ethyl 1-(4-fluorobenzyl)-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate | 1616491-55-4

• 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: ethyl 1-(4-fluorobenzyl)-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate
• 英文别名: Ethyl 1-[(4-fluorophenyl)methyl]-6-nitro-4-oxoquinoline-3-carboxylate；ethyl 1-[(4-fluorophenyl)methyl]-6-nitro-4-oxoquinoline-3-carboxylate
• CAS: 1616491-55-4
• 化学式: C₁₉H₁₅FN₂O₅
• 分子量: 370.337
• InChiKey: VYXYPHDTLSMUCL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  92.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 1-(4-fluorobenzyl)-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate 在 盐酸 、 水 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 4.25h， 生成 methyl 2-(3-(1-(4-fluorobenzyl)-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxamido)propoxy)-6-hydroxybenzoate
  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-氟-5-硝基苯甲酸 在 氯化亚砜 、 potassium carbonate 、 三乙胺 作用下， 以 乙醚 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 0.67h， 生成 ethyl 1-(4-fluorobenzyl)-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate
  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

• Easily accessed nitroquinolones exhibiting potent and selective anti-tubercular activity
  作者：Phelelisiwe S. Dube、Lesetja J. Legoabe、Audrey Jordaan、Omobolanle J. Jesumoroti、Tendamudzimu Tshiwawa、Digby F. Warner、Richard M. Beteck

  DOI：10.1016/j.ejmech.2021.113207

  日期：2021.3

  weight of 399 Da and ClogP value of 2.7 is the most active (MIC90: <0.244 μM) in this series. The SAR analyses suggest that anti-tubercular activity was influenced by substituents at position N-1 (R2) and C-3 (R3) of the quinolone ring. The activity data suggest that the nature of R3 has a stronger influence on the SAR compared to R2; with a fluorobenzyl and chlorobenzyl moiety at R2 being the most

  据报道，以苯并噻嗪酮为代表的基于硝基的DprE1抑制剂可引起有效的抗结核活性。与苯并噻嗪酮相关的不良PK性能激发了发现其他基于硝基的DprE1抑制剂的灵感。另一方面，基于喹诺酮的抗生素具有良好的PK特性。硝基化合物的有效抗结核活性和喹诺酮类药物的良好PK特性引起我们对在喹诺酮支架周围构建一类新型含硝基化合物的兴趣，目的是鉴定具有有效抗结核活性的新型DprE1抑制剂。因此，我们在此报道了使用少于五种廉价的合成转化所获得的新型6-硝基喹诺酮-3-羧酰胺衍生物的抗结核活性。在评估抗结核活性的23种目标化合物中，有12种对Mtb具有活性-表现出的活性范围<0.244-31.865μM。复合25具有2.7 399 Da和的ClogP值的分子量是最活跃的（MIC 90：<0.244μM）在这个系列。SAR分析表明，抗结核活性受喹诺酮环N-1（R 2）和C-3（R 3）位置的取代基影响。活动数据表明，与R
• 6‐Nitro‐1‐benzylquinolones exhibiting specific antitubercular activity
  作者：Richard M. Beteck、Audrey Jordaan、Tarryn Swart、Frank Van Der Kooy、Digby F. Warner、Heinrich C. Hoppe、Lesetja J. Legoabe

  DOI：10.1111/cbdd.13747

  日期：2020.12

  baumannii , Klebsiella pneumonia , Staphylococcus aureus , and Escherichia coli for antibacterial activities and also against HeLa cells for overt cytotoxicity. Compound 8e was identified as a non‐toxic, potent hit with selective activity (MIC90 ˂ 0.24 µm ) against MTB. 8e , however, showed no activity against DprE1 mutant, suggesting DprE1 as the likely target for this compound class.

  在这项研究中，我们合成了新型硝基喹诺酮类化合物，并针对一系列革兰氏阳性和革兰氏阴性病原体进行了体外测试，包括结核分枝杆菌(MTB)、铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌、金黄色葡萄球菌和埃希氏菌大肠杆菌具有抗菌活性，也针对 HeLa 细胞具有明显的细胞毒性。化合物8e被鉴定为对 MTB具有选择性活性 (MIC 90  ˂ 0.24 µm )的无毒、有效打击。8e然而，对 DprE1 突变体没有活性，表明 DprE1 可能是该化合物类别的目标。
• Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase
  作者：Antonella Messore、Angela Corona、Valentina Noemi Madia、Francesco Saccoliti、Valeria Tudino、Alessandro De Leo、Davide Ialongo、Luigi Scipione、Daniela De Vita、Giorgio Amendola、Ettore Novellino、Sandro Cosconati、Mathieu Métifiot、Marie-Line Andreola、Francesca Esposito、Nicole Grandi、Enzo Tramontano、Roberta Costi、Roberto Di Santo

  DOI：10.1021/acs.jmedchem.1c00535

  日期：2021.6.24
• 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.