2-(4-ethoxybenzyl)-N,N-diethyl-1-(4-((1,2,3,4-tetrahydroacridin-9-yl)amino)butyl)-1H-benzo[d]imidazole-5-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: 2-(4-ethoxybenzyl)-N,N-diethyl-1-(4-((1,2,3,4-tetrahydroacridin-9-yl)amino)butyl)-1H-benzo[d]imidazole-5-carboxamide
• 英文别名: 2-[(4-ethoxyphenyl)methyl]-N,N-diethyl-1-[4-(1,2,3,4-tetrahydroacridin-9-ylamino)butyl]benzimidazole-5-carboxamide
• 化学式: C₃₈H₄₅N₅O₂
• 分子量: 603.808
• InChiKey: BLVUOIKRKMBLEC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.8
• 重原子数：
  45
• 可旋转键数：
  13
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  72.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  9-氯-1,2,3,4-四氢吖啶 在 tin(II) chloride dihdyrate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 、 正己醇 为溶剂， 反应 29.0h， 生成 2-(4-ethoxybenzyl)-N,N-diethyl-1-(4-((1,2,3,4-tetrahydroacridin-9-yl)amino)butyl)-1H-benzo[d]imidazole-5-carboxamide
  参考文献：
  名称：

  Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo

  摘要：

  We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB(2)R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of beta-amyloid (A beta), and A beta self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB(1)R and hCB(2)R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer's mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).

  DOI：

  10.1021/acs.jmedchem.9b00623

文献信息

• Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo
  作者：Matthias Scheiner、Dominik Dolles、Sandra Gunesch、Matthias Hoffmann、Massimo Nabissi、Oliviero Marinelli、Marina Naldi、Manuela Bartolini、Sabrina Petralla、Eleonora Poeta、Barbara Monti、Christina Falkeis、Michael Vieth、Harald Hübner、Peter Gmeiner、Rangan Maitra、Tangui Maurice、Michael Decker

  DOI：10.1021/acs.jmedchem.9b00623

  日期：2019.10.24

  We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB(2)R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of beta-amyloid (A beta), and A beta self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB(1)R and hCB(2)R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer's mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).