2-(4-((2-fluorobenzyl)(methyl)amino)butyl)isoindoline-1,3-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-(4-((2-fluorobenzyl)(methyl)amino)butyl)isoindoline-1,3-dione
• 英文别名: 2-[4-[(2-Fluorophenyl)methyl-methylamino]butyl]isoindole-1,3-dione；2-[4-[(2-fluorophenyl)methyl-methylamino]butyl]isoindole-1,3-dione
• 化学式: C₂₀H₂₁FN₂O₂
• 分子量: 340.397
• InChiKey: BLYRIZLPMFTJFY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(4-((2-fluorobenzyl)(methyl)amino)butyl)isoindoline-1,3-dione 在 盐酸 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 以278 mg的产率得到2-(4-((2-fluorobenzyl)(methyl)amino)butyl)isoindoline-1,3-dione hydrochloride
  参考文献：
  名称：

  Isoindoline-1,3-dione derivatives targeting cholinesterases: Design, synthesis and biological evaluation of potential anti-Alzheimer’s agents

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2015.01.045
• 作为产物：
  描述：

  potassium phtalimide 在 四丁基溴化铵 、 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 31.0h， 生成 2-(4-((2-fluorobenzyl)(methyl)amino)butyl)isoindoline-1,3-dione
  参考文献：
  名称：

  Isoindoline-1,3-dione derivatives targeting cholinesterases: Design, synthesis and biological evaluation of potential anti-Alzheimer’s agents

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2015.01.045

文献信息

• 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.