ethyl 1-benzyl-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxylate | 1567847-36-2

• 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: ethyl 1-benzyl-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxylate
• 英文别名: ethyl 1-benzyl-5-(4-chlorophenyl)-3,4-dihydro-2H-benzo[h][1,6]naphthyridine-9-carboxylate
• CAS: 1567847-36-2
• 化学式: C₂₈H₂₅ClN₂O₂
• 分子量: 456.972
• InChiKey: KNHYHZFNDHJMIL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  42.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 1-benzyl-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxylate 在 盐酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 以92 mg的产率得到ethyl 1-benzyl-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxylate hydrochloride
  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：

  1-苄基-3,4-二氢-1H-吡啶-2-酮 在 三乙氧基硅烷 、 zinc diacetate 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 scandium tris(trifluoromethanesulfonate) 作用下， 以 四氢呋喃 、 氯仿 、 乙腈 为溶剂， 反应 144.08h， 生成 ethyl 1-benzyl-5-(4-chlorophenyl)-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

文献信息

• 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
  作者：Ornella Di Pietro、Elisabet Viayna、Esther Vicente-García、Manuela Bartolini、Rosario Ramón、Jordi Juárez-Jiménez、M. Victòria Clos、Belén Pérez、Vincenza Andrisano、F. Javier Luque、Rodolfo Lavilla、Diego Muñoz-Torrero

  DOI：10.1016/j.ejmech.2013.12.008

  日期：2014.2

  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.