7-amino-4-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 7-amino-4-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione
• 英文别名: 7-Amino-4-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[[4-(trifluoromethyl)phenyl]methyl]pyrrolo[3,4-c]pyridine-1,3-dione；7-amino-4-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[[4-(trifluoromethyl)phenyl]methyl]pyrrolo[3,4-c]pyridine-1,3-dione
• 化学式: C₁₉H₁₄F₃N₅O₃
• 分子量: 417.347
• InChiKey: IYLGILJOYOJTLA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  N-乙酰基-2-氰基甘氨酸乙酯 在 sodium hydride 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 、 mineral oil 为溶剂， 反应 91.0h， 生成 7-amino-4-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione
  参考文献：
  名称：

  Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration

  摘要：

  High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (Delta cydKO) was hypersusceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cyto chrome bc1 complex, a validated drug target in M. tuberculosis.

  DOI：

  10.1021/acs.jmedchem.5b01542

文献信息

• Pyrrolo[3,4-<i>c</i>]pyridine-1,3(2<i>H</i>)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration
  作者：Renier van der Westhuyzen、Susan Winks、Colin R. Wilson、Grant A. Boyle、Richard K. Gessner、Candice Soares de Melo、Dale Taylor、Carmen de Kock、Mathew Njoroge、Christel Brunschwig、Nina Lawrence、Srinivasa P.S. Rao、Frederick Sirgel、Paul van Helden、Ronnett Seldon、Atica Moosa、Digby F. Warner、Luca Arista、Ujjini H. Manjunatha、Paul W. Smith、Leslie J. Street、Kelly Chibale

  DOI：10.1021/acs.jmedchem.5b01542

  日期：2015.12.10

  High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (Delta cydKO) was hypersusceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cyto chrome bc1 complex, a validated drug target in M. tuberculosis.