5-cyclopropyl-1-(2,6-difluorobenzyl)-3-isothiocyanato-1H-pyrazole | 1473417-31-0

• 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: 5-cyclopropyl-1-(2,6-difluorobenzyl)-3-isothiocyanato-1H-pyrazole
• CAS: 1473417-31-0
• 化学式: C₁₄H₁₁F₂N₃S
• 分子量: 291.324
• InChiKey: BWYSFHVMIXDYGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.82
• 重原子数：
  20.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  30.18
• 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 、 5-cyclopropyl-1-(2,6-difluorobenzyl)-3-isothiocyanato-1H-pyrazole 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (N-(5-cyclopropyl-1-(2,6-difluorobenzyl)-1H-pyrazol-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