1-(5-(4-(2,6-difluorobenzyl)pyrimidin-2-ylamino)-1,3,4-thiadiazol-2-yl)-1-(4-methylthiazol-2-yl)ethanol | 1473417-17-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1-(5-(4-(2,6-difluorobenzyl)pyrimidin-2-ylamino)-1,3,4-thiadiazol-2-yl)-1-(4-methylthiazol-2-yl)ethanol
• 英文别名: 1-[5-[[4-[(2,6-Difluorophenyl)methyl]pyrimidin-2-yl]amino]-1,3,4-thiadiazol-2-yl]-1-(4-methylthiazol-2-yl)ethanol；1-[5-[[4-[(2,6-difluorophenyl)methyl]pyrimidin-2-yl]amino]-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
• CAS: 1473417-17-2
• 化学式: C₁₉H₁₆F₂N₆OS₂
• 分子量: 446.504
• InChiKey: DPHUWWUEQQHWPC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  153
• 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 7.0h， 生成 1-(5-(4-(2,6-difluorobenzyl)pyrimidin-2-ylamino)-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

文献信息

• Methyl-Thiazoles: A Novel Mode of Inhibition with the Potential to Develop Novel Inhibitors Targeting InhA in Mycobacterium tuberculosis
  作者：Pravin S. Shirude、Prashanti Madhavapeddi、Maruti Naik、Kannan Murugan、Vikas Shinde、Radha Nandishaiah、Jyothi Bhat、Anupriya Kumar、Shahul Hameed、Geoffrey Holdgate、Gareth Davies、Helen McMiken、Naina Hegde、Anisha Ambady、Janani Venkatraman、Manoranjan Panda、Balachandra Bandodkar、Vasan K. Sambandamurthy、Jon A. Read

  DOI：10.1021/jm4012033

  日期：2013.11.14

  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.