N-(7-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)heptyl)benzofuran-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-(7-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)heptyl)benzofuran-2-carboxamide
• 英文别名: N-[7-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)heptyl]-1-benzofuran-2-carboxamide
• 化学式: C₂₈H₃₁N₃O₂
• 分子量: 441.573
• InChiKey: ALUMRCODWIMCFJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  67.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  苯并呋喃-2-羧酸 、 N'-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)heptane-1,7-diamine 在 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 7.0h， 以68%的产率得到N-(7-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)heptyl)benzofuran-2-carboxamide
  参考文献：
  名称：

  Novel Tacrine–Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography

  摘要：

  Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimers disease. Most hybrids exhibited good inhibitory activities on cholinesterases and beta-amyloid self-aggregation. Selected compounds displayed significant inhibition of human beta-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both beta-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 mu M). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.

  DOI：

  10.1021/acs.jmedchem.5b01119

文献信息

• Novel Tacrine–Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography
  作者：Xiaoming Zha、Doriano Lamba、Lili Zhang、Yinghan Lou、Changxu Xu、Di Kang、Li Chen、Yungen Xu、Luyong Zhang、Angela De Simone、Sarah Samez、Alessandro Pesaresi、Jure Stojan、Manuela G. Lopez、Javier Egea、Vincenza Andrisano、Manuela Bartolini

  DOI：10.1021/acs.jmedchem.5b01119

  日期：2016.1.14

  Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimers disease. Most hybrids exhibited good inhibitory activities on cholinesterases and beta-amyloid self-aggregation. Selected compounds displayed significant inhibition of human beta-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both beta-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 mu M). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.