1-cyclopropyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid | 1207200-26-7

• 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: 1-cyclopropyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid
• 英文别名: 1-Cyclopropyl-4-oxo-6-piperazin-1-ylquinoline-3-carboxylic acid；1-cyclopropyl-4-oxo-6-piperazin-1-ylquinoline-3-carboxylic acid
• CAS: 1207200-26-7
• 化学式: C₁₇H₁₉N₃O₃
• 分子量: 313.356
• InChiKey: IDLNXUNIFHVOJG-UHFFFAOYSA-N

物化性质

• 沸点：
  569.8±50.0 °C(Predicted)
• 密度：
  1.408±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  72.9
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-cyclopropyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid 、 苯甲醛 在 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 6.0h， 以43%的产率得到6-(4-benzylpiperazin-1-yl)-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
  参考文献：
  名称：

  4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B

  摘要：

  Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.

  DOI：

  10.1016/j.bmc.2014.05.028
• 作为产物：
  描述：

  2,5-二氟苯甲酸 在 盐酸 、 氯化亚砜 、 水 、 potassium carbonate 、 三乙胺 作用下， 以 N-甲基吡咯烷酮 、 甲醇 、 乙醚 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 8.42h， 生成 1-cyclopropyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid
  参考文献：
  名称：

  4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B

  摘要：

  Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.

  DOI：

  10.1016/j.bmc.2014.05.028

文献信息

• Synthesis of novel 15-membered 8a-azahomoerythromycin A acylides: Consequences of structural modification at the C-3 and C-6 position on antibacterial activity
  作者：Dražen Pavlović、Scott Kimmins、Stjepan Mutak

  DOI：10.1016/j.ejmech.2016.09.022

  日期：2017.1

  A novel series of 6-O-substituted 8a-aza-8a-homoerythromycin A 3-O-acylides has been discovered with potent activity against key respiratory pathogens, including those inducibly and constitutively resistant to erythromycin. The best compounds in this series 15na and 15nd showed activity comparable to telithromycin, especially against Haemophilus influenzae and constitutively MLSB-resistant strains

  已经发现了一系列新颖的6 - O-取代的8a-氮杂-8a-同型红霉素A 3- O-酰化物，其对关键的呼吸道病原体具有有效的活性，所述病原体包括对红霉素具有诱导性和组成型抗性的病原体。该系列15na和15nd中最好的化合物显示出与telithromycin相当的活性，尤其是对流感嗜血杆菌和构成性MLS B耐药的肺炎链球菌和化脓性链球菌菌株。此外，15na表现出许多类似药物的特性，包括有利的药代动力学特性和体内功效。例如，15na表现出良好的口服生物利用度（平均F = 42％），并且在体内对红霉素易感性肺炎链球菌的疗效优于telithromycin（1）。因此，15na具有进一步开发这种新型大环内酯类抗生素的巨大潜力。
• Novel hybrids of 15-membered 8a- and 9a-azahomoerythromycin A ketolides and quinolones as potent antibacterials
  作者：Dražen Pavlović、Andrea Fajdetić、Stjepan Mutak

  DOI：10.1016/j.bmc.2010.10.024

  日期：2010.12

  well as fastidious Gram-negative pathogens. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens and display hitherto unprecedented in vitro activity against the constitutively MLSB-resistant strain of Staphylococcus aureus. In addition, they also represent an improvement over telithromycin (2) and cethromycin (3) against fastidious Gram-negative

  合成了一系列新颖的6-O-取代和6,12-二-O-取代的8a-氮杂-8a-红霉素A和9a-氮杂-9a-红霉素A酮醇化物，并评估了其对一组抗菌肽的体外抗菌活性。代表性的红霉素易感和抗红霉素的测试菌株。还合成了另一系列的基于14元红霉素肟支架的酮缩酮，与15元氮杂红霉素类似物相比，它们具有抗菌活性。一般而言，结构活性研究表明，与9a-azahomoerythromycin系列中相应的15元类似物相比，14元酮化物显示出良好的抗菌活性。但是，在8a-azahomoerythromycin系列中，B）抗性革兰氏阳性病原体以及挑剔的革兰氏阴性病原体。该系列中最好的化合物克服了相关临床革兰氏阳性病原体的所有抗药性，并且对金黄色葡萄球菌的组成型MLS B耐药菌株显示出前所未有的体外活性。此外，它们还代表了针对抗革兰氏阴性病原体流感嗜血杆菌和卡他莫拉菌的泰利霉素（2）和cethromycin（3）的改良。
• 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B
  作者：Ying Zhi、Li-Xin Gao、Yi Jin、Chun-Lan Tang、Jing-Ya Li、Jia Li、Ya-Qiu Long

  DOI：10.1016/j.bmc.2014.05.028

  日期：2014.7

  Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.