2-Chlor-6-o-tolyloxy-pyrimidin | 956039-59-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-Chlor-6-o-tolyloxy-pyrimidin
• 英文别名: 2-chloro-4-m-tolyloxy-pyrimidine；2-Chloro-4-(3-methylphenoxy)pyrimidine
• CAS: 956039-59-1
• 化学式: C₁₁H₉ClN₂O
• 分子量: 220.658
• InChiKey: GKEGNAOEASXSSV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  35
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-Chlor-6-o-tolyloxy-pyrimidin 在 18-冠醚-6 、 potassium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 N-[1-(1H-indazol-3-ylmethyl)-4-piperidyl]-4-(3-methylphenoxy)pyrimidin-2-amine
  参考文献：
  名称：

  Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities

  摘要：

  A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with ECK values ranging from 1.5 to 0.0064 mu M. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 mu M), Y181C (EC50 = 0.11 mu M), E138K (EC50 = 0.057 mu M), and moderate activity against double mutants RES056 (EC50 = 8.7 mu M). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111864
• 作为产物：
  描述：

  2,4-二氯嘧啶 、 间甲酚 在 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 2-Chlor-6-o-tolyloxy-pyrimidin
  参考文献：
  名称：

  地拉韦啶和哌啶-4-基-氨基嘧啶 (DPAPY) 的杂合体作为有效的 HIV-1 NNRTIs：设计、合成和生物活性

  摘要：

  地拉韦啶和哌啶-4-基-氨基嘧啶(DPAPY)杂合体是由两种优良的HIV-1 NNRTIs地拉韦啶和哌啶-4-基-氨基嘧啶通过分子杂交设计而成。制备了目标化合物4a-r，并评估了其细胞抗HIV活性和细胞毒性以及对HIV-1逆转录酶（RT）的抑制活性。所有新合成的化合物均表现出中等至优异的抗野生型 (WT) HIV-1 效力，EC 50值在 5.7 至 0.0086 μM 范围内，而对抗 RT，IC 50值在 12.0 至 0.11 μM 范围内，表明 DPAPY是特异性 RT 抑制剂。其中，4d显示出针对 WT HIV-1 的最有效活性（EC 50  = 8.6 nM，SI = 2151）。令人欣慰的是，它对单一 HIV-1 突变体 L100I、K103N、Y181C、Y188L、E138K 以及双突变体 F227L + V106A 表现出良好至优异的效力。此外，还总结了初步的构效关系，并

  DOI：

  10.1016/j.ejmech.2023.115114

文献信息

• Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity
  作者：Runzhe Song、Yue Wang、Minghui Wang、Ruixuan Gao、Teng Yang、Song Yang、Cai-Guang Yang、Yongsheng Jin、Siyuan Zou、Jianfeng Cai、Renhua Fan、Qiuqin He

  DOI：10.1016/j.bioorg.2020.104176

  日期：2020.10

  desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group was designed and synthesized. The biological results showed majority of these hybrids still demonstrated potent anti-MRSA activity with MIC values between 0.38-1.5 μg/mL, despite the lack of the typical C-6 fluorine atom. Particularly, the most active B14 exhibited activities at submicromolar concentration against a

  尽管事实上在C-6位置引入了氟原子导致了氟喹诺酮类药物的发展，但氟喹诺酮类引起的心脏毒性引起了相当大的关注。在这种情况下，设计并合成了基于C-7氨基嘧啶官能团的基于脱氟喹诺酮的杂种。生物学结果显示，尽管缺乏典型的C-6氟原子，但这些杂种中的大多数仍显示出有效的抗MRSA活性，MIC值为0.38-1.5μg/ mL。特别地，最具活性的B14在亚微摩尔浓度下对一组MRSA菌株具有活性，这些菌株包括万古霉素中间菌株，耐左氧氟沙星的分离株和耐利奈唑胺的分离株等。。如预期的那样，它还显示出对细菌细胞的高度选择性毒性和低hERG抑制作用。进一步的抗药性研究表明，MRSA不太可能获得针对B14的抗药性。对接研究表明，在C-7取代基和周围的DNA碱基之间形成了两个氢键，这可能有助于通过减少对镁-水桥与拓扑异构酶IV的依赖性来克服耐药性。这些结果表明开发一种新的抗生素喹诺酮类药物以对抗多药耐药性和心脏毒性的有希望的策略。
• Development and Experimental Validation of a Docking Strategy for the Generation of Kinase-Targeted Libraries
  作者：Rafael Gozalbes、Laurence Simon、Nicolas Froloff、Eric Sartori、Claude Monteils、Romuald Baudelle

  DOI：10.1021/jm701367r

  日期：2008.6.1

  A high-throughput docking strategy for the filtering of in silico compounds and the generation of kinase-targeted libraries is described. Systematic docking and scoring in three kinase crystal 3D structures of 123 structurally diverse kinase ligands led to the determination of six thresholds for each kinase. These thresholds were used as filters for the virtual screening of two collections of compounds: a collection of more than 2500 drugs and drug-like compounds (negative control) and a kinase-targeted library of 1440 compounds. This strategy was then experimentally validated by testing 60 compounds from the kinase-targeted library on 41 kinases from five different families. The 60 compounds were split into those passing all the thresholds and the others (30 compounds in each group). The overall hit enrichment was 6.70-fold higher in the first group, validating our approach for the generation of kinase-targeted libraries and the identification of scaffolds with high kinase inhibitory potential.
• Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities
  作者：Ting Xiao、Jia-Fan Tang、Ge Meng、Christophe Pannecouque、Yuan-Yuan Zhu、Gen-Yan Liu、Zhi-Qiang Xu、Feng-Shou Wu、Shuang-Xi Gu、Fen-Er Chen

  DOI：10.1016/j.ejmech.2019.111864

  日期：2020.1

  A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with ECK values ranging from 1.5 to 0.0064 mu M. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 mu M), Y181C (EC50 = 0.11 mu M), E138K (EC50 = 0.057 mu M), and moderate activity against double mutants RES056 (EC50 = 8.7 mu M). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase. (C) 2019 Elsevier Masson SAS. All rights reserved.
• Hybrids of delavirdine and piperdin-4-yl-aminopyrimidines (DPAPYs) as potent HIV-1 NNRTIs: Design, synthesis and biological activities
  作者：Wei Ming、Wen-Long Lu、Christophe Pannecouque、Jiong Chen、Hai-Feng Wang、Ya-Qi Xiao、Sha Hu、Shuang-Xi Gu、Yuan-Yuan Zhu、Fen-Er Chen

  DOI：10.1016/j.ejmech.2023.115114

  日期：2023.2

  excellent HIV-1 NNRTIs delavirdine and piperidin-4-yl-aminopyrimidine via molecular hybridization. The target compounds 4a-r were prepared and evaluated for their cellular anti-HIV activities and cytotoxicities as well as the inhibitory activities against HIV-1 reverse transcriptase (RT). All the newly synthesized compounds demonstrated moderate to excellent potency against wild-type (WT) HIV-1 with EC50

  地拉韦啶和哌啶-4-基-氨基嘧啶(DPAPY)杂合体是由两种优良的HIV-1 NNRTIs地拉韦啶和哌啶-4-基-氨基嘧啶通过分子杂交设计而成。制备了目标化合物4a-r，并评估了其细胞抗HIV活性和细胞毒性以及对HIV-1逆转录酶（RT）的抑制活性。所有新合成的化合物均表现出中等至优异的抗野生型 (WT) HIV-1 效力，EC 50值在 5.7 至 0.0086 μM 范围内，而对抗 RT，IC 50值在 12.0 至 0.11 μM 范围内，表明 DPAPY是特异性 RT 抑制剂。其中，4d显示出针对 WT HIV-1 的最有效活性（EC 50  = 8.6 nM，SI = 2151）。令人欣慰的是，它对单一 HIV-1 突变体 L100I、K103N、Y181C、Y188L、E138K 以及双突变体 F227L + V106A 表现出良好至优异的效力。此外，还总结了初步的构效关系，并