ethyl 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-5-(3-pyridyl)benzo[h][1,6]naphthyridine-9-carboxylate | 1567847-50-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: ethyl 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-5-(3-pyridyl)benzo[h][1,6]naphthyridine-9-carboxylate
• CAS: 1567847-50-0
• 化学式: C₂₅H₂₇N₃O₄
• 分子量: 433.507
• InChiKey: LFRBWMKAAGCSRI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.16
• 重原子数：
  32.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  81.62
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  ethyl 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-5-(3-pyridyl)benzo[h][1,6]naphthyridine-9-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 18.0h， 以76%的产率得到ethyl 5-(3-pyridyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxylate
  参考文献：
  名称：

  1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: Synthesis, pharmacological evaluation and mechanistic studies

  摘要：

  A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-ciquinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O -> NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (>11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities. 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.12.008
• 作为产物：
  描述：

  ethyl 1-(tert-butoxycarbonyl)-1,2,3,4,4a,5,6,10b-octahydro-5-(3-pyridyl)benzo[h][1,6]naphthyridine-9-carboxylate 在 吡啶 、 manganese(IV) oxide 作用下， 以 甲苯 为溶剂， 反应 3.0h， 以48%的产率得到ethyl 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-5-(3-pyridyl)benzo[h][1,6]naphthyridine-9-carboxylate
  参考文献：
  名称：

  1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: Synthesis, pharmacological evaluation and mechanistic studies

  摘要：

  A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-ciquinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O -> NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (>11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities. 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.12.008