N-(3-methoxyphenyl)-N-methyl-2,3-dioxo-1,2,3,4-tetrahydro-6-quinoxalinesulfonamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-(3-methoxyphenyl)-N-methyl-2,3-dioxo-1,2,3,4-tetrahydro-6-quinoxalinesulfonamide
• 英文别名: N-(3-methoxyphenyl)-N-methyl-2,3-dioxo-1,4-dihydroquinoxaline-6-sulfonamide
• 化学式: C₁₆H₁₅N₃O₅S
• 分子量: 361.378
• InChiKey: ZYUVUTFKMHIMBV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-甲基-3-甲氧基苯胺 、 2,3-二氧代-1,2,3,4-四氢喹噁啉-6-磺酰氯 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 以17%的产率得到N-(3-methoxyphenyl)-N-methyl-2,3-dioxo-1,2,3,4-tetrahydro-6-quinoxalinesulfonamide
  参考文献：
  名称：

  Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis

  摘要：

  A two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis. Rational systematic derivatization of this scaffold to maximize Eis inhibition and abolish the Eis-mediated KAN resistance of M. tuberculosis yielded several highly potent agents. A crystal structure of Eis in complex with one of the most potent inhibitors revealed that the inhibitor bound Eis in the AG-binding pocket held by a conformationally malleable region of Eis (residues 28-37) bearing key hydrophobic residues. These Eis inhibitors are promising leads for preclinical development of innovative AG combination therapies against resistant TB.

  DOI：

  10.1021/acs.jmedchem.6b01161

文献信息

• Eis inhibitors
  申请人：University of Kentucky Research Foundation

  公开号：US10208000B2

  公开（公告）日：2019-02-19

  Provided herein are novel small-molecules that have use in the inhibition of Eis, which mediates kanamycin resistance in Mycobacterium tuberculosis. The presently-disclosed subject matter further includes a pharmaceutical composition including a small molecule inhibitor, as described herein, and a suitable pharmaceutical carrier. Methods of treating tuberculosis comprising administering to an individual an effective amount of the disclosed small molecule inhibitors to mediate kanamycin A resistance and treat tuberculosis are also provided.

  本文提供的新型小分子可用于抑制介导结核分枝杆菌卡那霉素耐药性的 Eis。目前公开的主题还包括一种药物组合物，其中包括本文所述的小分子抑制剂和合适的药物载体。还提供了治疗结核病的方法，包括向个体施用有效量的所公开的小分子抑制剂，以介导卡那霉素 A 抗性和治疗结核病。
• EIS INHIBITORS
  申请人：University of Kentucky Research Foundation

  公开号：US20170174639A1

  公开（公告）日：2017-06-22

  Provided herein are novel small-molecules that have use in the inhibition of Eis, which mediates kanamycin resistance in Mycobacterium tuberculosis . The presently-disclosed subject matter further includes a pharmaceutical composition including a small molecule inhibitor, as described herein, and a suitable pharmaceutical carrier. Methods of treating tuberculosis comprising administering to an individual an effective amount of the disclosed small molecule inhibitors to mediate kanamycin A resistance and treat tuberculosis are also provided.
• Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in <i>Mycobacterium tuberculosis</i>
  作者：Atefeh Garzan、Melisa J. Willby、Keith D. Green、Chathurada S. Gajadeera、Caixia Hou、Oleg V. Tsodikov、James E. Posey、Sylvie Garneau-Tsodikova

  DOI：10.1021/acs.jmedchem.6b01161

  日期：2016.12.8

  A two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis. Rational systematic derivatization of this scaffold to maximize Eis inhibition and abolish the Eis-mediated KAN resistance of M. tuberculosis yielded several highly potent agents. A crystal structure of Eis in complex with one of the most potent inhibitors revealed that the inhibitor bound Eis in the AG-binding pocket held by a conformationally malleable region of Eis (residues 28-37) bearing key hydrophobic residues. These Eis inhibitors are promising leads for preclinical development of innovative AG combination therapies against resistant TB.