N-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl-methyl]phthalimide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: N-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl-methyl]phthalimide
• 英文别名: 2-((3-p-tolyl-[1,2,4]oxadiazol-5-yl)methyl)isoindole-1,3-dione；2-{[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-isoindole-1,3(2H)-dione；2-[[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]isoindole-1,3-dione
• 化学式: C₁₈H₁₃N₃O₃
• mdl: MFCD05853938
• 分子量: 319.32
• InChiKey: LNRMVXWABDWMTA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  76.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl-methyl]phthalimide 在 肼 作用下， 以 乙醇 为溶剂， 反应 0.5h， 以77%的产率得到1-[3-(4-甲基苯基)-1,2,4-恶二唑-5-基]甲胺
  参考文献：
  名称：

  [EN] PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS
  [FR] INHIBITION DE CHYMOTRYPSINE-LIKE DU PROTÉASOME À L'AIDE D'ANALOGUES DE PI-1833

  摘要：

  公开号：

  WO2012129564A3
• 作为产物：
  描述：

  邻苯二甲酰甘氨酸 在 N,N'-二环己基碳二亚胺 作用下， 以 乙二醇二甲醚 为溶剂， 生成 N-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl-methyl]phthalimide
  参考文献：
  名称：

  具有有效止痛活性的新型邻苯二甲酰亚胺衍生物：II。

  摘要：

  由N-邻苯二甲酰基甘氨酸6和芳酰胺基肟7a-g合成了七个新的具有与氮相连的1,2,4-恶二唑-5-基甲基的邻苯二甲酰亚胺衍生物（9a-g）。所有这些都显示了乙酸引起的小鼠“扭体”试验的有效镇痛作用。发现更好的化合物之一（ID50 = 2.2 mg / Kg ip）为9a，它也显示出抗炎性疼痛的镇痛活性。

  DOI：

  10.1016/s0960-894x(98)00558-7

文献信息

• Oxadiazole-isopropylamides as Potent and Noncovalent Proteasome Inhibitors
  作者：Sevil Ozcan、Aslamuzzaman Kazi、Frank Marsilio、Bin Fang、Wayne C. Guida、John Koomen、Harshani R. Lawrence、Saïd M. Sebti

  DOI：10.1021/jm400221d

  日期：2013.5.23

  inhibited chymotrypsin-like (CT-L) activity (IC50 = 0.60 μM) with little effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L). LC–MS/MS and dialysis show that 1 is a noncovalent and rapidly reversible CT-L inhibitor. Focused library synthesis provided 11ad (PI-1840) with CT-L activity (IC50 = 27 nM). Detailed SAR studies

  对 50 000 ChemBridge 化合物库的筛选导致鉴定出恶二唑-异丙基酰胺1 (PI-1833)，其抑制胰凝乳蛋白酶样 (CT-L) 活性（IC 50 = 0.60 μM），对其他两种主要蛋白酶体几乎没有影响蛋白水解活性，胰蛋白酶样 (TL) 和谷氨酰肽水解样 (PGPH-L)。LC-MS/MS 和透析表明1是一种非共价且快速可逆的 CT-L 抑制剂。集中文库合成为11ad (PI-1840) 提供了 CT-L 活性 (IC 50= 27 纳米）。详细的 SAR 研究表明酰胺部分和两个苯环对修饰敏感。疏水性残基，如在对位丙基或丁基（未邻位或间位）的A环和一个的米-吡啶基团作为B环，显著提高活性。化合物11ad (IC 50 = 0.37 μM)在抑制完整 MDA-MB-468 人乳腺癌细胞中的 CT-L 活性和抑制其存活方面比1 (IC 50 = 3.5 μM)更有效。11ad的活
• PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS
  申请人：H. Lee Moffitt Cancer Center and Research Institute, Inc

  公开号：US20140073650A1

  公开（公告）日：2014-03-13

  Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

  聚焦于氧代二唑-异丙酰胺核心蛋白酶体抑制剂的合成和药物化学，提供了一种强烈抑制CT-L活性的先导化合物。结构活性关系研究表明，酰胺基团和两个苯环对合成修饰非常敏感。只有在A环上的对位取代对维持强效的CT-L抑制活性至关重要。A环对位的疏水基团和B环的间吡啶基团显著提高了抑制作用。间吡啶基团提高了细胞渗透性。A环对位的脂肪链长度是关键，丙基产生了最有效的抑制剂，而较短（即乙基，甲基或氢）或较长（即丁基，异丙基和己基）的链逐渐表现出较少的效力。在醚基团旁引入一个立体异构中心（即将一个氢原子取代为甲基）表明在蛋白酶体CT-L活性抑制中具有手性歧视（S-对映体比R-对映体更有效，效力提高了35-40倍）。
• Proteasome chymotrypsin-like inhibition using PI-1833 analogs
  申请人：H. Lee Moffitt Cancer Center and Research Institute, Inc.

  公开号：US10662180B2

  公开（公告）日：2020-05-26

  Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

  通过对一种噁二唑-异丙基酰胺核心蛋白酶体抑制剂进行重点文库合成和药物化学研究，获得了能强烈抑制 CT-L 活性的先导化合物。结构活性关系研究表明，酰胺分子和两个苯基环对合成修饰很敏感。只有 A 环中的对位取代对保持 CT-L 的强效抑制活性非常重要。A 环的对位疏水残基和 B 环的元吡啶基能显著改善抑制作用。偏吡啶基提高了细胞渗透性。A 环对位脂肪族链的长度至关重要，丙基产生的抑制作用最强，而较短的链（即乙基、甲基或氢基）或较长的链（即丁基、丙基和己基）的抑制作用则逐渐减弱。在醚分子旁边引入一个立体中心（即用甲基取代其中一个氢）可在蛋白酶体 CT-L 活性抑制方面显示出手性差异（S-对映体的效力比 R-对映体高 35-40 倍）。
• Synthesis, Molecular Docking, Analgesic, and Anti-Inflammatory Activities of New 1,2,4-Oxadiazolo-Sulfonamides
  作者：M. Vijaya Bhargavi、P. Shashikala、M. Sumakanth、C. Krishna

  DOI：10.1134/s1070363218040278

  日期：2018.4

  In the present study novel 1,2,4-oxadiazolo sulfonamides 3a-3o are synthesized by an efficient method based on the reaction of 1,2,4-oxadiazole amines with aryl sulfonyl chlorides. Structures of the synthesized compounds are confirmed by IR, NMR and Mass spectra. Molecular interactions of the obtained compounds are studied by Discovery Studio v3.5, molecular docking with COX-2 enzyme. The compounds with high LibDock score are screened for their in vivo analgesic and anti inflammatory activities. The compound 3l demonstrates the highest activity.
• Synthesis, characterization and interaction mechanism of new oxadiazolo-phthalimides as peripheral analgesics. IV
  作者：Roberto Antunes、Hildson Batista、Rajendra M. Srivastava、George Thomas、Clidenor C. Araújo、Ricardo L. Longo、Hélio Magalhães、Marcelo B.C. Leão、Antônio C. Pavão

  DOI：10.1016/s0022-2860(03)00418-6

  日期：2003.11

  The synthesis, characterization and spectroscopic studies of compounds 6a-g with analgesic activity is described. A new model of interaction between the drug and the enzyme is suggested. Application of the Resonance Valence Bond theory led us to propose. for the first time, an entirely new mechanism involving an electron transfer from the amino acid residue of the enzyme to the drug. Theoretical studies of various transition states involved in the interaction mechanism employing the semi-empirical molecular orbital calculations (AMI method) have been carried out. This article also deals with an extensive study of the structure-activity relationships of seven oxadiazolo-phthalimides 6a-g. (C) 2003 Elsevier B.V. All rights reserved.