ethyl 1-(pyridin-4-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate | 1446123-70-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: ethyl 1-(pyridin-4-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate
• CAS: 1446123-70-1
• 化学式: C₂₂H₁₇F₃N₄O₂
• 分子量: 426.398
• InChiKey: WTJTXKOIISOUAX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.74
• 重原子数：
  31.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  69.9
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  ethyl 1-(pyridin-4-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate 在 sodium hydroxide 、 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 4.0h， 以48%的产率得到1-(Pyridin-4-ylmethyl)-6-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]pyridine-4-carboxylic acid
  参考文献：
  名称：

  Non-Nucleoside Inhibitors of BasE, an Adenylating Enzyme in the Siderophore Biosynthetic Pathway of the Opportunistic PathogenAcinetobacter baumannii

  摘要：

  Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high-throughput screening against BasE, which is involved in siderophore biosynthesis in A. baumannii, and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a K-D of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveals that they bind in a unique orientation in the active site, occupying all three substrate binding sites, and thus can be considered as multisubstrate inhibitors. These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity.

  DOI：

  10.1021/jm301709s
• 作为产物：
  描述：

  diethyl 2-(5-amino-1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-2-hydroxysuccinate 在 溶剂黄146 、 三乙胺 、 bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate 作用下， 以 1,4-二氧六环 为溶剂， 反应 10.0h， 生成 ethyl 1-(pyridin-4-ylmethyl)-6-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate
  参考文献：
  名称：

  Non-Nucleoside Inhibitors of BasE, an Adenylating Enzyme in the Siderophore Biosynthetic Pathway of the Opportunistic PathogenAcinetobacter baumannii

  摘要：

  Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high-throughput screening against BasE, which is involved in siderophore biosynthesis in A. baumannii, and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a K-D of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveals that they bind in a unique orientation in the active site, occupying all three substrate binding sites, and thus can be considered as multisubstrate inhibitors. These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity.

  DOI：

  10.1021/jm301709s