC:  In Vitro Enzyme Inhibition and Antibacterial Properties
  作者：Michael C. Pirrung、L. Nathan Tumey、Amanda L. McClerren、Christian R. H. Raetz

  DOI：10.1021/ja0209114

  日期：2003.2.1

  LpxC is a zinc amidase that catalyses the second step of lipid A biosynthesis in Gram-negative bacteria. Oxazolines incorporating a hydroxamic acid, which is believed to coordinate to the single essential zinc ion, at the 4-position are known inhibitors of this enzyme. Some of these enzyme inhibitors exhibit antibacterial activity through their inhibition of LpxC. We recently developed a method for the synthesis of oxazolines using resin capture and ring-forming release that eliminates traditional purification steps and can be used in high-throughput synthesis. Using our method, oxazoline hydroxamates with diverse 2-substituents were prepared in library form as candidate inhibitors for LpxC. Two conventional methods for oxazoline synthesis were also applied to generate more than 70 compounds. The groups at the 2-position included a wide variety of substituted aromatic rings and a limited selection of alkyl groups. These compounds were screened against wild-type and LpxC inhibitor-sensitive strains of Escherichia coli, as well as wildtype Pseudomonas aeruginosa. Inhibition of the E coli LpxC enzyme was also investigated. A broad correlation between enzyme inhibitory and antibacterial activity was observed, and novel compounds were discovered that exhibit antibacterial activity but fall outside earlier-known structural classes.