pyridine-4-carboxaldehyde (E)-O-(2,6-dichlorobenzyl)oxime | 155591-95-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: pyridine-4-carboxaldehyde (E)-O-(2,6-dichlorobenzyl)oxime
• 英文别名: pyridine-4-carboxaldehyde (e)-O-(2,6-dichlorobenzyl)-oxime；(E)-N-[(2,6-dichlorophenyl)methoxy]-1-pyridin-4-ylmethanimine
• CAS: 155591-95-0
• 化学式: C₁₃H₁₀Cl₂N₂O
• 分子量: 281.141
• InChiKey: CPUZYCDOMKCEBG-CAOOACKPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  34.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(3-溴丙基)-4-甲氧基苯 、 pyridine-4-carboxaldehyde (E)-O-(2,6-dichlorobenzyl)oxime 以 乙腈 为溶剂， 反应 80.0h， 以74%的产率得到4-[(2,6-Dichloro-benzyloxyimino)-methyl]-1-[3-(4-methoxy-phenyl)-propyl]-pyridinium; bromide
  参考文献：
  名称：

  Search for the Pharmacophore of Bispyridinium-Type Allosteric Modulators of Muscarinic Receptors

  摘要：

  The bis(dichlorobenzyl) ether of the bispyridinium oxime TMB 4 stabilizes antagonist binding to M(2)-cholinoceptors which is indicative of an allosteric action. More than 10 derivatives of the lead compound were synthesized to investigate structure-activity relationships. The allosteric potency of the compounds was indicated by the concentrations which retarded the rate of dissociation of [H-3]N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC(50)). Compared with TMB 4, the bis(dichlorobenzyl) derivative 4a displayed a more than 200-fold higher potency (EC(50) = 4.7 mu M). One of the dichlorobenzyl groups could be replaced by a methyl group without loss of activity (EC(50) = 4.5 mu M). Further shortening of this end of the molecule was accompanied by a moderate decline in potency to a minimum of EC(50) = 26 mu M. The second quaternary nitrogen was not a prerequisite for an allosteric activity. It is concluded that one half of the lead compound is pivotal for an interaction with the allosteric site of the M(2)-cholinoceptor, whereas the opposite end of the molecule modulates the allosteric activity.

  DOI：

  10.1021/jm00036a008
• 作为产物：
  描述：

  4-吡啶甲醛肟 、 2,6-二氯氯苄 在 sodium hydroxide 、 四甲基氯化铵 作用下， 以 二氯甲烷 为溶剂， 反应 15.0h， 以88%的产率得到pyridine-4-carboxaldehyde (E)-O-(2,6-dichlorobenzyl)oxime
  参考文献：
  名称：

  双吡啶鎓型乙酰胆碱酯酶抑制剂的合成、生物活性和对接研究

  摘要：

  合成了一系列新的双吡啶类型乙酰胆碱酯酶 (AChE) 抑制剂，并测量了对 AChE 和丁酰胆碱酯酶 (BChE) 的抑制活性。从本质上讲，取代模式影响了对 AChE 的抑制效力，其中最活跃的双吡啶鎓肟 (TMB-4) 是双苄基取代的，其次是 TMB-4 的单苄基取代、双甲基取代和未取代衍生物。因此，进一步研究了TMB-4的双苄基醚。为了获得这些双苄基双吡啶鎓衍生物（所谓的 DUO 系列）的多种亲脂性和电子特性，系统地改变了侧环取代。迄今为止在 DUO 系列中发现的针对 AChE 的最低 IC50 值为 0.34 μM。进行对接研究以阐明生物活性的差异。通过这些研究可以确定几乎所有化合物的通用结合模式。在这种结合模式下，对接的配体跨越狭窄、深埋的活性位点峡谷，与峡谷底部的 Trp84、峡谷中途的 Tyr334 或 Phe331 以及峡谷口外围阴离子位点的 Trp279 相互作用. 对于特定的

  DOI：

  10.1002/ardp.200300795

文献信息

• Inkmann; Holzgrabe; Hesse, Pharmazie, 1997, vol. 52, # 10, p. 764 - 774
  作者：Inkmann、Holzgrabe、Hesse

  DOI：——

  日期：——
• A Fast and Efficient Track to Allosteric Modulators of Muscarinic Receptors: Microwave-Assisted Syntheses
  作者：Jens Schmitz、Eberhard Heller、Ulrike Holzgrabe

  DOI：10.1007/s00706-006-0575-0

  日期：2007.2

  By using microwave irradiation bisammonium-and bispyridinium-type allosteric modulators of muscarinic receptors can be obtained fast and efficiently.
• Search for the Pharmacophore of Bispyridinium-Type Allosteric Modulators of Muscarinic Receptors
  作者：Mario H. Botero Cid、Ulrike Holzgrabe、Evi Kostenis、Klaus Mohr、Christian Traenkle

  DOI：10.1021/jm00036a008

  日期：1994.5

  The bis(dichlorobenzyl) ether of the bispyridinium oxime TMB 4 stabilizes antagonist binding to M(2)-cholinoceptors which is indicative of an allosteric action. More than 10 derivatives of the lead compound were synthesized to investigate structure-activity relationships. The allosteric potency of the compounds was indicated by the concentrations which retarded the rate of dissociation of [H-3]N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC(50)). Compared with TMB 4, the bis(dichlorobenzyl) derivative 4a displayed a more than 200-fold higher potency (EC(50) = 4.7 mu M). One of the dichlorobenzyl groups could be replaced by a methyl group without loss of activity (EC(50) = 4.5 mu M). Further shortening of this end of the molecule was accompanied by a moderate decline in potency to a minimum of EC(50) = 26 mu M. The second quaternary nitrogen was not a prerequisite for an allosteric activity. It is concluded that one half of the lead compound is pivotal for an interaction with the allosteric site of the M(2)-cholinoceptor, whereas the opposite end of the molecule modulates the allosteric activity.
• Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type
  作者：Petra Kapková、Nikolaus Stiefl、Ulf Sürig、Bernd Engels、Knut Baumann、Ulrike Holzgrabe

  DOI：10.1002/ardp.200300795

  日期：2003.11

  diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so‐called DUO series), the lateral ring substitution was systematically varied. The lowest IC50 value against AChE found thus far in the DUO series was 0.34 μM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified

  合成了一系列新的双吡啶类型乙酰胆碱酯酶 (AChE) 抑制剂，并测量了对 AChE 和丁酰胆碱酯酶 (BChE) 的抑制活性。从本质上讲，取代模式影响了对 AChE 的抑制效力，其中最活跃的双吡啶鎓肟 (TMB-4) 是双苄基取代的，其次是 TMB-4 的单苄基取代、双甲基取代和未取代衍生物。因此，进一步研究了TMB-4的双苄基醚。为了获得这些双苄基双吡啶鎓衍生物（所谓的 DUO 系列）的多种亲脂性和电子特性，系统地改变了侧环取代。迄今为止在 DUO 系列中发现的针对 AChE 的最低 IC50 值为 0.34 μM。进行对接研究以阐明生物活性的差异。通过这些研究可以确定几乎所有化合物的通用结合模式。在这种结合模式下，对接的配体跨越狭窄、深埋的活性位点峡谷，与峡谷底部的 Trp84、峡谷中途的 Tyr334 或 Phe331 以及峡谷口外围阴离子位点的 Trp279 相互作用. 对于特定的