4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-ynyl)amino)butanenitrile | 1609078-42-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-ynyl)amino)butanenitrile
• 英文别名: DPH6；4-(1-Benzylpiperidin-4-yl)-2-[(8-hydroxyquinolin-5-yl)methyl-prop-2-ynylamino]butanenitrile；4-(1-benzylpiperidin-4-yl)-2-[(8-hydroxyquinolin-5-yl)methyl-prop-2-ynylamino]butanenitrile
• CAS: 1609078-42-3
• 化学式: C₂₉H₃₂N₄O
• 分子量: 452.599
• InChiKey: ATRSFRGWPPYVGZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  63.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (2E)-3-(1-benzylpiperidin-4-yl)prop-2-enenitrile 在 碘 、 二异丁基氢化铝 、 magnesium 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 1.17h， 生成 4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-ynyl)amino)butanenitrile
  参考文献：
  名称：

  Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease

  摘要：

  The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

  DOI：

  10.1016/j.ejmech.2014.04.078

文献信息

• Neuroprotective multi-target directed drugs
  申请人：Universitat Autònoma de Barcelona

  公开号：EP2727916A1

  公开（公告）日：2014-05-07

  A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil, connected through an oligomethylene linker, to a central nitrogen atom substituted with the propargyl moiety responsible for the MAO inhibition, and a 8-hydroxy-5-methylaminoquinoline functional group, the biometal pro-chelator motif. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potencial impact for AD therapy.

  一种新的多靶分子家族已经合成，能够与乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）以及单胺氧化酶（MAO）A和B相互作用。新颖的化合物是使用联合方法设计的，该方法将AChE抑制剂多奈哌齐的苄哌啶基团与经过寡亚甲基连接的中央氮原子相连接，该中央氮原子上取代了负责MAO抑制的丙炔基团，以及8-羟基-5-甲基氨基喹啉功能基团，生物金属前螯合物基序。总体而言，结果表明这些新化合物是有潜力对阿尔茨海默病治疗产生影响的多靶药物候选物。
• JP6004894
  申请人：——

  公开号：——

  公开（公告）日：——
• Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease
  作者：Li Wang、Gerard Esteban、Masaki Ojima、Oscar M. Bautista-Aguilera、Tsutomu Inokuchi、Ignacio Moraleda、Isabel Iriepa、Abdelouahid Samadi、Moussa B.H. Youdim、Alejandro Romero、Elena Soriano、Raquel Herrero、Ana Patricia Fernández Fernández、Ricardo-Martínez-Murillo、José Marco-Contelles、Mercedes Unzeta

  DOI：10.1016/j.ejmech.2014.04.078

  日期：2014.6

  The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.