1-(2,6-difluorobenzyl)-3-isothiocyanato-1H-1,2,4-triazole | 1473417-25-2

• 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: 1-(2,6-difluorobenzyl)-3-isothiocyanato-1H-1,2,4-triazole
• CAS: 1473417-25-2
• 化学式: C₁₀H₆F₂N₄S
• 分子量: 252.247
• InChiKey: RGNCQWVJUIDGIK-UHFFFAOYSA-N

物化性质

• 沸点：
  387.0±52.0 °C(predicted)
• 密度：
  1.43±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.34
• 重原子数：
  17.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  43.07
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  2-hydroxy-2-(4-methylthiazol-2-yl)propanehydrazide 、 1-(2,6-difluorobenzyl)-3-isothiocyanato-1H-1,2,4-triazole 以 二氯甲烷 为溶剂， 反应 0.5h， 以46.4%的产率得到N-(1-(2,6-difluorobenzyl)-1H-1,2,4-triazol-3-yl)-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