6-((4-cyanophenyl)amino)-4-(mesityloxy)-N-(prop-2-yn-1-yl)nicotinamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-((4-cyanophenyl)amino)-4-(mesityloxy)-N-(prop-2-yn-1-yl)nicotinamide
• 英文别名: 6-(4-cyanoanilino)-N-prop-2-ynyl-4-(2,4,6-trimethylphenoxy)pyridine-3-carboxamide
• 化学式: C₂₅H₂₂N₄O₂
• 分子量: 410.475
• InChiKey: BPGJBCJVDGOSGO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-azido-acetamide 、 6-((4-cyanophenyl)amino)-4-(mesityloxy)-N-(prop-2-yn-1-yl)nicotinamide 在 copper(II) sulfate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 12.0h， 以72.4%的产率得到N-((1-(2-amino-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methyl)-6-((4-cyanophenyl)amino)-4-(2,4,6-trimethylphenoxy)nicotinamide
  参考文献：
  名称：

  针对NNIBP的进入通道：发现二芳基烟酰胺1,4-二取代的1,2,3-三唑类作为新型HIV-1 NNRTI，对野生型和E138K突变病毒具有高效力

  摘要：

  受我们先前对将二芳基嘧啶修饰为HIV-1非核苷逆转录酶抑制剂（NNRTI）的启发和已报道的晶体学研究的启发，设计了新颖的二芳基烟酰胺衍生物，其“三唑尾”占据了NNRTI结合口袋中的进入通道。逆转录酶以提供额外的相互作用。然后合成新设计的化合物，并评估其在MT-4细胞中的抗HIV活性。所有化合物均对EC 50的野生型HIV-1菌株表现出优异至良好的活性0.02–1.77μM。对所选化合物针对更具耐药性菌株的评估表明，这些化合物具有抑制E138K突变病毒的优势，而E138K突变病毒是新一代NNRTIs的关键耐药突变体。在该系列中，丙腈（3b2，EC 50（IIIB）  = 0.020μM，EC 50（E138K）  = 0.015μM，CC 50  = 40.15μM），吡咯烷-1-基甲酮（3b8，EC 50（IIIB）  = 0.020μM， EC 50（E138K）  = 0.014μM，CC

  DOI：

  10.1016/j.ejmech.2018.03.059
• 作为产物：
  描述：

  4,6-二羟基烟酸乙酯 在 三甲基铝 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 54.25h， 生成 6-((4-cyanophenyl)amino)-4-(mesityloxy)-N-(prop-2-yn-1-yl)nicotinamide
  参考文献：
  名称：

  Design, synthesis and anti-HIV evaluation of novel diarylnicotinamide derivatives (DANAs) targeting the entrance channel of the NNRTI binding pocket through structure-guided molecular hybridization

  摘要：

  Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 mu M, Among them, compound 6b11 (EC50 = 0.027 mu M, SI > 12518) and 6b5 (EC50 = 0.029 mu M, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 mu M) and delavirdine (EC50 = 0.66 mu M). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 mu M). Preliminary structure-activity relationships (SARs) and molecular modeling of these new DANAs have been discussed. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.09.054

文献信息

• 一种取代二芳基烟酰胺类衍生物及其制备方法与应用
  申请人：山东大学

  公开号：CN106967047A

  公开（公告）日：2017-07-21

  本发明涉及一种取代二芳基烟酰胺类衍生物及其制备方法与应用。如通式Ⅰ所示的取代二芳基烟酰胺类衍生物及其药学上可接受的盐，本发明还提供通式Ⅰ化合物的制备方法以及含有一个或多个此类化合物的组合物在制备治疗和预防人免疫缺陷病毒(HIV)感染药物中的应用。
• Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus
  作者：Ye Tian、Zhaoqiang Liu、Jinghan Liu、Boshi Huang、Dongwei Kang、Heng Zhang、Erik De Clercq、Dirk Daelemans、Christophe Pannecouque、Kuo-Hsiung Lee、Chin-Ho Chen、Peng Zhan、Xinyong Liu

  DOI：10.1016/j.ejmech.2018.03.059

  日期：2018.5

  on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a “triazole tail” occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated

  受我们先前对将二芳基嘧啶修饰为HIV-1非核苷逆转录酶抑制剂（NNRTI）的启发和已报道的晶体学研究的启发，设计了新颖的二芳基烟酰胺衍生物，其“三唑尾”占据了NNRTI结合口袋中的进入通道。逆转录酶以提供额外的相互作用。然后合成新设计的化合物，并评估其在MT-4细胞中的抗HIV活性。所有化合物均对EC 50的野生型HIV-1菌株表现出优异至良好的活性0.02–1.77μM。对所选化合物针对更具耐药性菌株的评估表明，这些化合物具有抑制E138K突变病毒的优势，而E138K突变病毒是新一代NNRTIs的关键耐药突变体。在该系列中，丙腈（3b2，EC 50（IIIB）  = 0.020μM，EC 50（E138K）  = 0.015μM，CC 50  = 40.15μM），吡咯烷-1-基甲酮（3b8，EC 50（IIIB）  = 0.020μM， EC 50（E138K）  = 0.014μM，CC
• Design, synthesis and anti-HIV evaluation of novel diarylnicotinamide derivatives (DANAs) targeting the entrance channel of the NNRTI binding pocket through structure-guided molecular hybridization
  作者：Zhaoqiang Liu、Wenmin Chen、Peng Zhan、Erik De Clercq、Christophe Pannecouque、Xinyong Liu

  DOI：10.1016/j.ejmech.2014.09.054

  日期：2014.11

  Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 mu M, Among them, compound 6b11 (EC50 = 0.027 mu M, SI > 12518) and 6b5 (EC50 = 0.029 mu M, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 mu M) and delavirdine (EC50 = 0.66 mu M). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 mu M). Preliminary structure-activity relationships (SARs) and molecular modeling of these new DANAs have been discussed. (C) 2014 Elsevier Masson SAS. All rights reserved.