2-(2-fluorobiphenyl-4-yl)-N-[8-(1,2,3,4-tetrahydroacridin-9-ylamino)octyl]propanamide | 1430219-37-6

• 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: 2-(2-fluorobiphenyl-4-yl)-N-[8-(1,2,3,4-tetrahydroacridin-9-ylamino)octyl]propanamide
• 英文别名: 2-(3-fluoro-4-phenylphenyl)-N-[8-(1,2,3,4-tetrahydroacridin-9-ylamino)octyl]propanamide
• CAS: 1430219-37-6
• 化学式: C₃₆H₄₂FN₃O
• 分子量: 551.747
• InChiKey: BHBIPNYAHFZVSM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.1
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  54
• 氢给体数：
  2
• 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 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 戊醇 为溶剂， 反应 42.0h， 生成 2-(2-fluorobiphenyl-4-yl)-N-[8-(1,2,3,4-tetrahydroacridin-9-ylamino)octyl]propanamide
  参考文献：
  名称：

  Design, synthesis and evaluation of tacrine–flurbiprofen–nitrate trihybrids as novel anti-Alzheimer’s disease agents

  摘要：

  To search for multifunctional anti-Alzheimer's disease (AD) agents with good safety, the previously synthesized tacrine-flurbiprofen hybrids 1a and 1b were modified into tacrine-flurbiprofen-nitrate trihybrids 3a-h. These compounds displayed comparable or higher cholinesterase inhibitory activity relative to the bivalent hybrids. Compound 3a was the most potent, which released moderate NO, exerted blood vessel relaxative activity, and showed significant A beta inhibitory effects whereas tacrine and flurbiprofen did not exhibit any Ab inhibitory activity at the same dose. In addition, 3a was active in improving memory impairment in vivo. More importantly, the hepatotoxicity study showed that 3a was much safer than tacrine, suggesting it might be a promising anti-AD agent for further investigation. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.03.005

文献信息

• Tacrine-Flurbiprofen Hybrids as Multifunctional Drug Candidates for the Treatment of Alzheimer's Disease
  作者：Yao Chen、Jianfei Sun、Sixun Peng、Hong Liao、Yihua Zhang、Jochen Lehmann

  DOI：10.1002/ardp.201300074

  日期：2013.12

  hybrid compounds (3a–e) were synthesized as multi‐target‐directed compounds for the treatment of Alzheimer's disease. Compared to tacrine, two compounds (3d and 3e) showed better acetylcholinesterase (AChE) inhibitory activity and others (3b–e) better or the same butyrylcholinesterase (BuChE) inhibitory activity. Notably, 3d showed a mixed‐type inhibitory action for AChE, indicating a “dual‐binding

  合成了五种他克林-氟比洛芬杂化化合物（3a-e）作为治疗阿尔茨海默病的多靶点化合物。与他克林相比，两种化合物（3d 和 3e）显示出更好的乙酰胆碱酯酶 (AChE) 抑制活性和其他化合物 (3b-e) 更好或相同的丁酰胆碱酯酶 (BuChE) 抑制活性。值得注意的是，3d 对 AChE 显示出混合型抑制作用，表明对催化活性位点 (CAS) 和外周阴离子位点 (PAS) 具有“双结合位点作用”，而对于 BuChE，竞争性抑制作用是观察到的。此外，基于细胞的β淀粉样蛋白抑制试验表明，选定的目标化合物 3d 在体外有效抑制了淀粉样蛋白 β 的形成。
• NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity
  作者：Yao Chen、Jianfei Sun、Zhangjian Huang、Hong Liao、Sixun Peng、Jochen Lehmann、Yihua Zhang

  DOI：10.1016/j.bmcl.2013.04.008

  日期：2013.6

  To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research. (C) 2013 Elsevier Ltd. All rights reserved.
• Design, synthesis and evaluation of tacrine–flurbiprofen–nitrate trihybrids as novel anti-Alzheimer’s disease agents
  作者：Yao Chen、Jianfei Sun、Zhangjian Huang、Hong Liao、Sixun Peng、Jochen Lehmann、Yihua Zhang

  DOI：10.1016/j.bmc.2013.03.005

  日期：2013.5

  To search for multifunctional anti-Alzheimer's disease (AD) agents with good safety, the previously synthesized tacrine-flurbiprofen hybrids 1a and 1b were modified into tacrine-flurbiprofen-nitrate trihybrids 3a-h. These compounds displayed comparable or higher cholinesterase inhibitory activity relative to the bivalent hybrids. Compound 3a was the most potent, which released moderate NO, exerted blood vessel relaxative activity, and showed significant A beta inhibitory effects whereas tacrine and flurbiprofen did not exhibit any Ab inhibitory activity at the same dose. In addition, 3a was active in improving memory impairment in vivo. More importantly, the hepatotoxicity study showed that 3a was much safer than tacrine, suggesting it might be a promising anti-AD agent for further investigation. (C) 2013 Elsevier Ltd. All rights reserved.