N-[4-chloro-3-(3-chlorophenyl)sulfanyl-phenyl]-4-methoxy-pyrimidin-2-amine | 1333950-21-2

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: N-[4-chloro-3-(3-chlorophenyl)sulfanyl-phenyl]-4-methoxy-pyrimidin-2-amine
• 英文别名: N-[4-chloro-3-(3-chlorophenyl)sulfanylphenyl]-4-methoxypyrimidin-2-amine
• CAS: 1333950-21-2
• 化学式: C₁₇H₁₃Cl₂N₃OS
• 分子量: 378.282
• InChiKey: HOXHYOLIPMOLGR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  72.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-溴-4-氯硝基苯 在 吡啶 、 喹啉 、 铁粉 、 氯化铵 、 对甲苯磺酸 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 7.0h， 生成 N-[4-chloro-3-(3-chlorophenyl)sulfanyl-phenyl]-4-methoxy-pyrimidin-2-amine
  参考文献：
  名称：

  Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase

  摘要：

  Non-nucleoside reverse transcriptase inhibitors (NNRTIs) that interfere with the replication of human immunodeficiency virus (HIV) are being pursued with guidance from molecular modeling including free-energy perturbation (FEP) calculations for protein inhibitor binding affinities. The previously reported pyrimidinylphenylamine 1 and its chloro analogue 2 are potent anti-HIV agents; they inhibit replication of wild-type HIV-1 in infected human T-cells with EC50 values of 2 and 10 nM, respectively. However, they show no activity against viral strains containing the Tyr181Cys (Y181C) mutation in HIV-RT. Modeling indicates that the problem is likely associated with extensive interaction between the dimethylallyloxy substituent and Tyr181. As an alternative, a phenoxy group is computed to be oriented in a manner diminishing the contact with Tyr181. However, this replacement leads to a roughly 1000-fold loss of activity for 3 (2.5 mu M). The present report details the efficient, computationally driven evolution of 3 to novel NNRTIs with sub-10 nM potency toward both wild-type HIV-1 and Y181C-containing variants. The critical contributors were FEP substituent scans for the phenoxy and pyrimidine rings and recognition of potential benefits of addition of a cyanovinyl group to the phenoxy ring.

  DOI：

  10.1021/ja2058583

文献信息

• Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase
  作者：William L. Jorgensen、Mariela Bollini、Vinay V. Thakur、Robert A. Domaoal、Krasimir A. Spasov、Karen S. Anderson

  DOI：10.1021/ja2058583

  日期：2011.10.5

  Non-nucleoside reverse transcriptase inhibitors (NNRTIs) that interfere with the replication of human immunodeficiency virus (HIV) are being pursued with guidance from molecular modeling including free-energy perturbation (FEP) calculations for protein inhibitor binding affinities. The previously reported pyrimidinylphenylamine 1 and its chloro analogue 2 are potent anti-HIV agents; they inhibit replication of wild-type HIV-1 in infected human T-cells with EC50 values of 2 and 10 nM, respectively. However, they show no activity against viral strains containing the Tyr181Cys (Y181C) mutation in HIV-RT. Modeling indicates that the problem is likely associated with extensive interaction between the dimethylallyloxy substituent and Tyr181. As an alternative, a phenoxy group is computed to be oriented in a manner diminishing the contact with Tyr181. However, this replacement leads to a roughly 1000-fold loss of activity for 3 (2.5 mu M). The present report details the efficient, computationally driven evolution of 3 to novel NNRTIs with sub-10 nM potency toward both wild-type HIV-1 and Y181C-containing variants. The critical contributors were FEP substituent scans for the phenoxy and pyrimidine rings and recognition of potential benefits of addition of a cyanovinyl group to the phenoxy ring.