(Z)-5-(4-methoxycarbonylbenzylidene)-2-(p-methylphenyl)thiazol-4(5H)one

• 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: (Z)-5-(4-methoxycarbonylbenzylidene)-2-(p-methylphenyl)thiazol-4(5H)one
• 英文别名: (Z)-methyl 4-((4-oxo-2-(p-tolyl)thiazol-5(4H)-ylidene)methyl)benzoate；methyl (Z)-4-((4-oxo-2-p-tolylthiazol-5(4H)-ylidene)methyl)benzoate；methyl 4-[(Z)-[2-(4-methylphenyl)-4-oxo-1,3-thiazol-5-ylidene]methyl]benzoate
• 化学式: C₁₉H₁₅NO₃S
• 分子量: 337.399
• InChiKey: AZLNFANHCDTUAJ-WJDWOHSUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  81
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  对甲苯腈 在 哌啶 、 三乙胺 作用下， 以 甲醇 为溶剂， 反应 0.42h， 生成 (Z)-5-(4-methoxycarbonylbenzylidene)-2-(p-methylphenyl)thiazol-4(5H)one
  参考文献：
  名称：

  Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy

  摘要：

  Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (IC50 values 0.14 mu M) and cell-free assays (IC50 values 0.03 mu M) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.10.054

文献信息

• Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations
  作者：Kongkai Zhu、Hongrui Tao、Jia-Li Song、Lu Jin、Yuanyuan Zhang、Jingqiu Liu、Zhifeng Chen、Cheng-Shi Jiang、Cheng Luo、Hua Zhang

  DOI：10.1016/j.bioorg.2018.08.021

  日期：2018.12

  mantel cell lymphoma. In the present study, 11 novel PRMT5 inhibitors with 5-benzylidene-2-phenylthiazolone scaffold were identified by molecular docking-based virtual screening and structural optimization. Their IC50 values against PRMT5 at enzymatic level were ranging from 0.77 to 23 μM. As expected, the top two active hits (5 and 19) showed potent anti-proliferative activity against MV4-11 cells with

  蛋白质精氨酸甲基转移酶5（PRMT5）是一种表观遗传学相关的酶，已被证实是胶质母细胞瘤和壁炉细胞淋巴瘤的重要治疗靶标。在本研究中，通过基于分子对接的虚拟筛选和结构优化，鉴定了11种新颖的具有5-亚苄基-2-苯基噻唑酮骨架的PRMT5抑制剂。在酶促水平下，它们针对PRMT5的IC 50值为0.77至23μM。如预期的那样，前两个有效命中位点（5和19）显示出对MV4-11细胞的有效抗增殖活性，其EC 50值低于10μM，并降低了SmD3蛋白的细胞对称精氨酸二甲基化水平。此外5和19在细胞周期停滞和凋亡效应中证明了细胞杀伤的机制。探索了这两种化合物的可能结合方式，并通过分子动力学模拟进一步验证了它们的结合方式。还讨论了此类结构的结构-活性关系（SAR），并通过分子对接模拟进一步证明了这一关系。
• Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy
  作者：Andreas P. Lill、Carmen B. Rödl、Dieter Steinhilber、Holger Stark、Bettina Hofmann

  DOI：10.1016/j.ejmech.2014.10.054

  日期：2015.1

  Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (IC50 values 0.14 mu M) and cell-free assays (IC50 values 0.03 mu M) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy. (C) 2014 Elsevier Masson SAS. All rights reserved.