4-(3-cyano-2-oxo-7-(1H-pyrazol-4-yl)-1,2,5,6-tetrahydrobenzo[h]quinolin-4-yl)benzoic acid

• 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-cyano-2-oxo-7-(1H-pyrazol-4-yl)-1,2,5,6-tetrahydrobenzo[h]quinolin-4-yl)benzoic acid
• 英文别名: 4-[3-Cyano-2-Oxo-7-(1h-Pyrazol-4-Yl)-5,6-Dihydro-1h-Benzo[h]quinolin-4-Yl]benzoic Acid；4-[3-cyano-2-oxo-7-(1H-pyrazol-4-yl)-5,6-dihydro-1H-benzo[h]quinolin-4-yl]benzoic acid
• 化学式: C₂₄H₁₆N₄O₃
• 分子量: 408.416
• InChiKey: STALUGJGAYBZIU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  119
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  、 对醛基苯甲酸 、 氰乙酸乙酯 在 ammonium acetate 作用下， 以 乙醇 为溶剂， 生成 4-(3-cyano-2-oxo-7-(1H-pyrazol-4-yl)-1,2,5,6-tetrahydrobenzo[h]quinolin-4-yl)benzoic acid
  参考文献：
  名称：

  Structure Guided Lead Generation for M. tuberculosis Thymidylate Kinase (Mtb TMK): Discovery of 3-Cyanopyridone and 1,6-Naphthyridin-2-one as Potent Inhibitors

  摘要：

  M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and an NMR based fragment screen through which we discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively. We describe three cyanopyridone subseries that arose during our hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment hit from 500 mu M to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivatives containing sulfoxides and sulfones showed cellular activity against M. tuberculosis. To the best of our knowledge, these compounds are the first reports of non-thymidine-like inhibitors of Mtb TMK.

  DOI：

  10.1021/jm5012947