3-(2,6-difluorobenzyl)-5-((5-(1-hydroxy-1-(4-methylthiazol-2-yl)ethyl)-1,3,4-thiadiazol-2-ylamino)methyl)oxazolidin-2-one | 1473417-19-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(2,6-difluorobenzyl)-5-((5-(1-hydroxy-1-(4-methylthiazol-2-yl)ethyl)-1,3,4-thiadiazol-2-ylamino)methyl)oxazolidin-2-one
• 英文别名: 3-[(2,6-Difluorophenyl)methyl]-5-[[[5-[1-hydroxy-1-(4-methylthiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-yl]amino]methyl]oxazolidin-2-one；3-[(2,6-difluorophenyl)methyl]-5-[[[5-[1-hydroxy-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-yl]amino]methyl]-1,3-oxazolidin-2-one
• CAS: 1473417-19-4
• 化学式: C₁₉H₁₉F₂N₅O₃S₂
• 分子量: 467.52
• InChiKey: CYBRTJWKDSMQDV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  157
• 氢给体数：
  2
• 氢受体数：
  11

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 6.83h， 生成 3-(2,6-difluorobenzyl)-5-((5-(1-hydroxy-1-(4-methylthiazol-2-yl)ethyl)-1,3,4-thiadiazol-2-ylamino)methyl)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