4-(benzyloxy)-1,2,5-oxadiazole-3-carboxylic acid | 1226869-66-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(benzyloxy)-1,2,5-oxadiazole-3-carboxylic acid
• 英文别名: 4-phenylmethoxy-1,2,5-oxadiazole-3-carboxylic acid
• CAS: 1226869-66-4
• 化学式: C₁₀H₈N₂O₄
• 分子量: 220.185
• InChiKey: JXULQGNKFYMSJX-UHFFFAOYSA-N

物化性质

• 熔点：
  106-107 °C(Solv: isopropyl ether (108-20-3); hexane (110-54-3))
• 沸点：
  410.5±53.0 °C(Predicted)
• 密度：
  1.412±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  85.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(benzyloxy)-1,2,5-oxadiazole-3-carboxylic acid 在 吡啶 、 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成 4-benzyloxy-N-[2,3,5,6-tetrafluoro-3'-trifluoromethylbiphenyl-4-yl]-1,2,5-oxadiazole-3-carboxamide
  参考文献：
  名称：

  New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy-1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold

  摘要：

  Based on some structural analogies with leflunomide and brequinar, two well-known inhibitors of dihydroorotate dehydrogenase (DHODH), a new series of products was designed, by joining the substituted biphenyl moiety to the 4-hydroxy-1,25-oxadiazol-3-yl scaffold through an amide bridge. The compounds were studied for their DHODH inhibitory activity on rat liver mitochondrial/microsomal membranes. The activity was found to be closely dependent on the substitution pattern at the biphenyl system; the most potent products were those bearing two or four fluorine atoms at the phenyl adjacent to the oxadiazole ring. A molecular modeling study suggested that these structures might have a bre-quinar-like binding mode. The greater potency of fluorinated analogs may depend partly on enhanced interactions with the hydrophobic ubiquinone channel, and partly on the role of fluorine in stabilizing the putative bioactive conformation. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.12.038
• 作为产物：
  描述：

  methyl 4-(benzyloxy)-1,2,5-oxadiazole-3-carboxylate 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 生成 4-(benzyloxy)-1,2,5-oxadiazole-3-carboxylic acid
  参考文献：
  名称：

  羟三唑衍生物作为有效的和选择性的醛酮还原酶1C3（AKR1C3）抑制剂，通过生物等排支架跳跃方法发现

  摘要：

  醛酮还原酶1C3亚型（AKR1C3）在雄激素的生物合成中起着至关重要的作用，使该酶成为去势抵抗性前列腺癌治疗的诱人靶标。尽管AKR1C3是有前途的药物靶标，但迄今为止尚未批准任何AKR1C3靶向剂用于临床。氟苯那酸是一种非甾体类抗炎药，已知会以非选择性方式有效抑制AKR1C3，因为还观察到了COX脱靶作用。为了减少脱靶效应，我们应用了一种支架跳跃策略，将氟苯那酸的苯甲酸部分替换为酸性羟唑羰基支架。特别是N取代的羟基化三唑被设计为同时与AKR1C3活性位点中的亚位1和2相互作用，对于AKR1C3而言，它比其他AKR1Cs同工型更大。通过计算设计以及合成和生物学评估的迭代轮次，报道了新型化合物，它们对AKR1C3的选择性高于1C2亚型（高达230倍），并且对COX1和COX2的脱靶抑制作用最小。化合物8的对接研究，该系列中最有趣的化合物，表明其甲氧基苄基取代基能够嵌入子链2内，参与与Trp22

  DOI：

  10.1016/j.ejmech.2017.08.046

文献信息

• 4-Hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: a novel inhibitor of the canonical NF-κB cascade
  作者：Agnese C. Pippione、Antonella Federico、Alex Ducime、Stefano Sainas、Donatella Boschi、Alessandro Barge、Elisa Lupino、Marco Piccinini、Michael Kubbutat、Jean-Marie Contreras、Christophe Morice、Salam Al-Karadaghi、Marco L. Lolli

  DOI：10.1039/c7md00278e

  日期：——

  Compound 4, derived from IMD-0354, blocks the canonical NF-κB pathway although it is inactive on the IKKβ enzyme.

  化合物4，源自IMD-0354，尽管对IKKβ酶无效，但可以阻断经典NF-κB途径。
• 4-Hydroxy-1,2,5-oxadiazol-3-yl Moiety as Bioisoster of the Carboxy Function. Synthesis, Ionization Constants, and Molecular Pharmacological Characterization at Ionotropic Glutamate Receptors of Compounds Related to Glutamate and Its Homologues
  作者：Marco L. Lolli、Cecilia Giordano、Darryl S. Pickering、Barbara Rolando、Kasper B. Hansen、Antonio Foti、Alberto Contreras-Sanz、Ahmad Amir、Roberta Fruttero、Alberto Gasco、Birgitte Nielsen、Tommy N. Johansen

  DOI：10.1021/jm1001452

  日期：2010.5.27

  In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 mu M at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
• New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy-1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold
  作者：Marco L. Lolli、Marta Giorgis、Paolo Tosco、Antonio Foti、Roberta Fruttero、Alberto Gasco

  DOI：10.1016/j.ejmech.2011.12.038

  日期：2012.3

  Based on some structural analogies with leflunomide and brequinar, two well-known inhibitors of dihydroorotate dehydrogenase (DHODH), a new series of products was designed, by joining the substituted biphenyl moiety to the 4-hydroxy-1,25-oxadiazol-3-yl scaffold through an amide bridge. The compounds were studied for their DHODH inhibitory activity on rat liver mitochondrial/microsomal membranes. The activity was found to be closely dependent on the substitution pattern at the biphenyl system; the most potent products were those bearing two or four fluorine atoms at the phenyl adjacent to the oxadiazole ring. A molecular modeling study suggested that these structures might have a bre-quinar-like binding mode. The greater potency of fluorinated analogs may depend partly on enhanced interactions with the hydrophobic ubiquinone channel, and partly on the role of fluorine in stabilizing the putative bioactive conformation. (C) 2012 Elsevier Masson SAS. All rights reserved.
• Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach
  作者：Agnese C. Pippione、Alessandro Giraudo、Davide Bonanni、Irene M. Carnovale、Elisabetta Marini、Clara Cena、Annalisa Costale、Daniele Zonari、Klaus Pors、Maria Sadiq、Donatella Boschi、Simonetta Oliaro-Bosso、Marco L. Lolli

  DOI：10.1016/j.ejmech.2017.08.046

  日期：2017.10

  Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles

  醛酮还原酶1C3亚型（AKR1C3）在雄激素的生物合成中起着至关重要的作用，使该酶成为去势抵抗性前列腺癌治疗的诱人靶标。尽管AKR1C3是有前途的药物靶标，但迄今为止尚未批准任何AKR1C3靶向剂用于临床。氟苯那酸是一种非甾体类抗炎药，已知会以非选择性方式有效抑制AKR1C3，因为还观察到了COX脱靶作用。为了减少脱靶效应，我们应用了一种支架跳跃策略，将氟苯那酸的苯甲酸部分替换为酸性羟唑羰基支架。特别是N取代的羟基化三唑被设计为同时与AKR1C3活性位点中的亚位1和2相互作用，对于AKR1C3而言，它比其他AKR1Cs同工型更大。通过计算设计以及合成和生物学评估的迭代轮次，报道了新型化合物，它们对AKR1C3的选择性高于1C2亚型（高达230倍），并且对COX1和COX2的脱靶抑制作用最小。化合物8的对接研究，该系列中最有趣的化合物，表明其甲氧基苄基取代基能够嵌入子链2内，参与与Trp22