3-(3-bromophenyl)-6-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)-2-methylquinazolin-4(3H)-one

• 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: 3-(3-bromophenyl)-6-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)-2-methylquinazolin-4(3H)-one
• 化学式: C₂₀H₁₅BrN₄O₃
• 分子量: 439.268
• InChiKey: ADHJTCDDGRXSHT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.13
• 重原子数：
  28.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  90.01
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为产物：
  描述：

  2-acetamido-5-(methoxycarbonyl)benzoic acid 在 三乙胺 、 丙酮氰醇 、 N,N'-二环己基碳二亚胺 、 sodium hydroxide 、 三氯化磷 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 1.0h， 生成 3-(3-bromophenyl)-6-(5-hydroxy-1-methyl-1H-pyrazole-4-carbonyl)-2-methylquinazolin-4(3H)-one
  参考文献：
  名称：

  Pyrazolone–quinazolone hybrids: A novel class of human 4-hydroxyphenylpyruvate dioxygenase inhibitors

  摘要：

  4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting 4-hydroxyphenylpyruvate acid to homogentisate, is an important target for treating type I tyrosinemia and alkaptonuria due to its significant role in tyrosine catabolism. However, only one commercial drug, NTBC, also known as nitisinone, has been available for clinical use so far. Herein, we have elucidated the structure-based design of a series of pyrazolone-quinazolone hybrids that are novel potent human HPPD inhibitors through the successful integration of various techniques including computational simulations, organic synthesis, and biochemical characterization. Most of the new compounds displayed potent inhibitory activity against the recombinant human HPPD in nanomolar range. Compounds 3h and 3u were identified as the most potent candidates with Ki values of around 10 nM against human HPPD, about three-fold more potent than NTBC. Molecular modeling indicated that the interaction between the pyrazolone ring and ferrous ion, and the hydrophobic interaction of quinazolone with its surrounding residues, such as Phe347 and Phe364, contributed greatly to the high potency of these inhibitors. Therefore, compounds 3h and 3u could be potentially useful for the treatment of type I tyrosinemia and other diseases with defects in tyrosine degradation.

  DOI：

  10.1016/j.bmc.2014.08.011

文献信息

• Pyrazolone–quinazolone hybrids: A novel class of human 4-hydroxyphenylpyruvate dioxygenase inhibitors
  作者：Yu-Ling Xu、Hong-Yan Lin、Run-Jie Cao、Ze-Zhong Ming、Wen-Chao Yang、Guang-Fu Yang

  DOI：10.1016/j.bmc.2014.08.011

  日期：2014.10

  4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting 4-hydroxyphenylpyruvate acid to homogentisate, is an important target for treating type I tyrosinemia and alkaptonuria due to its significant role in tyrosine catabolism. However, only one commercial drug, NTBC, also known as nitisinone, has been available for clinical use so far. Herein, we have elucidated the structure-based design of a series of pyrazolone-quinazolone hybrids that are novel potent human HPPD inhibitors through the successful integration of various techniques including computational simulations, organic synthesis, and biochemical characterization. Most of the new compounds displayed potent inhibitory activity against the recombinant human HPPD in nanomolar range. Compounds 3h and 3u were identified as the most potent candidates with Ki values of around 10 nM against human HPPD, about three-fold more potent than NTBC. Molecular modeling indicated that the interaction between the pyrazolone ring and ferrous ion, and the hydrophobic interaction of quinazolone with its surrounding residues, such as Phe347 and Phe364, contributed greatly to the high potency of these inhibitors. Therefore, compounds 3h and 3u could be potentially useful for the treatment of type I tyrosinemia and other diseases with defects in tyrosine degradation.