(2S,4R)-methyl 1-(benzofuran-3-carbonyl)-4-(3-ethyl-1-methyl-1H-pyrazole-5-carboxamido)pyrrolidine-2-carboxylatea | 1558040-45-1

• 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: (2S,4R)-methyl 1-(benzofuran-3-carbonyl)-4-(3-ethyl-1-methyl-1H-pyrazole-5-carboxamido)pyrrolidine-2-carboxylatea
• 英文别名: (4R)-1-(1-benzofuran-3-ylcarbonyl)-4-{[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-L-prolinate；methyl (2S,4R)-1-(1-benzofuran-3-carbonyl)-4-[(5-ethyl-2-methylpyrazole-3-carbonyl)amino]pyrrolidine-2-carboxylate
• CAS: 1558040-45-1
• 化学式: C₂₂H₂₄N₄O₅
• 分子量: 424.456
• InChiKey: FJQNJOUUZJZMOP-KDOFPFPSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S,4R)-methyl 1-(benzofuran-3-carbonyl)-4-(3-ethyl-1-methyl-1H-pyrazole-5-carboxamido)pyrrolidine-2-carboxylatea 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-((3R,5S)-1-(benzofuran-3-carbonyl)-5-(diethylcarbamoyl)pyrrolidin-3-yl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide
  参考文献：
  名称：

  Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium tuberculosis InhA

  摘要：

  Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.

  DOI：

  10.1021/jm401326j
• 作为产物：
  描述：

  N-Boc-反式-4-氨基-L-脯氨酸甲酯 在 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (2S,4R)-methyl 1-(benzofuran-3-carbonyl)-4-(3-ethyl-1-methyl-1H-pyrazole-5-carboxamido)pyrrolidine-2-carboxylatea
  参考文献：
  名称：

  Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium tuberculosis InhA

  摘要：

  Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.

  DOI：

  10.1021/jm401326j

文献信息

• Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of <i>Mycobacterium tuberculosis</i> InhA
  作者：Lourdes Encinas、Heather O’Keefe、Margarete Neu、Modesto J. Remuiñán、Amish M. Patel、Ana Guardia、Christopher P. Davie、Natalia Pérez-Macías、Hongfang Yang、Maire A. Convery、Jeff A. Messer、Esther Pérez-Herrán、Paolo A. Centrella、Daniel Álvarez-Gómez、Matthew A. Clark、Sophie Huss、Gary K. O’Donovan、Fátima Ortega-Muro、William McDowell、Pablo Castañeda、Christopher C. Arico-Muendel、Stane Pajk、Joaquín Rullás、Iñigo Angulo-Barturen、Emilio Álvarez-Ruíz、Alfonso Mendoza-Losana、Lluís Ballell Pages、Julia Castro-Pichel、Ghotas Evindar

  DOI：10.1021/jm401326j

  日期：2014.2.27

  Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.