1-(5-((5-cyclopropyl-1-(2,6-difluorobenzyl)-1H-pyrazol-3-yl)amino)-1,3,4-thiadiazol-2-yl)-1-(4-methylthiazol-2-yl)-ethanol | 1473417-18-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(5-((5-cyclopropyl-1-(2,6-difluorobenzyl)-1H-pyrazol-3-yl)amino)-1,3,4-thiadiazol-2-yl)-1-(4-methylthiazol-2-yl)-ethanol
• 英文别名: 1-[5-[[5-Cyclopropyl-1-[(2,6-difluorophenyl)methyl]pyrazol-3-yl]amino]-1,3,4-thiadiazol-2-yl]-1-(4-methylthiazol-2-yl)ethanol；1-[5-[[5-cyclopropyl-1-[(2,6-difluorophenyl)methyl]pyrazol-3-yl]amino]-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
• CAS: 1473417-18-3
• 化学式: C₂₁H₂₀F₂N₆OS₂
• 分子量: 474.558
• InChiKey: SRTAYMOEKZXGSO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  145
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-羟基-2-(4-甲基-1,3-噻唑-2-基)丙酸乙酯 在 硫酸 、 一水合肼 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 7.0h， 生成 1-(5-((5-cyclopropyl-1-(2,6-difluorobenzyl)-1H-pyrazol-3-yl)amino)-1,3,4-thiadiazol-2-yl)-1-(4-methylthiazol-2-yl)-ethanol
  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