(S)-2-acetamido-3-(1H-indol-3-yl)-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)propanamide

• 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: (S)-2-acetamido-3-(1H-indol-3-yl)-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)propanamide
• 英文别名: S-2-acetamido-3-(1H-Indol-3-yl)-N-(6-((1,2,3,4,-tetrahydro-acridine-9-yl)amino)hexyl)propionamide；(2S)-2-acetamido-3-(1H-indol-3-yl)-N-[6-(1,2,3,4-tetrahydroacridin-9-ylamino)hexyl]propanamide
• 化学式: C₃₂H₃₉N₅O₂
• 分子量: 525.694
• InChiKey: PVXRLGDBKZOULP-PMERELPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  98.9
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  9-氯-1,2,3,4-四氢吖啶 在 N,N'-羰基二咪唑 、 potassium iodide 作用下， 以 四氢呋喃 、 戊醇 为溶剂， 反应 1.0h， 生成 (S)-2-acetamido-3-(1H-indol-3-yl)-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)propanamide
  参考文献：
  名称：

  Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease

  摘要：

  A series of tacrine-(beta-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced beta-amyloid (A beta) aggregation, Cu2+-induced A beta (1-42) aggregation, and to chelate metal ions. Especially, 11l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of A beta aggregation (65.8% at 20 mu M) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11l might be an excellent multifunctional agent for AD treatment. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.08.035

文献信息

• Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease
  作者：Jin-Shuai Lan、Sai-Sai Xie、Su-Yi Li、Long-Fei Pan、Xiao-Bing Wang、Ling-Yi Kong

  DOI：10.1016/j.bmc.2014.08.035

  日期：2014.11

  A series of tacrine-(beta-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced beta-amyloid (A beta) aggregation, Cu2+-induced A beta (1-42) aggregation, and to chelate metal ions. Especially, 11l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of A beta aggregation (65.8% at 20 mu M) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11l might be an excellent multifunctional agent for AD treatment. (C) 2014 Elsevier Ltd. All rights reserved.