N¹-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]-N¹-methyl-propane-1,3-diamine | 490025-50-8

• 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: N¹-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]-N¹-methyl-propane-1,3-diamine
• 英文别名: N-methyl-N-[3-[(1,2,3,4-tetrahydroacridin-9-yl)amino]propyl]propane-1,3-diamine；N1-(3-aminopropyl)-N1-methyl-N3-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine；N1-[3-(1,2,3,4-tetrahydro-acridin-9-ylamino)-propyl]-N1-methyl-propane-1,3-diamine；N'-methyl-N'-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]propane-1,3-diamine
• CAS: 490025-50-8
• 化学式: C₂₀H₃₀N₄
• 分子量: 326.485
• InChiKey: ZKGXLYIZQWJURA-UHFFFAOYSA-N

物化性质

• 沸点：
  528.6±50.0 °C(Predicted)
• 密度：
  1.114±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  54.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-吲哚丙酸 、 N¹-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]-N¹-methyl-propane-1,3-diamine 在 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 以46%的产率得到N-(3-{[3-(1,2,3,4-tetrahydro-acridin-9-ylamino)-propyl]-methyl-amino}-propyl)-3-(1H-indol-3-yl)-propionamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Dual Binding Site Acetylcholinesterase Inhibitors:  New Disease-Modifying Agents for Alzheimer's Disease

  摘要：

  New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as new potent drugs that may simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting the P-amyloid (M) peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. Particularly, compounds 5 and 6 emerged as the most potent heterodimers reported so far, displaying IC50 values for AChE inhibition of 20 and 60 pM, respectively. More importantly, these dual AChE inhibitors inhibit the AChE-induced A beta peptide aggregation with IC50 values 1 order of magnitude lower than that of propidium, thus being the most potent derivatives with this activity reported up to date. We therefore conclude that these compounds are very promising disease-modifying agents for the treatment of Alzheimer's disease (AD).

  DOI：

  10.1021/jm0503289
• 作为产物：
  描述：

  9-氯-1,2,3,4-四氢吖啶 、 N,N-双(3-氨丙基)甲胺 以 戊醇 为溶剂， 以35%的产率得到N¹-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]-N¹-methyl-propane-1,3-diamine
  参考文献：
  名称：

  Specific Targeting of Acetylcholinesterase and Butyrylcholinesterase Recognition Sites. Rational Design of Novel, Selective, and Highly Potent Cholinesterase Inhibitors

  摘要：

  Tacrine-based AChE and BuChE inhibitors were designed by investigating the topology of the active site gorge of the two enzymes. The homobivalent ligands characterized by a nitrogen-bridged atom at the tether level could be considered among the most potent and selective cholinesterase inhibitors described to date. The nitrogen-containing homobivalent ligands 3e,g and the sulfur-containing 3h validated the hypothesis of extra sites of interaction in the AChE and BuChE active site gorges.

  DOI：

  10.1021/jm0255668

文献信息

• Acetylcholinesterase dual inhibitors
  申请人：Gil Martinez Ana

  公开号：US20050148621A1

  公开（公告）日：2005-07-07

  The invention provides compounds of formula: which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the β-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

  该发明提供了公式的化合物：其中通过连接剂连接了一种Tacrine基团和一个杂环基团。通过精心选择取代基和连接剂，可以调节对乙酰胆碱酯酶的活性和选择性。这些化合物显示出强大的AChE抑制活性，同时通过同时结合催化和周围AChE位点，修改β淀粉样聚集物的聚集特性。它们在治疗AChE介导的疾病，如阿尔茨海默病中很有用。
• ACETYLCHOLINESTERASE DUAL INHIBITORS
  申请人：Gil Ana Martinez

  公开号：US20110144148A1

  公开（公告）日：2011-06-16

  The invention provides compounds of formula: which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the β-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

  本发明提供了公式如下的化合物: 通过连接剂将Tacrine基团连接到杂环基团上。通过对取代基和连接剂的精心选择，可以调节其对乙酰胆碱酯酶的活性和选择性。这些化合物表现出强效的AChE抑制活性，并通过同时结合催化和周边AChE位点来改变β-淀粉样聚集物的聚集特性。它们在治疗AChE介导的疾病，如阿尔茨海默病方面非常有用。
• Novel Tacrine−8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Neuroprotective, Cholinergic, Antioxidant, and Copper-Complexing Properties
  作者：María Isabel Fernández-Bachiller、Concepción Pérez、Gema C. González-Muñoz、Santiago Conde、Manuela G. López、Mercedes Villarroya、Antonio G. García、María Isabel Rodríguez-Franco

  DOI：10.1021/jm100329q

  日期：2010.7.8

  Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (A beta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit A beta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood brain barrier model.
• Specific Targeting of Acetylcholinesterase and Butyrylcholinesterase Recognition Sites. Rational Design of Novel, Selective, and Highly Potent Cholinesterase Inhibitors
  作者：Luisa Savini、Alessandra Gaeta、Caterina Fattorusso、Bruno Catalanotti、Giuseppe Campiani、Luisa Chiasserini、Cesare Pellerano、Ettore Novellino、Dawn McKissic、Ashima Saxena

  DOI：10.1021/jm0255668

  日期：2003.1.1

  Tacrine-based AChE and BuChE inhibitors were designed by investigating the topology of the active site gorge of the two enzymes. The homobivalent ligands characterized by a nitrogen-bridged atom at the tether level could be considered among the most potent and selective cholinesterase inhibitors described to date. The nitrogen-containing homobivalent ligands 3e,g and the sulfur-containing 3h validated the hypothesis of extra sites of interaction in the AChE and BuChE active site gorges.
• Design, Synthesis, and Biological Evaluation of Dual Binding Site Acetylcholinesterase Inhibitors:  New Disease-Modifying Agents for Alzheimer's Disease
  作者：Pilar Muñoz-Ruiz、Laura Rubio、Esther García-Palomero、Isabel Dorronsoro、María del Monte-Millán、Rita Valenzuela、Paola Usán、Celia de Austria、Manuela Bartolini、Vincenza Andrisano、Axel Bidon-Chanal、Modesto Orozco、F. Javier Luque、Miguel Medina、Ana Martínez

  DOI：10.1021/jm0503289

  日期：2005.11.1

  New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as new potent drugs that may simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting the P-amyloid (M) peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. Particularly, compounds 5 and 6 emerged as the most potent heterodimers reported so far, displaying IC50 values for AChE inhibition of 20 and 60 pM, respectively. More importantly, these dual AChE inhibitors inhibit the AChE-induced A beta peptide aggregation with IC50 values 1 order of magnitude lower than that of propidium, thus being the most potent derivatives with this activity reported up to date. We therefore conclude that these compounds are very promising disease-modifying agents for the treatment of Alzheimer's disease (AD).