6-(1-Benzothiophen-2-yl)-1-(pyridin-4-ylmethyl)pyrazolo[3,4-b]pyridine-4-carboxylic acid | 1426935-29-6

• 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: 6-(1-Benzothiophen-2-yl)-1-(pyridin-4-ylmethyl)pyrazolo[3,4-b]pyridine-4-carboxylic acid
• 英文别名: 6-(1-benzothiophen-2-yl)-1-(pyridin-4-ylmethyl)pyrazolo[3,4-b]pyridine-4-carboxylic acid
• CAS: 1426935-29-6
• 化学式: C₂₁H₁₄N₄O₂S
• 分子量: 386.434
• InChiKey: QOFACKVAGOBCMY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(pyridin-4-ylmethyl)-1H-pyrazol-5-amine 在 溶剂黄146 、 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 、 苯 为溶剂， 反应 37.0h， 生成 6-(1-Benzothiophen-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

文献信息

• 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.