N-cyclohexyl-4-oxo-5H-thieno[3,2-c]quinoline-2-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-cyclohexyl-4-oxo-5H-thieno[3,2-c]quinoline-2-carboxamide
• 化学式: C₁₈H₁₈N₂O₂S
• 分子量: 326.419
• InChiKey: IPLOFIMEZLPWHK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  86.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  N,N'-二(苯基)丙二酰胺 在 草酰氯 、 水 、 potassium carbonate 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 、 lithium hydroxide 、 三氯氧磷 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 乙二醇 为溶剂， 反应 40.33h， 生成 N-cyclohexyl-4-oxo-5H-thieno[3,2-c]quinoline-2-carboxamide
  参考文献：
  名称：

  Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening

  摘要：

  Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer's disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[ 3,2-c] quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP noncompetitive CDK5/p25 inhibitors with good CDK2/E selectivity. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2014.09.043

文献信息

• Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening
  作者：Arindam Chatterjee、Stephen J. Cutler、Robert J. Doerksen、Ikhlas A. Khan、John S. Williamson

  DOI：10.1016/j.bmc.2014.09.043

  日期：2014.11

  Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer's disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[ 3,2-c] quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP noncompetitive CDK5/p25 inhibitors with good CDK2/E selectivity. Published by Elsevier Ltd.