acs.jmedchem.1c00409_ST.75 | 1007551-99-6

• 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: acs.jmedchem.1c00409_ST.75
• 英文别名: (5-chloropyridin-3-yl) 5-(4-chloro-2-nitrophenyl)furan-2-carboxylate
• CAS: 1007551-99-6
• 化学式: C₁₆H₈Cl₂N₂O₅
• 分子量: 379.156
• InChiKey: YEGHZGNCUKGRIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  98.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  5-氯-3-羟基吡啶 、 5-(4-氯-2-硝基苯基)-2-糠酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 acs.jmedchem.1c00409_ST.75
  参考文献：
  名称：

  Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action

  摘要：

  The related 3C and 3C-like proteinase (3C(pro) and 3CL(pro)) of picornaviruses and coronaviruses, respectively, are good drug targets. As part of an effort to generate broad-spectrum inhibitors of these enzymes, we screened a library of inhibitors based on a halopyridinyl ester from a previous study of the severe acute respiratory syndrome (SARS) 3CL proteinase against Hepatitis A virus (HAV) 3C(pro). Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3C(pro) with K-icS of 120-240 nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3C(pro) and SARS 3CL(pro), confirming the identity of the expected products. Mass spectrometric analyses indicated that this hydrolysis proceeded via an acylenzyme intermediate. Modeling studies indicated that the halopyridinyl moiety of the inhibitor fits tightly into the S1-binding pocket, consistent with the lack of tolerance of the inhibitors to modi. cation in this portion of the molecule. These compounds are among the most potent non-peptidic inhibitors reported to date against a 3C(pro). (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.03.059

文献信息

• Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro
  作者：Chunying Niu、Jiang Yin、Jianmin Zhang、John C. Vederas、Michael N.G. James

  DOI：10.1016/j.bmc.2007.09.034

  日期：2008.1

  in complex with these synthetic inhibitors, molecular docking tools have been employed to study possible interactions between these inhibitors and SARS-CoV M(pro). The docking results suggest two major modes for the initial binding of these inhibitors to the active site of SARS-CoV M(pro). They also establish a structural basis for the 'core design' of these inhibitors by showing that the 3-chloropyridine

  严重急性呼吸系统综合症 (SARS) 冠状病毒 SARS-CoV M(pro) 的 3C 样主要蛋白酶被广泛认为是开发抗 SARS 治疗的主要药物靶点。基于先前筛选的先导化合物的化学结构，我们设计并合成了许多非肽基抑制剂，其中一些对 SARS-CoV M(pro) 的抑制活性显着提高，IC(50) 值约 60 nM。在没有与这些合成抑制剂复合的 SARS-CoV M(pro) 晶体结构的情况下，分子对接工具已被用于研究这些抑制剂与 SARS-CoV M(pro) 之间可能的相互作用。对接结果表明这些抑制剂与 SARS-CoV M(pro) 活性位点的初始结合有两种主要模式。他们还通过表明所有现有抑制剂共有的 3-氯吡啶功能倾向于聚集在 S1 特异性口袋中，从而为这些抑制剂的“核心设计”建立了结构基础。此外，S4 口袋内在的灵活性允许容纳苯环等庞大的基团，这表明可以进一步利用这种结构可塑性来
• Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action
  作者：Carly Huitema、Jianmin Zhang、Jiang Yin、Michael N.G. James、John C. Vederas、Lindsay D. Eltis

  DOI：10.1016/j.bmc.2008.03.059

  日期：2008.5

  The related 3C and 3C-like proteinase (3C(pro) and 3CL(pro)) of picornaviruses and coronaviruses, respectively, are good drug targets. As part of an effort to generate broad-spectrum inhibitors of these enzymes, we screened a library of inhibitors based on a halopyridinyl ester from a previous study of the severe acute respiratory syndrome (SARS) 3CL proteinase against Hepatitis A virus (HAV) 3C(pro). Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3C(pro) with K-icS of 120-240 nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3C(pro) and SARS 3CL(pro), confirming the identity of the expected products. Mass spectrometric analyses indicated that this hydrolysis proceeded via an acylenzyme intermediate. Modeling studies indicated that the halopyridinyl moiety of the inhibitor fits tightly into the S1-binding pocket, consistent with the lack of tolerance of the inhibitors to modi. cation in this portion of the molecule. These compounds are among the most potent non-peptidic inhibitors reported to date against a 3C(pro). (C) 2008 Elsevier Ltd. All rights reserved.