9-(piperidin-1-yl)indolo[2,1-b]quinazoline-6,12-dione | 1421765-58-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 9-(piperidin-1-yl)indolo[2,1-b]quinazoline-6,12-dione
• 英文别名: 9-(1-Piperidyl)indolo[2,1-b]quinazoline-6,12-dione；9-piperidin-1-ylindolo[2,1-b]quinazoline-6,12-dione
• CAS: 1421765-58-3
• 化学式: C₂₀H₁₇N₃O₂
• 分子量: 331.374
• InChiKey: ZDSLRWOXIRQJBT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  53
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  6-氯靛红 在 三乙胺 作用下， 以 N-甲基吡咯烷酮 、 甲苯 为溶剂， 反应 2.0h， 生成 9-(piperidin-1-yl)indolo[2,1-b]quinazoline-6,12-dione
  参考文献：
  名称：

  Design, Synthesis, and Structure–Activity Relationship Studies of Tryptanthrins As Antitubercular Agents

  摘要：

  The natural product tryptanthrin (la) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB.

  DOI：

  10.1021/np3007167

文献信息

• Targeting topoisomerase II with trypthantrin derivatives: Discovery of 7-((2-(dimethylamino)ethyl)amino)indolo[2,1-b]quinazoline-6,12-dione as an antiproliferative agent and to treat cancer
  作者：Elena Catanzaro、Nibal Betari、Jose M. Arencibia、Serena Montanari、Claudia Sissi、Angela De Simone、Ivano Vassura、Alan Santini、Vincenza Andrisano、Vincenzo Tumiatti、Marco De Vivo、Dmitri V. Krysko、Marco B.L. Rocchi、Carmela Fimognari、Andrea Milelli

  DOI：10.1016/j.ejmech.2020.112504

  日期：2020.9

  appearance of resistance mechanisms upon treatment with topoII-targeted anticancer drugs. In the present investigation, we report the discovery of a new topoII inhibitor, whose design was based on the structure of the natural product trypthantrin, a natural alkaloidal compound containing a basic indoloquinazoline moiety. This new topoII inhibitor, here numbered compound 5, is found to inhibit topoII with

  几十年来，针对人类拓扑异构酶II（topoII）的药物一直在临床实践中使用。然而，由于继发性恶性肿瘤的出现以及以靶向topoII的抗癌药物治疗后出现的耐药机制，迫切需要新的和更安全的topoII抑制剂。在本研究中，我们报告了一种新的topoII抑制剂的发现，该抑制剂的设计基于天然产物胰蛋白p聚糖的结构，胰蛋白ant呤是一种含有碱性吲哚并喹唑啉部分的天然生物碱化合物。发现这种新的topoII抑制剂（此处编号为化合物5）以26.6± 4.7μM的IC 50抑制topoII 。值得注意的是，化合物5它比模板化合物胰蛋白聚糖更有效，甚至比广泛使用的靶向topoII的临床药物依托泊苷更有效。另外，化合物5还显示出高水溶性，对不同的肿瘤细胞系例如急性白血病，结肠癌和乳腺癌有希望的抗增殖活性。根据这些结果，化合物5代表了开发新的topoII抑制剂作为抗癌治疗剂的有希望的先导。
• Design, Synthesis, and Structure–Activity Relationship Studies of Tryptanthrins As Antitubercular Agents
  作者：Jae-Min Hwang、Taegwon Oh、Takushi Kaneko、Anna M. Upton、Scott G. Franzblau、Zhenkun Ma、Sang-Nae Cho、Pilho Kim

  DOI：10.1021/np3007167

  日期：2013.3.22

  The natural product tryptanthrin (la) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB.