5-[(2-Nitrophenyl)methyl]-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4-one | 1414861-66-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 英文名称: 5-[(2-Nitrophenyl)methyl]-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4-one
• 英文别名: 5-[(2-nitrophenyl)methyl]-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4-one
• CAS: 1414861-66-7
• 化学式: C₂₂H₁₈N₂O₃S
• 分子量: 390.463
• InChiKey: JRGHTWHRFQCWSR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  91.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  苯甲醛 在 哌啶 、 吡啶 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 8.5h， 生成 5-[(2-Nitrophenyl)methyl]-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4-one
  参考文献：
  名称：

  Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)

  摘要：

  Glycogen synthase kinase-3 beta (GSK-3 beta) plays a key role in type II diabetes and Alzheimer's diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity. Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3 beta have been designed and synthesized. The in vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale. Among them compounds 61, 6t and 6v have the IC50 values of 25.0 mu M, 27.8 mu M and 23.0 mu M, respectively. Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.09.021

文献信息

• Identification of novel scaffold of benzothiazepinones as non-ATP competitive glycogen synthase kinase-3β inhibitors through virtual screening
  作者：Peng Zhang、Hai-Rong Hu、Zhao-Hui Huang、Jia-Yi Lei、Yong Chu、De-Yong Ye

  DOI：10.1016/j.bmcl.2012.09.043

  日期：2012.12

  Glycogen synthase kinase-3 beta (GSK-3 beta) is an important serine/threonine kinase that has been proved as a key target for neurodegenerative diseases and diabetes. Up to date, most of known inhibitors are bound to the ATP-binding pocket of GSK-3 beta, which might lead widespread effects due to the high homology between kinases. Recently, some of its non-ATP competitive inhibitors had been confirmed having therapeutical effects owing to their high selectivity. This finding opens a new pathway to study hopeful drugs for treatment of these diseases. However, it is still a challenge nowadays on how to efficiently find non-ATP competitors. Here, we successfully discovered a novel scaffold of benzothiazepinones (BTZs) as selective non-ATP competitive GSK-3 beta inhibitors through virtual screening approach. A 3D receptor model of substrate binding site of GSK-3 beta was constructed and applied to screen against drug-like Maybridge database through Autodock program. BTZ compounds were top ranked as efficient hits and were then synthesized for further screening. Among them, the representative compound 4j showed activity to GSK-3 beta (IC50: 25 mu M) in non-ATP competitive mechanism, and nearly no inhibitory effect on other 10 related protein kinases. Overall, the results point out that BTZ compounds might be useful in treatment of Alzheimer's disease and diabetes mellitus as novel GSK-3 beta inhibitors. It also suggests, on the other hand, that virtual screening would provide a valuable tool in combination with in vitro assays for the identification of novel selective and potent inhibitors. (C) 2012 Elsevier Ltd. All rights reserved.
• Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)
  作者：Peng Zhang、Hai-Rong Hu、Shi-Hui Bian、Zhao-Hui Huang、Yong Chu、De-Yong Ye

  DOI：10.1016/j.ejmech.2012.09.021

  日期：2013.3

  Glycogen synthase kinase-3 beta (GSK-3 beta) plays a key role in type II diabetes and Alzheimer's diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity. Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3 beta have been designed and synthesized. The in vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale. Among them compounds 61, 6t and 6v have the IC50 values of 25.0 mu M, 27.8 mu M and 23.0 mu M, respectively. Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design. (C) 2012 Elsevier Masson SAS. All rights reserved.