N,N-dimethyl-1-{[2-(4-propoxyphenyl)-4-quinolinyl]oxy}-2-propanamine hydrochloride | 1443120-56-6

• 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: N,N-dimethyl-1-{[2-(4-propoxyphenyl)-4-quinolinyl]oxy}-2-propanamine hydrochloride
• 英文别名: N,N-dimethyl-1-[2-(4-propoxyphenyl)quinolin-4-yl]oxypropan-2-amine;hydrochloride
• CAS: 1443120-56-6
• 化学式: C₂₃H₂₈N₂O₂*ClH
• 分子量: 400.948
• InChiKey: XWQPEXKGPORFSO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.44
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  34.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N,N-dimethyl-1-{[2-(4-propoxyphenyl)-4-quinolinyl]oxy}-2-propanamine hydrochloride 在 ChiralpakZwix (-) 作用下， 以 甲醇 、 水 为溶剂， 以90%的产率得到
  参考文献：
  名称：

  The “racemic approach” in the evaluation of the enantiomeric NorA efflux pump inhibition activity of 2-phenylquinoline derivatives

  摘要：

  Among the mechanisms adopted by bacteria, efflux pumps (EPs) have been recognized as being significantly involved in contributing to resistance to commonly used antibacterial agents. However, little is known about their three-dimensional structures or the steric requirements for their inhibition. Lack of such knowledge includes NorA, one of the most studied Staphylococcus aureus EPs. In the present study, the use of two commercialized Cinchona alkaloid-based zwitterionic chiral stationary phases allowed the enantioseparation of four 2-((2-(4-propoxyphenyl)quinolin-4-yl)oxy)alkylamines 1-4 previously found to be potent S. aureus NorA efflux pump inhibitors when tested as racemates. In the identified optimal polar-ionic conditions (MeOH/THF/H2O-49/49/2 (v/v/v)+ 25 mM formic acid, 12.5 mM diethylamine), repeated consecutive injections of 1 allowed the isolation of sufficient amount of its enantiomers (2.6 mg and 2.8 mg, for (R)-1 and (S)-1, respectively) and then to evaluate their ability to inhibit the S. aureus NorA efflux pump. The biological evaluation highlighted the main contribution of the (R)-1 enantiomer to both the EtBr efflux inhibition and synergistic effect with against SA-1199B (norA+/A116E GrlA) respect to the racemate activity. The comparison between the experimental electronic circular dichroism and the time-dependent density functional theory calculations spectra of the two isolated enantiomeric fractions allowed for all compounds a clear and easy assignment of the enantiomeric elution order. (C) 2016 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.jpba.2016.07.003
• 作为产物：
  描述：

  2-[4-(propyloxy)phenyl]quinolin-4-ol 、 2-氯-1-甲基乙基(二甲基)胺盐酸盐 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以34%的产率得到N,N-dimethyl-1-{[2-(4-propoxyphenyl)-4-quinolinyl]oxy}-2-propanamine hydrochloride
  参考文献：
  名称：

  Re-evolution of the 2-Phenylquinolines: Ligand-Based Design, Synthesis, and Biological Evaluation of a Potent New Class of Staphylococcus aureus NorA Efflux Pump Inhibitors to Combat Antimicrobial Resistance

  摘要：

  Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of antimicrobial agents that are substrates. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, biocides, and dyes, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 2-phenylquinoline derivatives was designed by means of ligand-based pharmacophore modeling in an attempt to identify improved S. aureus NorA efflux pump inhibitors (EPIs). Most of the 2-phenylquinoline derivatives displayed potent EPI activity against the norA overexpressing strain SA-1199B. The antibacterial activity of ciprofloxacin, when used in combination with some of the synthesized compounds, was completely restored in SA-1199B and SA-K2378, a strain overexpressing norA from a multicopy plasmid. Compounds 3m and 3q also showed potent synergistic activity with the ethidium bromide dye in a strain overexpressing the MepA MDR efflux pump.

  DOI：

  10.1021/jm400262a

文献信息

• Re-evolution of the 2-Phenylquinolines: Ligand-Based Design, Synthesis, and Biological Evaluation of a Potent New Class of Staphylococcus aureus NorA Efflux Pump Inhibitors to Combat Antimicrobial Resistance
  作者：Stefano Sabatini、Francesca Gosetto、Nunzio Iraci、Maria Letizia Barreca、Serena Massari、Luca Sancineto、Giuseppe Manfroni、Oriana Tabarrini、Mirjana Dimovska、Glenn W. Kaatz、Violetta Cecchetti

  DOI：10.1021/jm400262a

  日期：2013.6.27

  Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of antimicrobial agents that are substrates. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, biocides, and dyes, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 2-phenylquinoline derivatives was designed by means of ligand-based pharmacophore modeling in an attempt to identify improved S. aureus NorA efflux pump inhibitors (EPIs). Most of the 2-phenylquinoline derivatives displayed potent EPI activity against the norA overexpressing strain SA-1199B. The antibacterial activity of ciprofloxacin, when used in combination with some of the synthesized compounds, was completely restored in SA-1199B and SA-K2378, a strain overexpressing norA from a multicopy plasmid. Compounds 3m and 3q also showed potent synergistic activity with the ethidium bromide dye in a strain overexpressing the MepA MDR efflux pump.
• The “racemic approach” in the evaluation of the enantiomeric NorA efflux pump inhibition activity of 2-phenylquinoline derivatives
  作者：Andrea Carotti、Federica Ianni、Stefano Sabatini、Alessandro Di Michele、Roccaldo Sardella、Glenn W. Kaatz、Wolfgang Lindner、Violetta Cecchetti、Benedetto Natalini

  DOI：10.1016/j.jpba.2016.07.003

  日期：2016.9

  Among the mechanisms adopted by bacteria, efflux pumps (EPs) have been recognized as being significantly involved in contributing to resistance to commonly used antibacterial agents. However, little is known about their three-dimensional structures or the steric requirements for their inhibition. Lack of such knowledge includes NorA, one of the most studied Staphylococcus aureus EPs. In the present study, the use of two commercialized Cinchona alkaloid-based zwitterionic chiral stationary phases allowed the enantioseparation of four 2-((2-(4-propoxyphenyl)quinolin-4-yl)oxy)alkylamines 1-4 previously found to be potent S. aureus NorA efflux pump inhibitors when tested as racemates. In the identified optimal polar-ionic conditions (MeOH/THF/H2O-49/49/2 (v/v/v)+ 25 mM formic acid, 12.5 mM diethylamine), repeated consecutive injections of 1 allowed the isolation of sufficient amount of its enantiomers (2.6 mg and 2.8 mg, for (R)-1 and (S)-1, respectively) and then to evaluate their ability to inhibit the S. aureus NorA efflux pump. The biological evaluation highlighted the main contribution of the (R)-1 enantiomer to both the EtBr efflux inhibition and synergistic effect with against SA-1199B (norA+/A116E GrlA) respect to the racemate activity. The comparison between the experimental electronic circular dichroism and the time-dependent density functional theory calculations spectra of the two isolated enantiomeric fractions allowed for all compounds a clear and easy assignment of the enantiomeric elution order. (C) 2016 Elsevier B.V. All rights reserved.