5-((dimethylcarbamoyl)oxy)-3-((2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethyl)carbamoyl)-1-methylquinolin-1-ium triflate

• 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: 5-((dimethylcarbamoyl)oxy)-3-((2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethyl)carbamoyl)-1-methylquinolin-1-ium triflate
• 英文别名: [3-[2-[2-[2-(1,3-dioxoisoindol-2-yl)ethoxy]ethoxy]ethylcarbamoyl]-1-methylquinolin-1-ium-5-yl] N,N-dimethylcarbamate;trifluoromethanesulfonate
• 化学式: CF₃O₃S*C₂₈H₃₁N₄O₇
• 分子量: 684.647
• InChiKey: LFGCRRHRHMMUPN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.84
• 重原子数：
  47
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  184
• 氢给体数：
  1
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  5-((dimethylcarbamoyl)oxy)-3-((2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethyl)carbamoyl)-1-methylquinolin-1-ium triflate 在 1-苯甲基-1,4-二氢烟酰胺 作用下， 以 乙腈 为溶剂， 反应 36.0h， 以87%的产率得到3-((2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethyl)carbamoyl)-1-methyl-1,4-dihydroquinolin-5-yl dimethylcarbamate
  参考文献：
  名称：

  Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies

  摘要：

  Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50> 10 mu M). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.05.057
• 作为产物：
  描述：

  5-氧代-1H-喹啉-3-羧酸 在 potassium carbonate 、 N,N'-羰基二咪唑 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 21.0h， 生成 5-((dimethylcarbamoyl)oxy)-3-((2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethyl)carbamoyl)-1-methylquinolin-1-ium triflate
  参考文献：
  名称：

  Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies

  摘要：

  Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50> 10 mu M). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.05.057