ethyl 6-oxo-1-(pyridin-4-ylmethyl)-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate | 1227077-01-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: ethyl 6-oxo-1-(pyridin-4-ylmethyl)-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate
• 英文别名: ethyl 6-oxo-1-(pyridin-4-ylmethyl)-7H-pyrazolo[3,4-b]pyridine-4-carboxylate
• CAS: 1227077-01-1
• 化学式: C₁₅H₁₄N₄O₃
• 分子量: 298.301
• InChiKey: VUUKEVUIRKJSPM-UHFFFAOYSA-N

物化性质

• 沸点：
  594.6±50.0 °C(predicted)
• 密度：
  1.39±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  86.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 6-oxo-1-(pyridin-4-ylmethyl)-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate 在 三乙胺 、 bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 18.0h， 生成 6-(5-Methylthiophen-2-yl)-1-(pyridin-4-ylmethyl)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：

  1-(pyridin-4-ylmethyl)-1H-pyrazol-5-amine 在 溶剂黄146 作用下， 以 苯 为溶剂， 反应 19.0h， 生成 ethyl 6-oxo-1-(pyridin-4-ylmethyl)-6,7-dihydro-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

文献信息

• Efficient Pd-Catalyzed Coupling of Tautomerizable Heterocycles with Terminal Alkynes via C−OH Bond Activation Using PyBrOP
  作者：Ce Shi、Courtney C. Aldrich

  DOI：10.1021/ol100657n

  日期：2010.5.21

  The direct alkynylation of tautomerizable heterocycles is described via a two-step process involving in situ C OH activation with bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) followed by Sonogashira coupling with a wide range of alkyl or aryl terminal alkynes using a copper-free system employing PdCl2(CH3CN)(2) and 2-(dicyclohexylphosphino)biphenyl.