N-9'-(1',2',3',4'-tetrahydroacridinyl)-1,12-diaminododecane | 249290-22-0

• 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-9'-(1',2',3',4'-tetrahydroacridinyl)-1,12-diaminododecane
• 英文别名: N¹-(1,2,3,4-tetrahydroacridin-9-yl)dodecane-1,12-diamine；N-(1,2,3,4-tetrahydroacridin-9-yl)-1,12-dodecanodiamine；N-(12-aminododecyl)-1,2,3,4-tetrahydroacridin-9-amine dihydrochloride；N'-(1,2,3,4-tetrahydroacridin-9-yl)dodecane-1,12-diamine
• CAS: 249290-22-0
• 化学式: C₂₅H₃₉N₃
• 分子量: 381.605
• InChiKey: AUWJPKWQQCCYFJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  28
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  50.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-9'-(1',2',3',4'-tetrahydroacridinyl)-1,12-diaminododecane 在 sodium tetrahydroborate 、 溶剂黄146 作用下， 以 甲醇 、 苯 为溶剂， 反应 28.0h， 生成 5-[12-(1,2,3,4-Tetrahydro-acridin-9-ylamino)-dodecylamino]-5,6,7,8-tetrahydro-1H-quinolin-2-one
  参考文献：
  名称：

  Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors

  摘要：

  Hybrid acetylcholinesterase inhibitors composed of a key fragment of huperzine A and an intact tacrine unit were prepared. The syntheses are quite direct, proceeding in a maximum of 4 linear steps from commercially available starting materials. The optimum hybrid inhibitor (+/-)-9g is 13-fold more potent than (-)-huperzine A, and 25-fold more potent than tacrine. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(99)00396-0
• 作为产物：
  描述：

  邻氨基苯甲酸 在 sodium iodide 、 三氯氧磷 作用下， 以 苯酚 为溶剂， 反应 5.0h， 生成 N-9'-(1',2',3',4'-tetrahydroacridinyl)-1,12-diaminododecane
  参考文献：
  名称：

  新型 N-磷酸化和 O-磷酸化他克林衍生物作为阿尔茨海默病潜在药物的设计、合成和生物学评价

  摘要：

  摘要 在这项工作中，我们设计、合成和生物学研究了一系列新的 14  N-和O-磷酸化他克林衍生物作为潜在的抗阿尔茨海默病药物。在 9-氯他克林和相应的二胺/氨基烷基醇的反应中，我们获得了二氨基和氨基烷基羟基他克林衍生物。接下来，将化合物酸化，得到最终产物6 – 13和16 – 21，其特征为1 H、13  C、31 P 核磁共振和质谱。对接研究的结果表明，设计的磷杂化物理论上可以与AChE和BChE结合。与他克林相比，所有化合物的 AutoDock Vina 评分均显着降低。使用Ellman方法进行抑制效力评估。对 AChE 的抑制活性最强的是化合物8，IC 50值为 6.11 nM，对 BChE 13的抑制活性最高，IC 50值为 1.97 nM，比他克林强 6 倍和 12 倍。化合物19在 MTT 测定中显示缺乏肝细胞毒性。

  DOI：

  10.1080/14756366.2022.2045591

文献信息

• Structure–Activity Relationship Studies of 9-Alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum Promastigotes
  作者：Carlos F. M. Silva、Teresa Leão、Filipa Dias、Ana M. Tomás、Diana C. G. A. Pinto、Eduardo F. T. Oliveira、Ana Oliveira、Pedro A. Fernandes、Artur M. S. Silva

  DOI：10.3390/pharmaceutics15020669

  日期：——

  Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures—there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential. The present work builds on computational studies focusing on a specific enzyme of the parasite, S-adenosylmethionine decarboxylase (AdoMet DC), with several 1,2,3,4-tetrahydro-acridines emerging as potential inhibitors, evidencing this scaffold as a promising building block for novel antileishmanial pharmaceuticals. Thus, several 1,2,3,4-tetrahydroacridine derivatives have been synthesized, their activity against Leishmania (Leishmania) infantum promastigotes evaluated and a structure–activity relationship (SAR) study was developed based on the results obtained. Even though the majority of the 1,2,3,4-tetrahydroacridines evaluated presented high levels of toxicity, the structural information gathered in this work allowed its application with another scaffold (quinoline), leading to the obtention of N1,N12-bis(7-chloroquinolin-4-yl)dodecane-1,12-diamine (12) as a promising novel antileishmanial agent (IC50 = 0.60 ± 0.11 μM, EC50 = 11.69 ± 3.96 μM and TI = 19.48).

  利什曼病是现代最被忽视的疾病之一，主要影响热带、亚热带和地中海盆地的发展中国家人群，约有3.5亿人可能患上该病。由于预防和治疗措施的失败，人类利什曼病的发病率在过去几十年中增加了，目前没有疫苗和化疗，这是一个问题。吖啶衍生物是一类氮杂环化合物，与众多生物活性相关，尤其是它们的抗利什曼病潜力。本研究基于对寄生虫酶S-腺苷甲硫氨酸脱羧酶（AdoMet DC）的计算研究，发现多种1,2,3,4-四氢-吖啶可能是潜在的抑制剂，表明该支架是新型抗利什曼病药物的有前途的构建块。因此，合成了多种1,2,3,4-四氢吖啶衍生物，评估了它们对利什曼原虫（利什曼原虫）幼虫的活性，并根据所得结果开展了结构-活性关系（SAR）研究。尽管大多数评估的1,2,3,4-四氢吖啶衍生物表现出高毒性，但本研究收集的结构信息使其可以与另一个支架（喹啉）结合使用，导致获得N1，N12-双（7-氯喹啉-4-基）十二烷基-1,12-二胺（12）作为有前途的新型抗利什曼病药物（IC50 = 0.60±0.11μM，EC50 = 11.69±3.96μM和TI = 19.48）。
• 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.
• New Tacrine–4-Oxo-4<i>H</i>-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties
  作者：María Isabel Fernández-Bachiller、Concepción Pérez、Leticia Monjas、Jörg Rademann、María Isabel Rodríguez-Franco

  DOI：10.1021/jm201460y

  日期：2012.2.9

  By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H-chromene was chosen for its radical capture and beta-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.
• Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors:  Investigating Ligand−Peripheral Site Interactions
  作者：Paul R. Carlier、Ella S.-H. Chow、Yifan Han、Jing Liu、Jamal El Yazal、Yuan-Ping Pang

  DOI：10.1021/jm990224w

  日期：1999.10.1

  Dimeric acetylcholinesterase (AChE) inhibitors containing a single 9-amino-1,2,3,4-tetrahydroacridine (tacrine) unit were constructed in an effort to further delineate structural requirements for optimal binding to the AChE peripheral site. Basic amines of differing hydrophobicity were selected as peripheral site ligands, and in each case, improvements in inhibitory potency and selectivity were seen relative to tacrine itself. AChE IC50 values of the optimum dimers decrease significantly as the peripheral site ligand was permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-aminoquinoline > tacrine. Calculated desolvation free energies of the optimum dimers match the trend in IC50 values, suggesting the importance of ligand hydrophobicity for effective cation-pi interaction with the peripheral site.
• Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors
  作者：Paul R. Carlier、Da-Ming Du、Yifan Han、Jing Liu、Yuan-Ping Pang

  DOI：10.1016/s0960-894x(99)00396-0

  日期：1999.8

  Hybrid acetylcholinesterase inhibitors composed of a key fragment of huperzine A and an intact tacrine unit were prepared. The syntheses are quite direct, proceeding in a maximum of 4 linear steps from commercially available starting materials. The optimum hybrid inhibitor (+/-)-9g is 13-fold more potent than (-)-huperzine A, and 25-fold more potent than tacrine. (C) 1999 Elsevier Science Ltd. All rights reserved.