3-(methylcarbamoyl)quinolin-5-yl dimethylcarbamate | 911108-97-9

• 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: 3-(methylcarbamoyl)quinolin-5-yl dimethylcarbamate
• 英文别名: [3-(methylcarbamoyl)-5-quinolyl] N,N-dimethylcarbamate；5-(N,N-dimethylcarbamate)-3-(N-methylcarboxamido)quinoline；[3-(methylcarbamoyl)quinolin-5-yl] N,N-dimethylcarbamate
• CAS: 911108-97-9
• 化学式: C₁₄H₁₅N₃O₃
• 分子量: 273.291
• InChiKey: MGFFSTHTXXBZEI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  71.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(methylcarbamoyl)quinolin-5-yl dimethylcarbamate 、 三氟甲烷磺酸甲酯 以 二氯甲烷 为溶剂， 反应 2.0h， 以100%的产率得到5-(N,N-dimethylcarbamate)-1-methyl-3-(N-methylcarboxamido)quinolinium triflate
  参考文献：
  名称：

  通过“生物可氧化前药”策略合理设计中枢选择性乙酰胆碱酯酶抑制剂†

  摘要：

  这项工作涉及开发新的中央选择性乙酰胆碱酯酶抑制剂的“生物可氧化前药”策略的设计。预期该前药方法会降低外周抗胆碱酯酶活性，从而导致目前市售的各种副作用疼痛抑制剂。这些新的设计疼痛 抑制剂 喹啉 系列大致基于的循环类似物 利凡斯的明。前药的关键活化步骤涉及N-烷基-1，4-二氢喹啉1氧化为相应的喹啉鎓盐2，从而掩盖了与酶的催化阴离子位点结合所需的正电荷。介绍了一组1,4-二氢喹啉1及其相应的喹啉鎓盐2的合成。的体外生物学评价显示，虽然所有的还原形式1无法表现出任何抗胆碱酯酶活性（IC 50 > 10 6 nm）时，大部分的喹啉盐的2显示高疼痛抑制活性（IC 50为6μM至7 nM）。这些初步的体外试验验证了这些环状类似物的使用。利凡斯的明喹啉系列的药物作为进一步在体内开发这种“生物可氧化前药”方法的诱人化学工具。

  DOI：

  10.1039/b903041g
• 作为产物：
  描述：

  5-氧代-1H-喹啉-3-羧酸 在 potassium carbonate 、 N,N-二异丙基乙胺 、 bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate 作用下， 以 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 3-(methylcarbamoyl)quinolin-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

文献信息

• WO2006/103120
  申请人：——

  公开号：——

  公开（公告）日：——
• Palladium-Catalyzed Carbonylation of (Hetero)Aryl, Alkenyl and Allyl Halides by Means of <i>N-</i>Hydroxysuccinimidyl Formate as CO Surrogate
  作者：Anaïs Barré、Mihaela-Liliana Ţînţaş、Florent Alix、Vincent Gembus、Cyril Papamicaël、Vincent Levacher

  DOI：10.1021/acs.joc.5b01119

  日期：2015.7.2

  An efficient Pd-catalyzed carbonylation protocol is described for the coupling of a large panel of aryl, heteroaryl, benzyl, vinyl and allyl halides 2 with the unusual N-hydroxysuccinimidyl (NHS) formate 1 as a CO surrogate to afford the corresponding valuable NHS esters 3. High conversion to the coupling products was achieved with up to 98% yield by means of Pd(OAc)(2)/Xantphos catalyst system.
• Rational design of central selective acetylcholinesterase inhibitors by means of a “bio-oxidisable prodrug” strategy
  作者：Pierre Bohn、Nicolas Le Fur、Guillaume Hagues、Jean Costentin、Nicolas Torquet、Cyril Papamicaël、Francis Marsais、Vincent Levacher

  DOI：10.1039/b903041g

  日期：——

  oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase

  这项工作涉及开发新的中央选择性乙酰胆碱酯酶抑制剂的“生物可氧化前药”策略的设计。预期该前药方法会降低外周抗胆碱酯酶活性，从而导致目前市售的各种副作用疼痛抑制剂。这些新的设计疼痛 抑制剂 喹啉 系列大致基于的循环类似物 利凡斯的明。前药的关键活化步骤涉及N-烷基-1，4-二氢喹啉1氧化为相应的喹啉鎓盐2，从而掩盖了与酶的催化阴离子位点结合所需的正电荷。介绍了一组1,4-二氢喹啉1及其相应的喹啉鎓盐2的合成。的体外生物学评价显示，虽然所有的还原形式1无法表现出任何抗胆碱酯酶活性（IC 50 > 10 6 nm）时，大部分的喹啉盐的2显示高疼痛抑制活性（IC 50为6μM至7 nM）。这些初步的体外试验验证了这些环状类似物的使用。利凡斯的明喹啉系列的药物作为进一步在体内开发这种“生物可氧化前药”方法的诱人化学工具。
• Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies
  作者：Mihaela-Liliana Ţînţaş、Vincent Gembus、Florent Alix、Anaïs Barré、Gaël Coadou、Lina Truong、Muriel Sebban、Cyril Papamicaël、Hassan Oulyadi、Vincent Levacher

  DOI：10.1016/j.ejmech.2018.05.057

  日期：2018.7

  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.