6-chloro-2-(2,4-dichlorophenoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6-chloro-2-(2,4-dichlorophenoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine
• 化学式: C₁₉H₁₂Cl₃N₃O₂
• 分子量: 420.682
• InChiKey: GUDINIUSGMZTHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  60.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  6-氯喹唑啉-2,4-二酮 在 盐酸 、 三乙胺 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 31.0h， 生成 6-chloro-2-(2,4-dichlorophenoxy)-N-(furan-2-ylmethyl)quinazolin-4-amine
  参考文献：
  名称：

  Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists

  摘要：

  Protease-activated receptor 2 (PAR(2)) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR(2) may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4-amino-quinazoline derivatives as PAR(2) antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8 mu M. Binding modes of the newly identified PAR(2) antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR(2) homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E-2 (PGE(2)), interleukin- 1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) through the regulation of various intracellular signaling pathways involving nuclear factor-kappa B (NF-kappa B), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS-induced sepsis in mice. These results provide useful insights into the development of novel PAR(2) antagonists with anti-inflammatory activity in vitro and in vivo. (c) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.11.016

文献信息

• Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists
  作者：Nam-Chul Cho、Ji Hyoun Cha、Hyojin Kim、Jinsook Kwak、Dohee Kim、Seung-Hwan Seo、Ji-Sun Shin、TaeHun Kim、Ki Duk Park、Jiyoun Lee、Kyoung Tai No、Yun Kyung Kim、Kyung-Tae Lee、Ae Nim Pae

  DOI：10.1016/j.bmc.2015.11.016

  日期：2015.12

  Protease-activated receptor 2 (PAR(2)) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR(2) may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4-amino-quinazoline derivatives as PAR(2) antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8 mu M. Binding modes of the newly identified PAR(2) antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR(2) homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E-2 (PGE(2)), interleukin- 1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) through the regulation of various intracellular signaling pathways involving nuclear factor-kappa B (NF-kappa B), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS-induced sepsis in mice. These results provide useful insights into the development of novel PAR(2) antagonists with anti-inflammatory activity in vitro and in vivo. (c) 2015 Elsevier Ltd. All rights reserved.