4-[5-[Bis(4-methylphenyl)sulfamoyl]-2,4-dimethoxyanilino]-4-oxobutanoic acid | 1411995-54-4

• 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: 4-[5-[Bis(4-methylphenyl)sulfamoyl]-2,4-dimethoxyanilino]-4-oxobutanoic acid
• 英文别名: 4-[5-[bis(4-methylphenyl)sulfamoyl]-2,4-dimethoxyanilino]-4-oxobutanoic acid
• CAS: 1411995-54-4
• 化学式: C₂₆H₂₈N₂O₇S
• 分子量: 512.584
• InChiKey: KSPFXCDJIGBEQP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  36
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  131
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,4-二甲氧基苯胺 在 吡啶 、 盐酸 、 氯磺酸 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 lithium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 乙腈 为溶剂， 反应 58.0h， 生成 4-[5-[Bis(4-methylphenyl)sulfamoyl]-2,4-dimethoxyanilino]-4-oxobutanoic acid
  参考文献：
  名称：

  Inhibitors of the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridylyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 2: Optimization of physical properties leading to antibacterial aryl sulfonamides

  摘要：

  A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low Log D and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC50 <0.1 mu M against GlmU isozymes from Gram-negative organisms), and the lipophilicity was increased giving compounds with Log D -1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.003

文献信息

• Inhibitors of the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridylyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 2: Optimization of physical properties leading to antibacterial aryl sulfonamides
  作者：Suzanne S. Stokes、Robert Albert、Ed T. Buurman、Beth Andrews、Adam B. Shapiro、Oluyinka M. Green、Andrew R. McKenzie、Ludovic R. Otterbein

  DOI：10.1016/j.bmcl.2012.10.003

  日期：2012.12

  A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low Log D and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC50 <0.1 mu M against GlmU isozymes from Gram-negative organisms), and the lipophilicity was increased giving compounds with Log D -1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13. (C) 2012 Elsevier Ltd. All rights reserved.