2-[6-[methyl(phenylmethyl)amino]hexyl]-1H-isoindole-1,3(2H)-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-[6-[methyl(phenylmethyl)amino]hexyl]-1H-isoindole-1,3(2H)-dione
• 英文别名: 2-(6-(benzyl(methyl)amino)hexyl)isoindoline-1,3-dione；2-[6-[Benzyl(methyl)amino]hexyl]isoindole-1,3-dione；2-[6-[benzyl(methyl)amino]hexyl]isoindole-1,3-dione
• 化学式: C₂₂H₂₆N₂O₂
• 分子量: 350.461
• InChiKey: NRAFVOCZEXVTPY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-[6-[methyl(phenylmethyl)amino]hexyl]-1H-isoindole-1,3(2H)-dione 在 一水合肼 作用下， 以 乙醇 为溶剂， 以76.3%的产率得到N-benzyl-N-methylhexane-1,6-diamine
  参考文献：
  名称：

  设计，合成和评估新型阿魏酸-拟喹啉杂化物作为潜在的多功能药物治疗阿尔茨海默氏病

  摘要：

  设计，合成和评估了一系列新的阿魏酸-拟喹啉杂化物，作为用于治疗阿尔茨海默氏病（AD）的多功能药物。体外研究表明，大多数化合物显示出显著能力以抑制乙酰胆碱酯酶（IC 50 3.2-34.7μM）和自感应β淀粉样蛋白（β 1-42）聚集（30.8-39.1％， 25μM）作为潜在的抗氧化剂（ORAC-FL值为0.9–1.3）。特别是，化合物17D具有抑制乙酰胆碱酯酶（IC最大能力50  = 3.2μM），和A β 1-42聚集（30.8％）也是一种出色的抗氧化剂和神经保护剂。此外，它能够解聚自诱导A的β聚集。此外，17d可能在体外穿过血脑屏障（BBB）。结果表明，化合物17d是用于治疗AD的潜在多功能剂。

  DOI：

  10.1016/j.bmcl.2016.03.086
• 作为产物：
  描述：

  邻苯二甲酰亚胺钠盐 在 potassium carbonate 作用下， 以 丙酮 、 乙腈 为溶剂， 生成 2-[6-[methyl(phenylmethyl)amino]hexyl]-1H-isoindole-1,3(2H)-dione
  参考文献：
  名称：

  设计，合成和评估黄cut素-O-乙酰氨基烷基苄胺作为潜在的多功能药物，可治疗阿尔茨海默氏病。

  摘要：

  基于多靶标指导的配体策略设计了一系列的黄cut素-O-乙酰氨基烷基苄胺衍生物，用于治疗阿尔茨海默氏病。在这些化合物中，化合物T-22表现出优异的乙酰胆碱酯酶抑制作用，对自身诱导的Aβ1-42聚集，Cu2 +诱导的Aβ1-42聚集，人AChE诱导的Aβ1-40聚集和分解的Cu2 +诱导的孔聚集具有中等抑制作用。结构的Aβ1-42原纤维，还可以作为潜在的抗氧化剂和生物金属螯合剂。AChE抑制的动力学分析和分子建模研究均表明T-22与AChE的催化活性位点和外围阴离子位点都相互作用。而且，化合物T-22对H 2 O 2诱导的PC12细胞损伤显示出良好的神经保护作用，并且在SH-SY5Y细胞中毒性低。此外，逐步降低的被动回避测试表明，T-22可以显着逆转东pol碱诱导的小鼠记忆缺陷。两者合计，数据表明T-22是有趣的多功能铅化合物，值得AD进一步研究。

  DOI：

  10.1016/j.ejmech.2017.04.054

文献信息

• Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer’s disease
  作者：Yuxing Li、Xiaoming Qiang、Yan Li、Xia Yang、Li Luo、Ganyuan Xiao、Zhongcheng Cao、Zhenghuai Tan、Yong Deng

  DOI：10.1016/j.bmcl.2016.02.079

  日期：2016.4

  designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1–42 aggregation and HuAChE-induced Aβ1–40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d

  设计，合成和评价了一系列蝶形-O-乙酰氨基烷基苄胺，作为AChE和BuChE的双重抑制剂。为了进一步探索上自诱导Aβ的新衍生物，它们的抗氧化活性和抑制作用的多功能性质1 - 42聚集和胡胆碱酯酶诱导的Aβ 1 - 40聚合也进行了测试。结果表明，这些化合物大多数可以有效抑制AChE和BuChE。特别是化合物21d表现出最佳的AChE抑制活性（IC 50  = 0.06μM）和对BuChE的良好抑制作用（IC 50 = 28.04μM）。抑制动力学分析和分子模型研究均表明，这些化合物表现出混合型抑制作用，同时与AChE的CAS和PAS结合。除了抑制胆碱酯酶的活性，这些化合物还显示出不同水平的抗氧化剂活性。然而，这些新衍生物对自诱导和Hu AChE诱导的Aβ聚集的抑制活性不令人满意。考虑到生物学评估的结果，将设计进一步的修饰以增加对不同靶标的效力。这封信中显示的结果可能是进一步开发用于治疗阿尔茨海默氏病的多功能药物的新起点。
• Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease
  作者：Wanli Pan、Ke Hu、Ping Bai、Lintao Yu、Qinge Ma、Tao Li、Xu Zhang、Changzhong Chen、Kelin Peng、Wenmin Liu、Zhipei Sang

  DOI：10.1016/j.bmcl.2016.03.086

  日期：2016.5

  ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2–34.7 μM) and self-induced β-amyloid (Aβ1–42) aggregation (30.8–39.1%, 25 μM), to act as potential antioxidants (ORAC-FL

  设计，合成和评估了一系列新的阿魏酸-拟喹啉杂化物，作为用于治疗阿尔茨海默氏病（AD）的多功能药物。体外研究表明，大多数化合物显示出显著能力以抑制乙酰胆碱酯酶（IC 50 3.2-34.7μM）和自感应β淀粉样蛋白（β 1-42）聚集（30.8-39.1％， 25μM）作为潜在的抗氧化剂（ORAC-FL值为0.9–1.3）。特别是，化合物17D具有抑制乙酰胆碱酯酶（IC最大能力50  = 3.2μM），和A β 1-42聚集（30.8％）也是一种出色的抗氧化剂和神经保护剂。此外，它能够解聚自诱导A的β聚集。此外，17d可能在体外穿过血脑屏障（BBB）。结果表明，化合物17d是用于治疗AD的潜在多功能剂。
• Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer’s disease
  作者：Zhipei Sang、Keren Wang、Huifang Wang、Lintao Yu、Huijuan Wang、Qianwen Ma、Mengyao Ye、Xue Han、Wenmin Liu

  DOI：10.1016/j.bmcl.2017.09.055

  日期：2017.11

  A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer’s disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2 μM, 3.8 μM

  合成了一系列新型邻苯二甲酰亚胺-烷基胺衍生物，并将其作为多功能抑制剂用于治疗阿尔茨海默氏病（AD）。结果表明，化合物TM - 9可以作为平衡的多靶标活性分子。它显示出对ChE和MAO-B（hu AChE，hu BuChE和hu MAO-B的有效且平衡的抑制活性，IC 50值分别为1.2μM，3.8μM和2.6μM）且选择性低。对AChE抑制的动力学分析和分子建模研究均表明TM - 9同时与AChE的催化活性位点和外围阴离子位点结合。有趣的是，化合物TM - 9遵循Lipinski的5条规则。此外，我们的研究证明TM - 9具有弱的细胞毒性，并且可以在体外穿过血脑屏障（BBB）。结果表明，化合物TM - 9是一种有趣的多目标活性分子，为针对阿尔茨海默氏病的药物发现过程中进一步的铅优化提供了有吸引力的起点。
• Design, synthesis and evaluation of chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the treatment of Alzheimer’s disease
  作者：Qiang Liu、Xiaoming Qiang、Yan Li、Zhipei Sang、Yuxing Li、Zhenghuai Tan、Yong Deng

  DOI：10.1016/j.bmc.2015.01.042

  日期：2015.3

  A series of chromone-2-carboxamido-alkylbenzylamines were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 49 displayed excellent inhibitory potency toward acetylcholinesterase (AChE), moderate anti-oxidative activity, selective biometal chelating, and possessed good inhibitory effects on self-induced and Cu2+-induced Ab aggregation. Both kinetic analysis of AChE inhibition and molecular modeling study indicated that 49 was a mixed-type inhibitor, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. These results suggested that 49 might be a potential multifunctional agent for AD treatment. (C) 2015 Elsevier Ltd. All rights reserved.
• Isoindoline-1,3-dione derivatives targeting cholinesterases: Design, synthesis and biological evaluation of potential anti-Alzheimer’s agents
  作者：Natalia Guzior、Marek Bajda、Jurand Rakoczy、Boris Brus、Stanislav Gobec、Barbara Malawska

  DOI：10.1016/j.bmc.2015.01.045

  日期：2015.4

  Alzheimer's disease is a fatal neurodegenerative disorder with a complex etiology. Because the available therapy brings limited benefits, the effective treatment for Alzheimer's disease remains the unmet challenge. Our aim was to develop a new series of donepezil-based compounds endowed with inhibitory properties against cholinesterases and beta-amyloid aggregation. We designed the target compounds as dual binding site acetylcholinesterase inhibitors with N-benzylamine moiety interacting with the catalytic site of the enzyme and an isoindoline-1,3-dione fragment interacting with the peripheral anionic site of the enzyme. The results of pharmacological evaluation lead us to identify a compound 3b as the most potent and selective human acetylcholinesterase inhibitor (hAChE IC50 = 0.361 mu M). Kinetic studies revealed that 3b inhibited acetylcholinesterase in non-competitive mode. The result of the parallel artificial membrane permeability assay for the blood-brain barrier indicated that the compound 3b would be able to cross the blood-brain barrier and reach its biological targets in the central nervous system. The selected compound 3b represents a potential lead structure for further development of anti-Alzheimer's agents. (C) 2015 Elsevier Ltd. All rights reserved.