12-methoxycarbonyl-2-methylbenzo[f]pyrido[1,2-a]indole-6,11-dione | 670259-43-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 12-methoxycarbonyl-2-methylbenzo[f]pyrido[1,2-a]indole-6,11-dione
• 英文别名: Methyl 2-methyl-6,11-dioxonaphtho[2,3-b]indolizine-12-carboxylate
• CAS: 670259-43-5
• 化学式: C₁₉H₁₃NO₄
• 分子量: 319.317
• InChiKey: OQYUCRGSAVFMNM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  64.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-甲基吡啶 、 2,3-二氯-1,4-萘醌 、 乙酰乙酸甲酯 以 乙醇 为溶剂， 生成 12-methoxycarbonyl-2-methylbenzo[f]pyrido[1,2-a]indole-6,11-dione
  参考文献：
  名称：

  6,11-Dioxobenzo[f]pyrido[1,2-a]indoles Kill Mycobacterium tuberculosis by Targeting Iron–Sulfur Protein Rv0338c (IspQ), A Putative Redox Sensor

  摘要：

  Screening of a diversity-oriented compound library led to the identification of two 6,11-dioxobenzo[f]pyrido[1,2-a]indoles (DBPI) that displayed low micromolar bactericidal activity against the Erdman strain of Mycobacterium tuberculosis in vitro. The activity of these hit compounds was limited to tubercle bacilli, including the nonreplicating form, and to Mycobacterium marinum. On hit expansion and investigation of the structure activity relationship, selected modifications to the dioxo moiety of the DBPI scaffold were either neutral or led to reduction or abolition of antimycobacterial activity. To find the target, DBPI-resistant mutants of M. tuberculosis Erdman were raised and characterized first microbiologically and then by whole genome sequencing. Four different mutations, all affecting highly conserved residues, were uncovered in the essential gene rv0338c (ispQ) that encodes a membrane-bound protein, named IspQ, with 2Fe-2S and 4Fe-4S centers and putative iron-sulfur-binding reductase activity. With the help of a structural model, two of the mutations were localized close to the 2Fe-2S domain in IspQ and another in transmembrane segment 3. The mutant genes were recessive to the wild type in complementation experiments and further confirmation of the hit-target relationship was obtained using a conditional knockdown mutant of rv0338c in M. tuberculosis H37Rv. More mechanistic insight was obtained from transcriptome analysis, following exposure of M. tuberculosis to two different DBPI; this revealed strong upregulation of the redox-sensitive SigK regulon and genes induced by oxidative and thiol-stress. The findings of this investigation pharmacologically validate a novel target in tubercle bacilli and open a new vista for tuberculosis drug discovery.

  DOI：

  10.1021/acsinfecdis.0c00531

文献信息

• Copper(II)-Catalyzed Synthesis of Benzo[<i>f</i>]pyrido[1,2-<i>a</i>]indole-6,11-dione Derivatives via Naphthoquinone Difunctionalization Reaction
  作者：Yun Liu、Jin-Wei Sun

  DOI：10.1021/jo2023312

  日期：2012.1.20

  and pyridine (or isoquinoline) via sp2–C–H difunctionalization of naphthoquinone followed by intramolecular cyclization and oxidative aromatization. In an attempt to expand the reaction scope and to help clarify the reaction mechanism, 1,3-dicarbonyl compounds are used in place of acyl bromides to take part in this reaction, and the benzo[f]pyrido[1,2-a]indole-6,11-diones derivatives are also obtained

  苯并[ f ]吡啶基[1,2 - a ]吲哚-6,11-二酮通过铜（II）催化的酰基溴，1,4-萘醌和吡啶的三组分反应（或异喹啉）通过萘醌的sp 2 -CH双官能化，然后进行分子内环化和氧化芳构化。为了扩大反应范围并澄清反应机理，使用1,3-二羰基化合物代替酰基溴参与了该反应，并使用了苯并[ f ]吡啶基[1,2- a ]还以优异的产率获得了吲哚-6，11-二酮衍生物。
• 6,11-Dioxobenzo[<i>f</i>]pyrido[1,2-<i>a</i>]indoles Kill <i>Mycobacterium tuberculosis</i> by Targeting Iron–Sulfur Protein Rv0338c (IspQ), A Putative Redox Sensor
  作者：Rita Székely、Monica Rengifo-Gonzalez、Vinayak Singh、Olga Riabova、Andrej Benjak、Jérémie Piton、Mena Cimino、Etienne Kornobis、Valerie Mizrahi、Kai Johnsson、Giulia Manina、Vadim Makarov、Stewart T. Cole

  DOI：10.1021/acsinfecdis.0c00531

  日期：2020.11.13

  Screening of a diversity-oriented compound library led to the identification of two 6,11-dioxobenzo[f]pyrido[1,2-a]indoles (DBPI) that displayed low micromolar bactericidal activity against the Erdman strain of Mycobacterium tuberculosis in vitro. The activity of these hit compounds was limited to tubercle bacilli, including the nonreplicating form, and to Mycobacterium marinum. On hit expansion and investigation of the structure activity relationship, selected modifications to the dioxo moiety of the DBPI scaffold were either neutral or led to reduction or abolition of antimycobacterial activity. To find the target, DBPI-resistant mutants of M. tuberculosis Erdman were raised and characterized first microbiologically and then by whole genome sequencing. Four different mutations, all affecting highly conserved residues, were uncovered in the essential gene rv0338c (ispQ) that encodes a membrane-bound protein, named IspQ, with 2Fe-2S and 4Fe-4S centers and putative iron-sulfur-binding reductase activity. With the help of a structural model, two of the mutations were localized close to the 2Fe-2S domain in IspQ and another in transmembrane segment 3. The mutant genes were recessive to the wild type in complementation experiments and further confirmation of the hit-target relationship was obtained using a conditional knockdown mutant of rv0338c in M. tuberculosis H37Rv. More mechanistic insight was obtained from transcriptome analysis, following exposure of M. tuberculosis to two different DBPI; this revealed strong upregulation of the redox-sensitive SigK regulon and genes induced by oxidative and thiol-stress. The findings of this investigation pharmacologically validate a novel target in tubercle bacilli and open a new vista for tuberculosis drug discovery.