4-((4-(mesityloxy)-6-(3-morpholinopropoxy)pyridin-2-yl)amino)benzonitrile

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 4-((4-(mesityloxy)-6-(3-morpholinopropoxy)pyridin-2-yl)amino)benzonitrile
• 英文别名: 4-[[6-(3-Morpholin-4-ylpropoxy)-4-(2,4,6-trimethylphenoxy)pyridin-2-yl]amino]benzonitrile；4-[[6-(3-morpholin-4-ylpropoxy)-4-(2,4,6-trimethylphenoxy)pyridin-2-yl]amino]benzonitrile
• 化学式: C₂₈H₃₂N₄O₃
• 分子量: 472.587
• InChiKey: NCPZKZXQYRXKKW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  79.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,4,6-三氯吡啶 在 palladium diacetate 、 sodium hydride 、 potassium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 0.5h， 生成 4-((4-(mesityloxy)-6-(3-morpholinopropoxy)pyridin-2-yl)amino)benzonitrile
  参考文献：
  名称：

  Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket

  摘要：

  Based on the crystallographic studies of diarylpyrimidines (DAPYs), we embarked on incorporating the hydrophilic piperidyl or morpholinyl group into the known DAPY derivatives bearing the pyridine moiety as a core structure, with the double aim to exploit additional interactions with the HIV-1 NNRTI binding pocket (NNIBP), as well as to improve the compound solubility. The antiviral evaluation result show that the most potent compounds I-8b2, I-8b3, I-8b4 and I-8c3 exhibited anti-HIV-1 (IIIB) strain activity ranging from 7.4 nM to 9.4 nM (SI = 168-1283), superior to FDA-approved drugs of nevirapine (NVP), lamivudine (3TC) and delavirdine (DLV), and comparable to etravirine (ETV), zidovudine (AZT) and efavirenz (EFV). Additionally, compounds I-8c2 and I-8c3 showed moderate activity against NNRTI resistant strains baring mutations K103N and Y181C with EC50 values of 6.2 mu M and 6.8 mu M, respectively. Preliminary structure-activity relationships (SARs), reverse transcriptase inhibition efficacy and molecular modeling of selected compounds are also presented. These outcomes support our design hypothesis and demonstrate that the piperidyl group modified pyridine-typed DAPY derivatives are highly potent NNRTIs with improved water solubility. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.05.054

文献信息

• Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket
  作者：Wenmin Chen、Peng Zhan、Dirk Daelemans、Jiapei Yang、Boshi Huang、Erik De Clercq、Christophe Pannecouque、Xinyong Liu

  DOI：10.1016/j.ejmech.2016.05.054

  日期：2016.10

  Based on the crystallographic studies of diarylpyrimidines (DAPYs), we embarked on incorporating the hydrophilic piperidyl or morpholinyl group into the known DAPY derivatives bearing the pyridine moiety as a core structure, with the double aim to exploit additional interactions with the HIV-1 NNRTI binding pocket (NNIBP), as well as to improve the compound solubility. The antiviral evaluation result show that the most potent compounds I-8b2, I-8b3, I-8b4 and I-8c3 exhibited anti-HIV-1 (IIIB) strain activity ranging from 7.4 nM to 9.4 nM (SI = 168-1283), superior to FDA-approved drugs of nevirapine (NVP), lamivudine (3TC) and delavirdine (DLV), and comparable to etravirine (ETV), zidovudine (AZT) and efavirenz (EFV). Additionally, compounds I-8c2 and I-8c3 showed moderate activity against NNRTI resistant strains baring mutations K103N and Y181C with EC50 values of 6.2 mu M and 6.8 mu M, respectively. Preliminary structure-activity relationships (SARs), reverse transcriptase inhibition efficacy and molecular modeling of selected compounds are also presented. These outcomes support our design hypothesis and demonstrate that the piperidyl group modified pyridine-typed DAPY derivatives are highly potent NNRTIs with improved water solubility. (C) 2016 Elsevier Masson SAS. All rights reserved.