N-(2-(2-methoxyphenoxy)ethyl)-2-cyanoacetamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-(2-(2-methoxyphenoxy)ethyl)-2-cyanoacetamide
• 英文别名: 2-cyano-N-(2-(2-methoxyphenoxy)ethyl)acetamide；2-cyano-N-[2-(2-methoxyphenoxy)ethyl]acetamide
• 化学式: C₁₂H₁₄N₂O₃
• 分子量: 234.255
• InChiKey: FXENMMYTKHRIIB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-羟基-2-氧代-2H-色烯-3-甲醛 、 N-(2-(2-methoxyphenoxy)ethyl)-2-cyanoacetamide 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以69%的产率得到2-imino-N-[2-(2-methoxyphenoxy)ethyl]-5-oxo-2,5-dihydropyrano[3,2-c]chromene-3-carboxamide
  参考文献：
  名称：

  Synthesis and Docking Study of Novel Pyranocoumarin Derivatives

  摘要：

  DOI：

  10.1134/s1070428021020196
• 作为产物：
  描述：

  2-甲氧基苯氧基乙胺 、 氰乙酸乙酯 生成 N-(2-(2-methoxyphenoxy)ethyl)-2-cyanoacetamide
  参考文献：
  名称：

  8-亚氨基-2-氧代-2H，8H-吡喃并[2,3-f]色烯类似物的合成，生物学评估和分子对接：新型双重AChE抑制剂可作为治疗阿尔茨海默氏病的潜在药物

  摘要：

  阿尔茨海默氏病的发作和发展与多种复杂生理过程的失调有关，因此成功的治疗方法应解决多个目标。根据这种现代范式，合成了一系列8-亚氨基-2-氧代-2 H，8 H-吡喃[2,3- f ]色烯类似物（4a – q）并评估了它们在多靶点上的活性。乙酰胆碱酯酶，丁酰胆碱酯酶（BuChE的），2,2'-连氮基-双（3-乙基苯并噻唑-6-磺酸）（ABTS）基团，和淀粉样蛋白β肽（A β）阿尔茨海默氏病治疗的特定目标。大多数合成的化合物在低n m浓度下表现出显着的乙酰胆碱酯酶抑制活性，并具有良好的ABTS自由基清除活性，但是，没有BuChE抑制活性的证据。其中，3-溴苄酰胺衍生物4m表现出最好的乙酰胆碱酯酶抑制活性，IC 50值为13±1.4 n m，是参比药物加兰他敏的51倍。动力学和分子对接研究表明4m是混合型抑制剂，同时与乙酰胆碱酯酶的催化活性和外围阴离子位点结合。五种化合物4e，4f，4g，4j和4k的抗氧化活性比trolox高1

  DOI：

  10.1111/cbdd.12732

文献信息

• Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents
  作者：Jeelan Basha Shaik、Bhagath Kumar Palaka、Mohan Penumala、Kasi Viswanath Kotapati、Subba Rao Devineni、Siddhartha Eadlapalli、M. Manidhar Darla、Dinakara Rao Ampasala、Ramakrishna Vadde、G. Damu Amooru

  DOI：10.1016/j.ejmech.2015.10.046

  日期：2016.1

  A series of fused tricyclic coumarin derivatives bearing iminopyran ring connected to various amido moieties were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. In vitro studies revealed that most of these compounds exhibited high inhibitory activity on acetylcholinesterase (AChE), with IC50 values ranging from 0.003 to 0.357 mu M which is 2-220 folds more potent than the positive control, galantamine. Their inhibition selectivity against AChE over butyrylcholinesterase (BuChE) has increased about 194 fold compared with galantamine. The developed compounds also showed potent ABTS radical scavenging activity (IC50 7.98 -15.99 mu M). Specifically, the most potent AChE inhibitor 6n (IC50 0.003 +/- 0.0007 mu M) has an excellent antioxidant profile as determined by the ABTS method (IC50 7.98 0.77 mu M). Moreover, cell viability studies in SK N SH cells showed that the compounds 6m-q have significant neuroprotective effects against H2O2-induced cell death, and are not neurotoxic at all concentrations except 6n and 6q. The kinetic analysis of compound 6n proved that it is a mixed-type inhibitor for EeAChE (K-i1 0.0103 mu M and K-i2 0.0193 mu M). Accordingly, the molecular modeling study demonstrated that 6m-q with substituted benzyl amido moiety possessed an optimal docking pose with interactions at catalytic active site (CAS) and peripheral anionic site (PAS) of AChE simultaneously and thereby they might prevent aggregation of A beta induced by AChE. Furthermore, in silico ADMET prediction studies indicated that these compounds satisfied all the characteristics of CNS acting drugs. Most active inhibitor 6n is permeable to BBB as determined in the in vivo brain AChE activity. To sum up, the multipotent therapuetic profile of these novel tricyclic coumarins makes them promising leads for developing anti-Alzheimer agents. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Synthesis and biological evaluation of flavone-8-acrylamide derivatives as potential multi-target-directed anti Alzheimer agents and investigation of binding mechanism with acetylcholinesterase
  作者：Jeelan Basha Shaik、Daniel Pushparaju Yeggoni、Yelamanda Rao Kandrakonda、Mohan Penumala、Raveendra Babu Zinka、Kasi Viswanath Kotapati、Mark Manidhar Darla、Dinakara Rao Ampasala、Rajagopal Subramanyam、Damu Gangaiah Amooru

  DOI：10.1016/j.bioorg.2019.102960

  日期：2019.7

  In a search for novel multifunctional anti-Alzheimer agents, a congeneric set of seventeen flavone-8-acrylamide derivatives (8a-q) were synthesized and evaluated for their cholinesterase inhibitory, antioxidant, neuroprotective and modulation of A beta aggregation activities. The target compounds showed effective and selective inhibitory activity against the AChE over BuChE. In addition, the target compounds also showed moderate antioxidant activity and strong neuroprotective capacities, and accelerated dosage-dependently the A beta aggregation. Also, we presented here a complete study on the interaction of 8a, 8d, 8e, 8h and 8i with AChE. Through fluorescence emission studies, the binding sites number found to be 1, binding constants were calculated as 2.04 x 10(4), 2.22 x 10(4), 1.18 x 10(4), 9.8 x 10(3) and 3.2 x 10(4) M-1 and free energy change as -5.83, -5.91, -5.51, -5.41 and -6.12 kcal M-1 at 25 degrees C which were well agreed with the computational calculations indicating a strong binding affinity of flavones and AChE. Furthermore, the CD studies revealed that the secondary structure of AChE became partly unfolded upon binding with 8a, 8d, 8e, 8h and 8i.
• New Flavone-Cyanoacetamide Hybrids with a Combination of Cholinergic, Antioxidant, Modulation of β-Amyloid Aggregation, and Neuroprotection Properties as Innovative Multifunctional Therapeutic Candidates for Alzheimer’s Disease and Unraveling Their Mechanism of Action with Acetylcholinesterase
  作者：Shaik Jeelan Basha、Penumala Mohan、Daniel Pushparaju Yeggoni、Zinka Raveendra Babu、Palaka Bhagath Kumar、Ampasala Dinakara Rao、Rajagopal Subramanyam、Amooru Gangaiah Damu

  DOI：10.1021/acs.molpharmaceut.8b00041

  日期：2018.6.4

  In line with the modern multi-target-directed ligand paradigm of Alzheimer's disease (AD), a series of 19 compounds composed of flavone and cyanoacetamide groups have been synthesized and evaluated as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (ACNE, IC50 of 0.27 +/- 10.012 to 1.006 +/- 0.075 mu M) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced A beta aggregation, low cytotoxicity, and neuroprotection in Havone-cyanoacetamide human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 70, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.