N¹-(1,2,3,4-tetrahydroacridin-9-yl)decane-1,10-diamine | 249290-21-9

• 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-(1,2,3,4-tetrahydroacridin-9-yl)decane-1,10-diamine
• 英文别名: N-(10-aminodecyl)-1,2,3,4-tetrahydroacridin-9-amine dihydrochloride；N'-(1,2,3,4-tetrahydroacridin-9-yl)decane-1,10-diamine
• CAS: 249290-21-9
• 化学式: C₂₃H₃₅N₃
• 分子量: 353.551
• InChiKey: ZKQCXLRXJGGZDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  26
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.61
• 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：

  N¹-(1,2,3,4-tetrahydroacridin-9-yl)decane-1,10-diamine 在 盐酸 、 三溴化硼 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 、 水 为溶剂， 生成 6,7-dihydroxy-4-oxo-N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)-amino]decyl}-4H-chromene-2-carboxamide hydrochloride
  参考文献：
  名称：

  New Tacrine–4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties

  摘要：

  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.

  DOI：

  10.1021/jm201460y
• 作为产物：
  描述：

  环己酮 在 potassium iodide 、 三氯氧磷 作用下， 以 戊醇 为溶剂， 反应 12.0h， 生成 N¹-(1,2,3,4-tetrahydroacridin-9-yl)decane-1,10-diamine
  参考文献：
  名称：

  Design, synthesis and evaluation of novel tacrine–rhein hybrids as multifunctional agents for the treatment of Alzheimer's disease

  摘要：

  一系列他克林-雷琐酸杂合化合物被设计并合成作为新型多功能的强效胆碱酯酶抑制剂。其中大多数化合物在体外有效地抑制了胆碱酯酶，抑制浓度在纳摩尔范围内。化合物10b 是最强的抑制剂之一，对乙酰胆碱酯酶（AChE）的活性比他克林高 5 倍，并且对丁酰胆碱酯酶（BuChE）表现出中等抑制作用，其 IC50 值为 200 nM。动力学和分子建模研究也表明 10b 是一种混合型抑制剂，同时结合 AChE 的活性位点和外周位点。在抑制 AChE 诱导的 Aβ 聚集实验中，10b（在 100 μM 下为 70.2%）显示出最大的抑制活性。此外，10b 表现出金属离子络合性质和低肝毒性。这些结果表明 10b 可能是一种优秀的多功效药物，用于阿尔茨海默病的治疗。

  DOI：

  10.1039/c3ob42010h

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）。
• Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease
  作者：Jin-Shuai Lan、Sai-Sai Xie、Su-Yi Li、Long-Fei Pan、Xiao-Bing Wang、Ling-Yi Kong

  DOI：10.1016/j.bmc.2014.08.035

  日期：2014.11

  A series of tacrine-(beta-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced beta-amyloid (A beta) aggregation, Cu2+-induced A beta (1-42) aggregation, and to chelate metal ions. Especially, 11l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of A beta aggregation (65.8% at 20 mu M) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11l might be an excellent multifunctional agent for AD treatment. (C) 2014 Elsevier Ltd. All rights reserved.
• 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.
• 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.
• Multifunctional tacrine–trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties
  作者：Sai-Sai Xie、Jin-Shuai Lan、Xiao-Bing Wang、Neng Jiang、Ge Dong、Zhong-Rui Li、Kelvin D.G. Wang、Ping-Ping Guo、Ling-Yi Kong

  DOI：10.1016/j.ejmech.2015.01.058

  日期：2015.3

  Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment. (C) 2015 Elsevier Masson SAS. All rights reserved.