3,4,5-trimethoxy-N-(pyridin-4-yl)benzamide | 31638-97-8

• 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: 3,4,5-trimethoxy-N-(pyridin-4-yl)benzamide
• 英文别名: 4-<3,4,5-Trimethoxy-benzoylamino>pyridin, 4-Tri-O-methyl-galloylamino-pyridin；3,4,5-trimethoxy-N-pyridin-4-ylbenzamide
• CAS: 31638-97-8
• 化学式: C₁₅H₁₆N₂O₄
• 分子量: 288.303
• InChiKey: ZKHSNEQBKZVFPB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  69.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3,4,5-trimethoxy-N-(pyridin-4-yl)benzamide 在 sodium hydroxide 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 18.0h， 生成
  参考文献：
  名称：

  通过轻松修饰C，N-二齿螯合亚吡啶基亚酰胺配体提高铱（III）配合物的催化活性。

  摘要：

  在五甲基环戊二烯基（Cp *）铱中心，将一组由于明显的两性离子和中性二烯型共振结构而具有可变的给体性质的芳基取代的吡啶基亚酰胺（PYA）配体用作电子柔性配体。这种类型的配体的直接合成使得可以容易地在C，N-二齿螯合PYA的苯环的不同位置引入供体取代基，例如甲氧基。这些修饰大大增强了配位铱中心对羰基和亚胺的需氧转移催化氢化以及苯乙炔的氢化硅烷化的催化活性。而且，这些PYA铱络合物催化醛的无碱转移氢化，并且在较小程度上也催化酮。

  DOI：

  10.1021/acs.inorgchem.7b01654
• 作为产物：
  描述：

  3,4,5-三甲氧基苯甲酸 在 草酰氯 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 3,4,5-trimethoxy-N-(pyridin-4-yl)benzamide
  参考文献：
  名称：

  Discovery of methoxy-naphthyl linked N-(1-benzylpiperidine) benzamide as a blood-brain permeable dual inhibitor of acetylcholinesterase and butyrylcholinesterase

  摘要：

  The cholinesterase enzymes play a vital role in maintaining balanced levels of the neurotransmitter acetylcholine in the central nervous system. However, the overexpression of these enzymes results in hampered neurotransmission. Both the major forms of cholinesterase enzymes viz. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play a crucial role in blocking neurotransmission; therefore, in recent years, a strategy of dual cholinesterase inhibition is being explored. Herein, we developed an energy-optimized e-pharmacophore hypothesis AHHPRR from AChE-donepezil complex and screened a set of 15 scaffolds that were designed imaginarily. The ligand with N-(1-benzylpyridinium) benzamide framework has shown the highest fitness and volume score, which was chosen for synthesis and validation. A series of pyridinium benzamides were synthesized and screened for cholinesterase inhibition that led to the identification of 7b, a naphthalene containing N-(1-benzylpiperidine) benzamide as a potent dual AChE and BChE inhibitor with IC₅₀ values of 0.176, and 0.47 μM, respectively. The kinetic study indicated that 7b inhibits AChE in a non-competitive manner with Ki value of 0.21 μM, and BChE in a mixed-fashion with Ki of 0.15 μM. The observed mode of inhibition was corroborated with molecular docking studies. The MD simulation studies pointed out that both AChE and BChE undergo low conformational changes in complex with 7b. The benzamide 7b displayed high BBB permeability in PAMPA assay, which indicates its potential for further exploration in preclinical studies for Alzheimer's disease.

  DOI：

  10.1016/j.ejmech.2020.112761

文献信息

• Kar, Pharmazie, 1983, vol. 38, # 5, p. 313 - 315
  作者：Kar

  DOI：——

  日期：——
• KAR, A., PHARMAZIE, 1983, 38, N 5, 313-315
  作者：KAR, A.

  DOI：——

  日期：——
• Discovery of methoxy-naphthyl linked N-(1-benzylpiperidine) benzamide as a blood-brain permeable dual inhibitor of acetylcholinesterase and butyrylcholinesterase
  作者：Mohd Abdullaha、Vijay K. Nuthakki、Sandip B. Bharate

  DOI：10.1016/j.ejmech.2020.112761

  日期：2020.12

  The cholinesterase enzymes play a vital role in maintaining balanced levels of the neurotransmitter acetylcholine in the central nervous system. However, the overexpression of these enzymes results in hampered neurotransmission. Both the major forms of cholinesterase enzymes viz. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play a crucial role in blocking neurotransmission; therefore, in recent years, a strategy of dual cholinesterase inhibition is being explored. Herein, we developed an energy-optimized e-pharmacophore hypothesis AHHPRR from AChE-donepezil complex and screened a set of 15 scaffolds that were designed imaginarily. The ligand with N-(1-benzylpyridinium) benzamide framework has shown the highest fitness and volume score, which was chosen for synthesis and validation. A series of pyridinium benzamides were synthesized and screened for cholinesterase inhibition that led to the identification of 7b, a naphthalene containing N-(1-benzylpiperidine) benzamide as a potent dual AChE and BChE inhibitor with IC₅₀ values of 0.176, and 0.47 μM, respectively. The kinetic study indicated that 7b inhibits AChE in a non-competitive manner with Ki value of 0.21 μM, and BChE in a mixed-fashion with Ki of 0.15 μM. The observed mode of inhibition was corroborated with molecular docking studies. The MD simulation studies pointed out that both AChE and BChE undergo low conformational changes in complex with 7b. The benzamide 7b displayed high BBB permeability in PAMPA assay, which indicates its potential for further exploration in preclinical studies for Alzheimer's disease.
• Enhanced Catalytic Activity of Iridium(III) Complexes by Facile Modification of C,N-Bidentate Chelating Pyridylideneamide Ligands
  作者：Miquel Navarro、Christene A. Smith、Martin Albrecht

  DOI：10.1021/acs.inorgchem.7b01654

  日期：2017.10.2

  phenylacetylene. Moreover, these PYA iridium complexes catalyze the base-free transfer hydrogenation of aldehydes, and to a lesser extent also of ketones. Under standard transfer hydrogenation conditions including base, aldehydes are rapidly oxidized to carboxylic acids rather than reduced to the corresponding alcohol, as is observed under base-free conditions.

  在五甲基环戊二烯基（Cp *）铱中心，将一组由于明显的两性离子和中性二烯型共振结构而具有可变的给体性质的芳基取代的吡啶基亚酰胺（PYA）配体用作电子柔性配体。这种类型的配体的直接合成使得可以容易地在C，N-二齿螯合PYA的苯环的不同位置引入供体取代基，例如甲氧基。这些修饰大大增强了配位铱中心对羰基和亚胺的需氧转移催化氢化以及苯乙炔的氢化硅烷化的催化活性。而且，这些PYA铱络合物催化醛的无碱转移氢化，并且在较小程度上也催化酮。