ethyl 1-(pyridin-4-yl)methyl-6-(triethylsilyl)ethynyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate | 1227077-07-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并吡啶类
• 英文名称: ethyl 1-(pyridin-4-yl)methyl-6-(triethylsilyl)ethynyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate
• 英文别名: Ethyl 1-(pyridin-4-ylmethyl)-6-(2-triethylsilylethynyl)pyrazolo[3,4-b]pyridine-4-carboxylate
• CAS: 1227077-07-7
• 化学式: C₂₃H₂₈N₄O₂Si
• 分子量: 420.586
• InChiKey: YCDYQVLUNIVHJY-UHFFFAOYSA-N

物化性质

• 沸点：
  552.9±50.0 °C(predicted)
• 密度：
  1.10±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.45
• 重原子数：
  30
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  69.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 1-(pyridin-4-yl)methyl-6-(triethylsilyl)ethynyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以35%的产率得到Ethyl 6-ethynyl-1-(pyridin-4-ylmethyl)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
• 作为产物：
  描述：

  三乙基矽乙炔 、 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 、 双(乙腈)氯化钯(II) 、 caesium carbonate 、 2-(二环己基膦基)联苯 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以77%的产率得到ethyl 1-(pyridin-4-yl)methyl-6-(triethylsilyl)ethynyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate
  参考文献：
  名称：

  Efficient Pd-Catalyzed Coupling of Tautomerizable Heterocycles with Terminal Alkynes via C−OH Bond Activation Using PyBrOP

  摘要：

  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.

  DOI：

  10.1021/ol100657n

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.
• Non-Nucleoside Inhibitors of BasE, an Adenylating Enzyme in the Siderophore Biosynthetic Pathway of the Opportunistic Pathogen<i>Acinetobacter baumannii</i>
  作者：João Neres、Curtis A. Engelhart、Eric J. Drake、Daniel J. Wilson、Peng Fu、Helena I. Boshoff、Clifton E. Barry、Andrew M. Gulick、Courtney C. Aldrich

  DOI：10.1021/jm301709s

  日期：2013.3.28

  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.