N-{3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl}-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxamide | 1621694-32-3

• 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: N-{3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl}-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxamide
• 英文别名: 5-(4-chlorophenyl)-N-[3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxamide
• CAS: 1621694-32-3
• 化学式: C₃₅H₃₃Cl₂N₅O
• 分子量: 610.586
• InChiKey: NOBALTDRZBHVTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.8
• 重原子数：
  43
• 可旋转键数：
  7
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  78.9
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-{3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl}-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxamide 在 盐酸 作用下， 以 甲醇 为溶剂， 以95 mg的产率得到N-{3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl}-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxamide dihydrochloride
  参考文献：
  名称：

  Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies

  摘要：

  Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O -> NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine -6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent A beta 42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities. (c) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.07.021
• 作为产物：
  描述：

  ethyl 1-(tert-butoxycarbonyl)-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxylate 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二甲基甲酰胺 、 potassium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 乙酸乙酯 为溶剂， 反应 60.58h， 生成 N-{3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]propyl}-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-9-carboxamide
  参考文献：
  名称：

  Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies

  摘要：

  Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O -> NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine -6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent A beta 42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities. (c) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.07.021

文献信息

• Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies
  作者：Ornella Di Pietro、F. Javier Pérez-Areales、Jordi Juárez-Jiménez、Alba Espargaró、M. Victòria Clos、Belén Pérez、Rodolfo Lavilla、Raimon Sabaté、F. Javier Luque、Diego Muñoz-Torrero

  DOI：10.1016/j.ejmech.2014.07.021

  日期：2014.9

  Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O -> NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine -6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent A beta 42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities. (c) 2014 Elsevier Masson SAS. All rights reserved.