N-(3-chlorobenzyl)-8-imino-4-methyl-2-oxo-2H,8H-pyrano[2,3-f]chromene-9-carboxamide

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: N-(3-chlorobenzyl)-8-imino-4-methyl-2-oxo-2H,8H-pyrano[2,3-f]chromene-9-carboxamide
• 英文别名: N-[(3-chlorophenyl)methyl]-8-imino-4-methyl-2-oxopyrano[2,3-f]chromene-9-carboxamide
• 化学式: C₂₁H₁₅ClN₂O₄
• 分子量: 394.814
• InChiKey: BNIZIDOQRRXXPZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  88.5
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-氯苄胺 在 三乙胺 作用下， 以 乙醇 为溶剂， 生成 N-(3-chlorobenzyl)-8-imino-4-methyl-2-oxo-2H,8H-pyrano[2,3-f]chromene-9-carboxamide
  参考文献：
  名称：

  Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2015.10.046

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.