4,4,4-trifluoro-1-[3-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)-azetidin-1-yl]-butan-1-one | 1286708-56-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4,4,4-trifluoro-1-[3-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)-azetidin-1-yl]-butan-1-one
• 英文别名: 4,4,4-Trifluoro-1-[3-[3-(2-thienyl)-1,2,4-oxadiazol-5-yl]azetidin-1-yl]butan-1-one；4,4,4-trifluoro-1-[3-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)azetidin-1-yl]butan-1-one
• CAS: 1286708-56-2
• 化学式: C₁₃H₁₂F₃N₃O₂S
• 分子量: 331.318
• InChiKey: QRMLGMSLHRDBEZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  87.5
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-氰基噻吩 在 盐酸 、 盐酸羟胺 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.16h， 生成 4,4,4-trifluoro-1-[3-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)-azetidin-1-yl]-butan-1-one
  参考文献：
  名称：

  Ethionamide Boosters: Synthesis, Biological Activity, and Structure−Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors

  摘要：

  We report in this article an extensive structure activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were 6:Insistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.

  DOI：

  10.1021/jm200076a

文献信息

• Ethionamide Boosters: Synthesis, Biological Activity, and Structure−Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors
  作者：Marion Flipo、Matthieu Desroses、Nathalie Lecat-Guillet、Bertrand Dirié、Xavier Carette、Florence Leroux、Catherine Piveteau、Fatma Demirkaya、Zoé Lens、Prakash Rucktooa、Vincent Villeret、Thierry Christophe、Hee Kyoung Jeon、Camille Locht、Priscille Brodin、Benoit Déprez、Alain R. Baulard、Nicolas Willand

  DOI：10.1021/jm200076a

  日期：2011.4.28

  We report in this article an extensive structure activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were 6:Insistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.