2-(adamantan-1-ylaminomethyl)-5-methoxyphenol | 1306481-09-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 2-(adamantan-1-ylaminomethyl)-5-methoxyphenol
• 英文别名: 2-[(1-Adamantylamino)methyl]-5-methoxyphenol
• CAS: 1306481-09-3
• 化学式: C₁₈H₂₅NO₂
• 分子量: 287.402
• InChiKey: ISODEIGYTQCULW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  41.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(adamantan-1-ylaminomethyl)-5-methoxyphenol 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以89%的产率得到4-(adamantan-1-ylaminomethyl)benzene-1,3-diol
  参考文献：
  名称：

  发现 A 型流感病毒 M2 质子通道的野生型和最普遍的耐药突变体 S31N 的新型双重抑制剂

  摘要：

  由于广泛的耐药性，针对甲型流感病毒 M2 通道的抗流感药物金刚烷胺和金刚乙胺不再有效。S31N 是主要的耐金刚烷胺 M2 突变体，几乎存在于所有流行的甲型流感病毒株以及大流行的 2009 H1N1 和高致病性 H5N1 流感病毒株中。因此，迫切需要开发针对 S31N 突变体的第二代 M2 抑制剂。然而，S31N 突变体对药物发现提出了巨大挑战，几十年来一直被认为是不可成药的。利用结构信息、经典药物化学方法和 M2 特异性生物测试，我们发现了对 S31N 和 WT 均具有活性的苄基取代的金刚烷胺衍生物，其中 4-(adamantan-1-ylaminomethyl)-benzo-1,3-diol (44 ) 是最有效的双重抑制剂。这些抑制剂表明 S31N 是一种可药物靶点，并为设计解决耐药甲型流感感染问题的新型 M2 抑制剂提供了新的起点。

  DOI：

  10.1021/jm301538e
• 作为产物：
  描述：

  (Z)-2-((adamantan-1-ylimino) methyl)-5-methoxyphenol 在 sodium tetrahydroborate 、 对甲苯磺酸 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以90%的产率得到2-(adamantan-1-ylaminomethyl)-5-methoxyphenol
  参考文献：
  名称：

  Chemical Probes for Blocking of Influenza A M2 Wild-type and S31N Channels

  摘要：

  We report on using the synthetic aminoadamantane-CH2-aryl derivatives 1-6 as sensitive probes for blocking M2 S31N and influenza A virus (IAV) M2 wild-type (WT) channels as well as virus replication in cell culture. The binding kinetics measured using electrophysiology (EP) for M2 S31N channel are very dependent on the length between the adamantane moiety and the first ring of the aryl headgroup realized in 2 and 3 and the girth and length of the adamantane adduct realized in 4 and 5. Study of 1-6 shows that, according to molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations, all bind in the M2 S31N channel with the adamantyl group positioned between V27 and G34 and the aryl group projecting out of the channel with the phenyl (or isoxazole in 6) embedded in the V27 cluster. In this outward binding configuration, an elongation of the ligand by only one methylene in rimantadine 2 or using diamantane or triamantane instead of adamantane in 4 and 5, respectively, causes incomplete entry and facilitates exit, abolishing effective block compared to the amantadine derivatives 1 and 6. In the active M2 S31N blockers 1 and 6, the phenyl and isoxazolyl head groups achieve a deeper binding position and high kon/low koff and high kon/high koff rate constants, compared to inactive 2-5, which have much lower kon and higher koff. Compounds 1-5 block the M2 WT channel by binding in the longer area from V27-H37, in the inward orientation, with high kon and low koff rate constants. Infection of cell cultures by influenza virus containing M2 WT or M2 S31N is inhibited by 1-5 or 1-4 and 6, respectively. While 1 and 6 block infection through the M2 block mechanism in the S31N variant, 2-4 may block M2 S31N virus replication in cell culture through the lysosomotropic effect, just as chloroquine is thought to inhibit SARS-CoV-2 infection.

  DOI：

  10.1021/acschembio.0c00553

文献信息

• [EN] INHIBITORS TARGETING DRUG-RESISTANT INFLUENZA A<br/>[FR] INHIBITEURS CIBLANT LA GRIPPE A PHARMACORÉSISTANTE
  申请人：UNIV PENNSYLVANIA

  公开号：WO2013086131A1

  公开（公告）日：2013-06-13

  Provided are compounds according to formula (la) or (lb) as described herein, that are capable of modulating the activity of influenza viruses (e.g., influenza A virus), for example, via interaction with the M2 transmembrane protein, and other similar viroporins. Also provided are methods for treating an influenza A-affected disease state or infection comprising administering a composition comprising one or more compounds according to according to formulas (la') or (lb), as described herein.

  根据本文描述的公式（la）或（lb），提供了一些化合物，这些化合物能够调节流感病毒（例如流感A病毒）的活性，例如通过与M2跨膜蛋白以及其他类似的病毒孔蛋白相互作用。还提供了一种治疗流感A感染疾病状态或感染的方法，包括通过给予包含根据本文描述的公式（la'）或（lb）的一个或多个化合物的组合物进行治疗。
• INHIBITORS TARGETING DRUG-RESISTANT INFLUENZA A
  申请人：THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

  公开号：US20150191439A1

  公开（公告）日：2015-07-09

  Provided are compounds according to formula (Ia) or (Ib) as described herein, that are capable of modulating the activity of influenza viruses (e.g., influenza A virus), for example, via interaction with the M2 transmembrane protein, and other similar viroporins. Also provided are methods for treating an influenza A-affected disease state or infection comprising administering a composition comprising one or more compounds according to according to formulas (Ia′) or (Ib), as described herein.

  提供了符合公式（Ia）或（Ib）的化合物，可以通过与M2跨膜蛋白和其他类似的病毒孔蛋白相互作用，调节流感病毒（例如流感A病毒）的活性。还提供了一种治疗流感A受影响的疾病状态或感染的方法，包括给予含有一个或多个符合公式（Ia′）或（Ib）的化合物的组合物。
• US9884832B2
  申请人：——

  公开号：US9884832B2

  公开（公告）日：2018-02-06
• Discovery of Novel Dual Inhibitors of the Wild-Type and the Most Prevalent Drug-Resistant Mutant, S31N, of the M2 Proton Channel from Influenza A Virus
  作者：Jizhou Wang、Chunlong Ma、Jun Wang、Hyunil Jo、Belgin Canturk、Giacomo Fiorin、Lawrence H. Pinto、Robert A. Lamb、Michael L. Klein、William F. DeGrado

  DOI：10.1021/jm301538e

  日期：2013.4.11

  targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N

  由于广泛的耐药性，针对甲型流感病毒 M2 通道的抗流感药物金刚烷胺和金刚乙胺不再有效。S31N 是主要的耐金刚烷胺 M2 突变体，几乎存在于所有流行的甲型流感病毒株以及大流行的 2009 H1N1 和高致病性 H5N1 流感病毒株中。因此，迫切需要开发针对 S31N 突变体的第二代 M2 抑制剂。然而，S31N 突变体对药物发现提出了巨大挑战，几十年来一直被认为是不可成药的。利用结构信息、经典药物化学方法和 M2 特异性生物测试，我们发现了对 S31N 和 WT 均具有活性的苄基取代的金刚烷胺衍生物，其中 4-(adamantan-1-ylaminomethyl)-benzo-1,3-diol (44 ) 是最有效的双重抑制剂。这些抑制剂表明 S31N 是一种可药物靶点，并为设计解决耐药甲型流感感染问题的新型 M2 抑制剂提供了新的起点。
• Chemical Probes for Blocking of Influenza A M2 Wild-type and S31N Channels
  作者：Christina Tzitzoglaki、Kelly McGuire、Panagiotis Lagarias、Athina Konstantinidi、Anja Hoffmann、Natalie A. Fokina、Chulong Ma、Ioannis P. Papanastasiou、Peter R. Schreiner、Santiago Vázquez、Michaela Schmidtke、Jun Wang、David D. Busath、Antonios Kolocouris

  DOI：10.1021/acschembio.0c00553

  日期：2020.9.18

  We report on using the synthetic aminoadamantane-CH2-aryl derivatives 1-6 as sensitive probes for blocking M2 S31N and influenza A virus (IAV) M2 wild-type (WT) channels as well as virus replication in cell culture. The binding kinetics measured using electrophysiology (EP) for M2 S31N channel are very dependent on the length between the adamantane moiety and the first ring of the aryl headgroup realized in 2 and 3 and the girth and length of the adamantane adduct realized in 4 and 5. Study of 1-6 shows that, according to molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations, all bind in the M2 S31N channel with the adamantyl group positioned between V27 and G34 and the aryl group projecting out of the channel with the phenyl (or isoxazole in 6) embedded in the V27 cluster. In this outward binding configuration, an elongation of the ligand by only one methylene in rimantadine 2 or using diamantane or triamantane instead of adamantane in 4 and 5, respectively, causes incomplete entry and facilitates exit, abolishing effective block compared to the amantadine derivatives 1 and 6. In the active M2 S31N blockers 1 and 6, the phenyl and isoxazolyl head groups achieve a deeper binding position and high kon/low koff and high kon/high koff rate constants, compared to inactive 2-5, which have much lower kon and higher koff. Compounds 1-5 block the M2 WT channel by binding in the longer area from V27-H37, in the inward orientation, with high kon and low koff rate constants. Infection of cell cultures by influenza virus containing M2 WT or M2 S31N is inhibited by 1-5 or 1-4 and 6, respectively. While 1 and 6 block infection through the M2 block mechanism in the S31N variant, 2-4 may block M2 S31N virus replication in cell culture through the lysosomotropic effect, just as chloroquine is thought to inhibit SARS-CoV-2 infection.