4-(8-(benzylamino)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl)-N'-(2,3,4-trihydroxybenzylidene)butanehydrazide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 4-(8-(benzylamino)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl)-N'-(2,3,4-trihydroxybenzylidene)butanehydrazide
• 英文别名: (4-(8-(benzylamino-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl)-N’-2,3,4-trihydroxybenzylidene))
• 化学式: C₂₅H₂₇N₇O₆
• 分子量: 521.533
• InChiKey: XHCLEDFUONOPHD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.09
• 重原子数：
  38.0
• 可旋转键数：
  9.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  176.0
• 氢给体数：
  5.0
• 氢受体数：
  12.0

反应信息

• 作为产物：
  描述：

  8-溴茶碱 在 盐酸 、 hydrazine hydrate 、 苄基三乙基氯化铵 、 potassium carbonate 作用下， 以 甲醇 、 乙醇 、 乙二醇甲醚 、 丙酮 为溶剂， 反应 172.0h， 生成 4-(8-(benzylamino)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl)-N'-(2,3,4-trihydroxybenzylidene)butanehydrazide
  参考文献：
  名称：

  新型嘌呤-2,6-二酮丁酰肼衍生物作为具有潜在抗炎活性的双重PDE4 / 7抑制剂：设计，合成和生物学评估。

  摘要：

  合成了一种新的基于配体的方法设计的嘌呤-2,6-二酮丁酰肼衍生物，并评估了它们对PDE4B和PDE7A同工酶的体外活性。7,8-二取代嘌呤-2,6-二酮衍生物31、34、37和40似乎是最有效的PDE4 / 7抑制剂，IC50值分别在参考咯利普兰和BRL-50481范围内。 。此外，对接研究解释了嘌呤-2,6-二酮核的7位上的N-（2,3,4-三羟基亚苄基）丁酰肼取代基对于双重PDE4 / 7抑制特性的重要性。两种cAMP特异性PDE同工酶的抑制作用均会产生强大的抗TNF-α作用。在体内研究中，LPS诱导的内毒素血症大鼠体内的化合物31、34和37使该促炎细胞因子的最大浓度降低了53，

  DOI：

  10.1016/j.ejmech.2018.01.068

文献信息

• Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling
  作者：Katarzyna Wójcik-Pszczoła、Grażyna Chłoń-Rzepa、Agnieszka Jankowska、Eugenie Ellen、Artur Świerczek、Krzysztof Pociecha、Paulina Koczurkiewicz、Kamil Piska、Anna Gawędzka、Elżbieta Wyska、Małgorzata Knapik-Czajka、Elżbieta Pękala、Reinoud Gosens

  DOI：10.1016/j.ejphar.2019.172779

  日期：2019.12

  Airway remodelling (AR) is an important pathological feature of chronic asthma and chronic obstructive pulmonary disease. The etiology of AR is complex and involves both lung structural and immune cells. One of the main contributors to airway remodelling is the airway smooth muscle (ASM), which is thickened by asthma, becomes more contractile and produces more extracellular matrix. As a second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to contribute to ASM cell (ASMC) relaxation as well as to anti-remodelling effects in ASMC. Phosphodiesterase (PDE) inhibitors have drawn attention as an interesting new group of potential anti-inflammatory and anti-remodelling drugs. Recently, new hydrazide and amide purine-2,6-dione derivatives with anti-inflammatory properties have been synthesized by our team (compounds 1 and 2). We expanded our study of their PDE selectivity profile, ability to increase intracellular cAMP levels, metabolic stability and, above all, their capacity to modulate cell responses associated with ASMC remodelling. The results show that both compounds have subtype specificity for several PDE isoforms (including inhibition of PDE1, PDE3, PDE4 and PDE7). Interestingly, such combined PDE subtype inhibition exerts improved anti-remodelling efficacies against several ASMC-induced responses such as proliferation, contractility, extracellular matrix (ECM) protein expression and migration when compared to other non-selective and selective PDE inhibitors. Our findings open novel perspectives in the search for new chemical entities with dual anti-inflammatory and anti-remodelling profiles in the group of purine-2,6-dione derivatives as broad-spectrum PDE inhibitors.
• Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation
  作者：Grażyna Chłoń-Rzepa、Agnieszka Jankowska、Marietta Ślusarczyk、Artur Świerczek、Krzysztof Pociecha、Elżbieta Wyska、Adam Bucki、Alicja Gawalska、Marcin Kołaczkowski、Maciej Pawłowski

  DOI：10.1016/j.ejmech.2018.01.068

  日期：2018.2

  A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively

  合成了一种新的基于配体的方法设计的嘌呤-2,6-二酮丁酰肼衍生物，并评估了它们对PDE4B和PDE7A同工酶的体外活性。7,8-二取代嘌呤-2,6-二酮衍生物31、34、37和40似乎是最有效的PDE4 / 7抑制剂，IC50值分别在参考咯利普兰和BRL-50481范围内。 。此外，对接研究解释了嘌呤-2,6-二酮核的7位上的N-（2,3,4-三羟基亚苄基）丁酰肼取代基对于双重PDE4 / 7抑制特性的重要性。两种cAMP特异性PDE同工酶的抑制作用均会产生强大的抗TNF-α作用。在体内研究中，LPS诱导的内毒素血症大鼠体内的化合物31、34和37使该促炎细胞因子的最大浓度降低了53，