(R)-2-(4-fluoro-3-methylphenylsulfonamido)-N-hydroxypropanamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (R)-2-(4-fluoro-3-methylphenylsulfonamido)-N-hydroxypropanamide
• 英文别名: N~2~-[(4-Fluoro-3-Methylphenyl)sulfonyl]-N-Hydroxy-D-Alaninamide；(2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxypropanamide
• 化学式: C₁₀H₁₃FN₂O₄S
• 分子量: 276.289
• InChiKey: PGNDHTMCXOFNMS-SSDOTTSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  在 盐酸羟胺 、 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 16.0h， 以45%的产率得到(R)-2-(4-fluoro-3-methylphenylsulfonamido)-N-hydroxypropanamide
  参考文献：
  名称：

  Probing the S2′ Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates

  摘要：

  The lethal factor (LF) enzyme secreted by Bacillus anthracis is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies of the design of small molecule LF inhibitors have been conducted, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2' subsite has not yet been systematically explored as a potential target for lead optimization. Here we present synthesis, experimental evaluation, modeling, and structural biology for a novel series of sulfonamide hydroxamate LF inhibitor analogues specifically designed to extend into, and probe chemical preferences of, this S2' subsite. We discovered that this region accommodates a wide variety of chemical functionalities and that a broad selection of ligand structural modifications directed to this area can be incorporated without significant deleterious alterations in biological activity. We also identified key residues in this subsite that can potentially be targeted to improve inhibitor binding.

  DOI：

  10.1021/acs.jmedchem.5b01446

文献信息

• The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection
  作者：Yusheng Xiong、Judyann Wiltsie、Andrea Woods、Jian Guo、James V. Pivnichny、Wei Tang、Alka Bansal、Richard T. Cummings、Barry R. Cunningham、Arthur M. Friedlander、Cameron M. Douglas、Scott P. Salowe、Dennis M. Zaller、Edward M. Scolnick、Dennis M. Schmatz、Kenneth Bartizal、Jeffrey D. Hermes、Malcolm MacCoss、Kevin T. Chapman

  DOI：10.1016/j.bmcl.2005.10.088

  日期：2006.2

  A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies. (c) 2005 Elsevier Ltd. All rights reserved.
• Probing the S2′ Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates
  作者：Elbek K. Kurbanov、Ting-Lan Chiu、Jonathan Solberg、Subhashree Francis、Kimberly M. Maize、Jenna Fernandez、Rodney L. Johnson、Jon E. Hawkinson、Michael A. Walters、Barry C. Finzel、Elizabeth Ambrose Amin

  DOI：10.1021/acs.jmedchem.5b01446

  日期：2015.11.12

  The lethal factor (LF) enzyme secreted by Bacillus anthracis is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies of the design of small molecule LF inhibitors have been conducted, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2' subsite has not yet been systematically explored as a potential target for lead optimization. Here we present synthesis, experimental evaluation, modeling, and structural biology for a novel series of sulfonamide hydroxamate LF inhibitor analogues specifically designed to extend into, and probe chemical preferences of, this S2' subsite. We discovered that this region accommodates a wide variety of chemical functionalities and that a broad selection of ligand structural modifications directed to this area can be incorporated without significant deleterious alterations in biological activity. We also identified key residues in this subsite that can potentially be targeted to improve inhibitor binding.