N¹,N¹-diethyl-N⁴-(7-nitroquinolin-4-yl)pentane-1,4-diamine | 251539-37-4

• 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: N¹,N¹-diethyl-N⁴-(7-nitroquinolin-4-yl)pentane-1,4-diamine
• 英文别名: 1-N,1-N-diethyl-4-N-(7-nitroquinolin-4-yl)pentane-1,4-diamine
• CAS: 251539-37-4
• 化学式: C₁₈H₂₆N₄O₂
• 分子量: 330.43
• InChiKey: ORUAKEMELJTUDK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  74
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N¹,N¹-diethyl-N⁴-(7-nitroquinolin-4-yl)pentane-1,4-diamine 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 反应 3.0h， 生成 N⁴-(4-Diethylamino-1-methyl-butyl)-quinoline-4,7-diamine
  参考文献：
  名称：

  Structural Specificity of Chloroquine−Hematin Binding Related to Inhibition of Hematin Polymerization and Parasite Growth

  摘要：

  Considerable data now support the! hypothesis that chloroquine (CQ)-hematin binding in the parasite food vacuole leads to inhibition of hemain polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC-), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin mu-oxo dimers in a cofacial pi-pi sandwich-type complex. Association constants (K-a's ranged from 0.46 to 2.9 x 10(5) M-1 compared to 4.0 x 10(5) M(-1)for CQ. Remarkably, we were not able to measure any significant interaction between hematin mu-oxo dimer and 11, the B-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin mu-oxa dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable pi-pi interaction observed in the CQ-hematin mu-oxo dimer complex derives from a favorable alignment of the out-of-plane pi-electron density in CQ and hematin Cc-ore dimer at the points of intermolecular contact. For 4-aminoquinolines related to CQ, our data suggest that, electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom,is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K-a and hematin polymerization IC50 values suggests that other properties of the CQ-humatin mu-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC50 values were normalized for hematin mu-oxo dimer binding affinities, adding further evidence that, antimalarial 4-aminoquinolines act by this mechanism.

  DOI：

  10.1021/jm9902180
• 作为产物：
  描述：

  二乙基(3-硝基苯胺亚甲基)丙二酸 在 ammonium hydroxide 、 sodium hydroxide 、 silver nitrate 、 三氯氧磷 作用下， 以 二苯醚 、 水 为溶剂， 反应 10.25h， 生成 N¹,N¹-diethyl-N⁴-(7-nitroquinolin-4-yl)pentane-1,4-diamine
  参考文献：
  名称：

  Structural Specificity of Chloroquine−Hematin Binding Related to Inhibition of Hematin Polymerization and Parasite Growth

  摘要：

  Considerable data now support the! hypothesis that chloroquine (CQ)-hematin binding in the parasite food vacuole leads to inhibition of hemain polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC-), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin mu-oxo dimers in a cofacial pi-pi sandwich-type complex. Association constants (K-a's ranged from 0.46 to 2.9 x 10(5) M-1 compared to 4.0 x 10(5) M(-1)for CQ. Remarkably, we were not able to measure any significant interaction between hematin mu-oxo dimer and 11, the B-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin mu-oxa dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable pi-pi interaction observed in the CQ-hematin mu-oxo dimer complex derives from a favorable alignment of the out-of-plane pi-electron density in CQ and hematin Cc-ore dimer at the points of intermolecular contact. For 4-aminoquinolines related to CQ, our data suggest that, electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom,is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K-a and hematin polymerization IC50 values suggests that other properties of the CQ-humatin mu-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC50 values were normalized for hematin mu-oxo dimer binding affinities, adding further evidence that, antimalarial 4-aminoquinolines act by this mechanism.

  DOI：

  10.1021/jm9902180

文献信息

• Assembly of 4-Aminoquinolines via Palladium Catalysis:  A Mild and Convenient Alternative to S_NAr Methodology
  作者：Brandon J. Margolis、Kimberly A. Long、Dana L. T. Laird、J. Craig Ruble、Shon R. Pulley

  DOI：10.1021/jo062168u

  日期：2007.3.1

  4-Aminoquinolines, classically prepared via SNAr chemistry from an amine and 4-haloquinoline, are important scaffolds in medicinal chemistry. Interest in these compounds prompted us to explore palladium catalysis as an alternative to the existing methods for their preparation. Initial results followed by an iterative screening paradigm confirmed Pd(OAc)(2)/ DPEphos/K3PO4 as a mild and convenient alternative for the formation of the C-N bond in 4-aminoquinolines. A description of the screen and the scope of this methodology are discussed herein.