3-(2,6-difluorobenzyl)-5-(isothiocyanatomethyl)oxazolidin-2-one | 1473417-33-2

• 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: 3-(2,6-difluorobenzyl)-5-(isothiocyanatomethyl)oxazolidin-2-one
• CAS: 1473417-33-2
• 化学式: C₁₂H₁₀F₂N₂O₂S
• 分子量: 284.286
• InChiKey: QJXCSONLKPEFBH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.39
• 重原子数：
  19.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  41.9
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-hydroxy-2-(4-methylthiazol-2-yl)propanehydrazide 、 3-(2,6-difluorobenzyl)-5-(isothiocyanatomethyl)oxazolidin-2-one 以 二氯甲烷 为溶剂， 反应 0.83h， 以64.4%的产率得到N-((3-(2,6-difluorobenzyl)-2-oxooxazolidin-5-yl)methyl)-2-(2-hydroxy-2-(4-methylthiazol-2-yl)propanoyl)hydrazinecarbothioamide
  参考文献：
  名称：

  Methyl-Thiazoles: A Novel Mode of Inhibition with the Potential to Develop Novel Inhibitors Targeting InhA in Mycobacterium tuberculosis

  摘要：

  InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported "Y158-out" inhibitor-bound conformation of the protein that accommodates a neutrally charged "warhead". An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a K-d of similar to 13.7 nM, as against the NAD(+)-bound form of the enzyme.

  DOI：

  10.1021/jm4012033
• 作为产物：
  描述：

  5-(chloromethyl)-3-(2,6-difluorobenzyl)oxazolidin-2-one 在 sodium azide 、 palladium on activated charcoal 、 碳酸氢钠 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 100.0 ℃ 、241.32 kPa 条件下， 反应 19.08h， 生成 3-(2,6-difluorobenzyl)-5-(isothiocyanatomethyl)oxazolidin-2-one
  参考文献：
  名称：

  Methyl-Thiazoles: A Novel Mode of Inhibition with the Potential to Develop Novel Inhibitors Targeting InhA in Mycobacterium tuberculosis

  摘要：

  InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported "Y158-out" inhibitor-bound conformation of the protein that accommodates a neutrally charged "warhead". An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a K-d of similar to 13.7 nM, as against the NAD(+)-bound form of the enzyme.

  DOI：

  10.1021/jm4012033