4-((3-Methoxyphenyl)amino)-8-methyl-6-(1H-pyrazol-4-yl)quinoline-3-carboxamide (17j)

• 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: 4-((3-Methoxyphenyl)amino)-8-methyl-6-(1H-pyrazol-4-yl)quinoline-3-carboxamide (17j)
• 英文别名: 4-(3-methoxyanilino)-8-methyl-6-(1H-pyrazol-4-yl)quinoline-3-carboxamide
• 化学式: C₂₁H₁₉N₅O₂
• 分子量: 373.414
• InChiKey: BANPCWFXBJUPMN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-碘-2-甲基苯胺 在 ammonium hydroxide 、 氯化亚砜 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 sodium carbonate 、 N,N-二甲基甲酰胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 二苯醚 、 乙醇 、 水 、 乙腈 为溶剂， 反应 5.08h， 生成 4-((3-Methoxyphenyl)amino)-8-methyl-6-(1H-pyrazol-4-yl)quinoline-3-carboxamide (17j)
  参考文献：
  名称：

  Repurposing Human PDE4 Inhibitors for Neglected Tropical Diseases. Evaluation of Analogs of the Human PDE4 Inhibitor GSK-256066 as Inhibitors of PDEB1 ofTrypanosoma brucei

  摘要：

  Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK‐256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure–activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents.

  DOI：

  10.1111/cbdd.12443

文献信息

• Repurposing Human PDE4 Inhibitors for Neglected Tropical Diseases. Evaluation of Analogs of the Human PDE4 Inhibitor GSK-256066 as Inhibitors of PDEB1 of<i>Trypanosoma brucei</i>
  作者：Stefan O. Ochiana、Nicholas D. Bland、Luca Settimo、Robert K. Campbell、Michael P. Pollastri

  DOI：10.1111/cbdd.12443

  日期：2015.5

  Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK‐256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure–activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents.