N-[(3',4'-(dihydroxy)phenyl)methyl]-1,2,3,4-tetrahydroacridin-9-amine

• 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',4'-(dihydroxy)phenyl)methyl]-1,2,3,4-tetrahydroacridin-9-amine
• 英文别名: 4-[(1,2,3,4-Tetrahydroacridin-9-ylamino)methyl]benzene-1,2-diol；4-[(1,2,3,4-tetrahydroacridin-9-ylamino)methyl]benzene-1,2-diol
• 化学式: C₂₀H₂₀N₂O₂
• 分子量: 320.391
• InChiKey: DHQHCSROVOIZIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  65.4
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (E)-N-[3',4'-bis(benzyloxy)benzylidene]-1,2,3,4-tetrahydroacridin-9-amine 在 10 wt% Pd(OH)2 on carbon 、 氢气 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 1.5h， 以55%的产率得到N-[(3',4'-(dihydroxy)phenyl)methyl]-1,2,3,4-tetrahydroacridin-9-amine
  参考文献：
  名称：

  Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors

  摘要：

  Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease.Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease.The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of A beta 42, lacking neurotoxicity up to 5 mu M concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound.So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.07.053

文献信息

• Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
  作者：Jesús M. Roldán-Peña、Valle Romero-Real、Javier Hicke、Inés Maya、Antonio Franconetti、Irene Lagunes、José M. Padrón、Sabrina Petralla、Eleonora Poeta、Marina Naldi、Manuela Bartolini、Barbara Monti、Maria L. Bolognesi、Óscar López、José G. Fernández-Bolaños

  DOI：10.1016/j.ejmech.2019.07.053

  日期：2019.11

  Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease.Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease.The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of A beta 42, lacking neurotoxicity up to 5 mu M concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound.So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.