7-(3,4-dichlorophenyl)-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine | 1393816-59-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并吡喃类
• 英文名称: 7-(3,4-dichlorophenyl)-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine
• 英文别名: 13-(3,4-Dichlorophenyl)-2-oxa-22-azapentacyclo[12.8.0.03,12.04,9.016,21]docosa-1(22),3(12),4,6,8,10,14,16(21)-octaen-15-amine
• CAS: 1393816-59-5
• 化学式: C₂₆H₂₀Cl₂N₂O
• 分子量: 447.364
• InChiKey: IFYBUPQCUTZITP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  31
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  48.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-(3,4-dichlorobenzylidene)malononitrile 在 哌啶 、 aluminum (III) chloride 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 26.0h， 生成 7-(3,4-dichlorophenyl)-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine
  参考文献：
  名称：

  Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease

  摘要：

  The synthesis, pharmacological analysis and molecular modeling of the readily available racemic tacrine analogs 21-30, bearing the 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b[quinolin-8-amine heterocyclic ring system (II), prepared by Friedlander reaction of 2-amino-4-aryl-4H-benzo[h] chromene-3-carbonitriles (11-20) with cyclohexanone, are described in this paper. Molecules 21-30 are potent and selective inhibitors of hAChE, in the low micromolar range, one of the most potent inhibitors, 4-(8-amino-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-blquinolin-7-y1)-2-methoxyphenol (25), showing a IC50 (hAChE) = 0.33 +/- 0.04 mu M. Kinetic studies of compound 25 proved that this compound is a mixed type inhibitor for EeAChE (K-i=81 nM). Accordingly, molecular modeling of inhibitor 25 showed that both enantiomers have two major predicted binding modes at the active and at the peripheral anionic sites of AChE. Inhibitor 25 has an excellent antioxidant profile as determined in the ORAC experiment (1.47 +/- 0.10 Trolox equiv). Inhibitors 26-28 and 30 are permeable to BBB as determined in the PAMPA assay. Compared to tacrine, selected compounds 26-28 and 30 showed less hepatic toxicity in HepG2 cells. Moreover, cell viability-related studies in cortical neurons in primary cultures show that compounds 26-28 and 30 (0.1-50 mu M) have significant neuroprotective effects against mitochondrial chain blockers-induced cell death, and, unlike tacrine, are not neurotoxic at concentrations lower than 50 mu M. It is worth highlighting that compound 27 has the best neuroprotective properties out of all assayed compounds and shows no neurotoxicity. To sum up, these tacrine analogs can be considered as attractive multipotent therapeutic molecules on pharmacological receptors playing key roles in the progress of Alzheimer's disease. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.06.038

文献信息

• Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease
  作者：Emna Maalej、Fakher Chabchoub、María Jesús Oset-Gasque、Mario Esquivias-Pérez、María P. González、Leticia Monjas、Concepción Pérez、Cristóbal de los Ríos、María Isabel Rodríguez-Franco、Isabel Iriepa、Ignacio Moraleda、Mourad Chioua、Alejandro Romero、José Marco-Contelles、Abdelouahid Samadi

  DOI：10.1016/j.ejmech.2012.06.038

  日期：2012.8

  The synthesis, pharmacological analysis and molecular modeling of the readily available racemic tacrine analogs 21-30, bearing the 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b[quinolin-8-amine heterocyclic ring system (II), prepared by Friedlander reaction of 2-amino-4-aryl-4H-benzo[h] chromene-3-carbonitriles (11-20) with cyclohexanone, are described in this paper. Molecules 21-30 are potent and selective inhibitors of hAChE, in the low micromolar range, one of the most potent inhibitors, 4-(8-amino-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-blquinolin-7-y1)-2-methoxyphenol (25), showing a IC50 (hAChE) = 0.33 +/- 0.04 mu M. Kinetic studies of compound 25 proved that this compound is a mixed type inhibitor for EeAChE (K-i=81 nM). Accordingly, molecular modeling of inhibitor 25 showed that both enantiomers have two major predicted binding modes at the active and at the peripheral anionic sites of AChE. Inhibitor 25 has an excellent antioxidant profile as determined in the ORAC experiment (1.47 +/- 0.10 Trolox equiv). Inhibitors 26-28 and 30 are permeable to BBB as determined in the PAMPA assay. Compared to tacrine, selected compounds 26-28 and 30 showed less hepatic toxicity in HepG2 cells. Moreover, cell viability-related studies in cortical neurons in primary cultures show that compounds 26-28 and 30 (0.1-50 mu M) have significant neuroprotective effects against mitochondrial chain blockers-induced cell death, and, unlike tacrine, are not neurotoxic at concentrations lower than 50 mu M. It is worth highlighting that compound 27 has the best neuroprotective properties out of all assayed compounds and shows no neurotoxicity. To sum up, these tacrine analogs can be considered as attractive multipotent therapeutic molecules on pharmacological receptors playing key roles in the progress of Alzheimer's disease. (C) 2012 Elsevier Masson SAS. All rights reserved.