8-hydroxy-5-quinolylmethylphosphonic acid diethyl ester | 1452589-33-1

• 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: 8-hydroxy-5-quinolylmethylphosphonic acid diethyl ester
• 英文别名: diethyl ((8-hydroxyquinolin-5-yl)methyl)phosphonate；5-(diethoxy)phosphinylmethyl-8-hydroxyquinoline
• CAS: 1452589-33-1
• 化学式: C₁₄H₁₈NO₄P
• 分子量: 295.275
• InChiKey: LCKGREPXLHSGGF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.71
• 重原子数：
  20.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  68.65
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  8-hydroxy-5-quinolylmethylphosphonic acid diethyl ester 在 碘 、 potassium iodide 、 potassium hydroxide 作用下， 以 水 为溶剂， 以65%的产率得到7-iodo-8-hydroxy-5-quinolylmethylphosphonic acid diethyl ester
  参考文献：
  名称：

  苯并呋喃喹啉衍生物及其在制备治疗阿尔茨 海默病症的药品中的应用

  摘要：

  本发明公开了一种苯并呋喃喹啉衍生物及其在制备治疗阿尔茨海默病症的药品中的应用。本发明的苯并呋喃喹啉衍生物是多靶点抗阿尔茨海默病活性分子，具有磷酸二酯酶4D抑制活性、抗氧化、抑制Aβ聚集和解聚作用，动物实验结果表明，本发明的苯并呋喃喹啉衍生物具有改善阿尔兹海默病大鼠认知能力及空间记忆，保护阿尔兹海默病大鼠大脑海马区神经细胞，抑制神经元细胞丢失及坏死的功效。

  公开号：

  CN105294662B
• 作为产物：
  描述：

  8-羟基喹啉 在 盐酸 作用下， 以 水 为溶剂， 反应 5.0h， 生成 8-hydroxy-5-quinolylmethylphosphonic acid diethyl ester
  参考文献：
  名称：

  New multi-target-directed small molecules against Alzheimer's disease: a combination of resveratrol and clioquinol

  摘要：

  阿尔茨海默病（AD）是目前治疗上最为困难和最具挑战性的疾病之一。结合白藜芦醇和氯碘羟喹的药效团，基于“多靶点导向的配体”（MTDLs）策略，我们设计并合成了一系列新的AD治疗药物。生物活性测试结果表明，这些化合物具有优异的MTDL特性：显著的自发β-淀粉样蛋白（Aβ）聚集抑制能力和铜（II）诱导的Aβ聚集抑制能力，潜在的抗氧化行为（ORAC-FL值为0.9–3.2 Trolox当量）和生物金属螯合作用。在这些化合物中，（E）-5-（4-羟基苯乙烯基）喹啉-8-醇（10c）表现出最强的自发性Aβ聚集抑制能力（IC50 = 8.50 μM）和铜（II）诱导的Aβ聚集抑制能力，以及分解自发和铜（II）诱导的Aβ聚集产生的结构良好的Aβ纤维的能力。需要注意的是，10c还能通过金属配位作用阻止铜的氧化还原循环，从而控制Cu（I/II）触发的羟基自由基（OH·）生成，这一点通过Cu–抗坏血酸盐氧化还原体系检测得到证实。重要的是，在小鼠中，10c在高达2000 mg kg^-1的剂量下未显示急性毒性，并且能够穿过血脑屏障（BBB），这一点通过平行人工膜渗透检测得到证实。这些结果表明，化合物10c是一种有前景的多功能化合物，可用于开发新型AD药物。

  DOI：

  10.1039/c4ob00998c

文献信息

• Phosphonates containing 8-hydroxyquinoline moiety and their metal complexes: structures, fluorescent and magnetic properties
  作者：Deng-Ke Cao、Bei Liu、Yan-Wei Gu、Jia-Qi Feng、Yue Zhao

  DOI：10.1039/c3dt51108a

  日期：——

  Two kinds of solid-state structures of 5-phosphonomethyl-8-hydroxyquinoline (5pm8hqH3) have been obtained, namely 1·HCl·H2O and 1·H2O, involving different hydrogen bonds and/or aromatic stacking interactions. As a derivative of 5pm8hqH3, 5-phosphonomethyl-8-(carboxymethoxy)quinoline (5pm8cmoqH3) was synthesized. Based on 5pm8hqH3 and 5pm8cmoqH3, three new metal phosphonates have been hydrothermally prepared, including Zn(5pm8hqH)(H2O)·H2O (2), Cu(5pm8cmoqH)·2H2O (3) and Fe(5pm8cmoqH) (4), exhibiting layered structures for 2 and 4, and a three-dimensional open framework for 3. The 8-hydroxyquinoline moieties in 1·H2O and 2–4 exhibit three kinds of interesting aromatic stacking modes, including pyridine ring–pyridine ring stacking between a pair of moieties, double benzene ring–pyridine ring stacking between a pair of moieties and alternating benzene ring–benzene ring and pyridine ring–pyridine ring stacking among a number of moieties in the layered structure. The solid-state fluorescence measurements indicate the emissions of 1·HCl·H2O and 1·H2O are significantly different due to their distinct packing structures. Compound 2 exhibits both ligand-centered (LC) and ligand-to-metal charge transition (LMCT) emissions. Magnetic studies reveal dominant antiferromagnetic interactions in 3 and 4.

  研究人员获得了 5-膦酰甲基-8-羟基喹啉（5pm8hqH3）的两种固态结构，即 1-HCl-H2O 和 1- ，其中涉及不同的氢键和/或芳香堆积相互作用。作为 5pm8hqH3 的衍生物，合成了 5-膦酰甲基-8-（羧基甲氧基）喹啉（5pm8cmoqH3）。在 5pm8hqH3 和 5pm8cmoqH3 的基础上，通过水热法制备了三种新的金属膦酸盐，包括 Zn(5pm8hqH)( )- (2)、Cu(5pm8cmoqH)-2 (3) 和 Fe(5pm8cmoqH) (4)，其中 2 和 4 具有层状结构，3 具有三维开放框架。1- 和 2-4 中的 8-羟基喹啉分子呈现出三种有趣的芳香堆积模式，包括一对分子之间的吡啶环-吡啶环堆积、一对分子之间的双苯环-吡啶环堆积以及层状结构中多个分子之间的苯环-苯环和吡啶环-吡啶环交替堆积。固态荧光测量结果表明，由于 1-HCl- 和 1- 的填料结构不同，它们的发射率也明显不同。化合物 2 同时显示出配体中心发射（LC）和配体到金属电荷转移发射（LMCT）。磁性研究显示 3 和 4 中的反铁磁相互作用占主导地位。
• Design, Synthesis, and Evaluation of Orally Bioavailable Quinoline–Indole Derivatives as Innovative Multitarget-Directed Ligands: Promotion of Cell Proliferation in the Adult Murine Hippocampus for the Treatment of Alzheimer’s Disease
  作者：Zhiren Wang、Jinhui Hu、Xiaoping Yang、Xing Feng、Xingshu Li、Ling Huang、Albert S. C. Chan

  DOI：10.1021/acs.jmedchem.7b01417

  日期：2018.3.8

  A novel series of quinoline-indole derivatives were synthesized and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease (AD). Biological evaluation revealed that the derivatives had multifunctional profiles including antioxidant effects, blood-brain barrier (BBB) penetration, biometal chelation, A beta aggregation modulation, neurotrophic and neuroprotective properties. Moreover, several representative target derivatives demonstrated hippocampal cell proliferation in living adult mice by intracerebroventricular (icv) injection or oral administration. Further drug-like property analysis demonstrated that the optimized compound, 8d (WI-1758), had liver microsomal metabolic stability, was well tolerated (>2000 mg/kg), and had a rational pharmacokinetic profile, as well as an oral bioavailability of 14.1% and a positive log BB (-0.19) to cross the BBB in vivo. Pharmacodynamics studies demonstrated that chronic oral administration of 8d center dot HCl substantially ameliorated the cognitive and spatial memory deficits in APP/PS1 AD mice and noticeably reduced overall cerebral beta-amyloid deposits.
• Design, Synthesis, and Evaluation of Orally Available Clioquinol-Moracin M Hybrids as Multitarget-Directed Ligands for Cognitive Improvement in a Rat Model of Neurodegeneration in Alzheimer’s Disease
  作者：Zhiren Wang、Yali Wang、Bo Wang、Wenrui Li、Ling Huang、Xingshu Li

  DOI：10.1021/acs.jmedchem.5b01222

  日期：2015.11.12

  A novel series of clioquinol-moracin hybrids were designed and synthesized by fusing the pharmacophores of clioquinol and moracin M, and their activities as multitarget-directed ligands against Alzheimer's disease were evaluated. Biological activity results demonstrated that these hybrids possessed significant inhibitory activities against phosphodiesterase 4D (PDE4D) and A beta aggregation as well as remarkable antioxidant effects and excellent blood brain barrier permeability. The optimal compound, 18d (WBQ5187), exhibited excellent PDE4D inhibitory potency (IC50 = 0.32 mu M), significant antioxidant effects, appropriate biometal chelating functions, and interesting properties that modulated self- and metal-induced A beta aggregation. Two-dimensional NMR studies revealed that 18d had significant interactions with A beta(1-42) at the R5, H6, H14, Q15, and F20 residues. Furthermore, this typical hybrid possessed preeminent neuroprotective effects against inflammation in microglial cells. Most importantly, oral administration of 18d center dot HCl demonstrated marked improvements in cognitive and spatial memory in a rat model of Alzheimer's disease and protected hippocampal neurons from necrosis.