4-(4-fluorobenzyloxy)-2-hydroxybenzoic acid | 761455-25-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-(4-fluorobenzyloxy)-2-hydroxybenzoic acid
• 英文别名: 4-[(4-fluorophenyl)methoxy]-2-hydroxy-benzoic Acid；4-[(4-fluorophenyl)methoxy]-2-hydroxybenzoic acid
• CAS: 761455-25-8
• 化学式: C₁₄H₁₁FO₄
• 分子量: 262.237
• InChiKey: AOPQKRFXKIDKRL-UHFFFAOYSA-N

物化性质

• 沸点：
  440.4±40.0 °C(Predicted)
• 密度：
  1.385±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(4-fluorobenzyloxy)-2-hydroxybenzoic acid 在 N-甲基吗啉 、 盐酸羟胺 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 3.5h， 生成 4-(4-fluorobenzyloxy)-N,2-dihydroxybenzamide
  参考文献：
  名称：

  Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups

  摘要：

  HIV-1 integrase (IN) is a validated therapeutic target for antiviral drug design. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands the discovery of novel inhibitors that are structurally as well mechanistically different. Herein, we describe the design and discovery of novel IN inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75, which is essential for the HIV-1 integration as an IN cofactor. By merging the pharmacophores of salicylate and catechol, the 2,3-dihydroxybenzamide (5a) was identified as a new scaffold to inhibit the strand transfer reaction efficiently. Further structural modifications on the 2,3-dihydroxybenzamide scaffold revealed that the heteroaromatic functionality attached on the carboxamide portion and the piperidin-1-ylsulfonyl substituted at the phenyl ring are beneficial for the activity, resulting in a low micromolar IN inhibitor (5p, IC(50) = 5 mu M) with more than 40-fold selectivity for the strand transfer over the 3'-processing reaction. More significantly, this active scaffold remarkably inhibited the interaction between IN and LEDGF/p75 cofactor. The prototype example, N-(cyclohexylmethyl)-2,3-dihydroxy-5-(piperidin-1-ylsulfonyl) benzamide (5u) inhibited the IN-LEDGF/p75 interaction with an IC(50) value of 8 mu M. Using molecular modeling, the mechanism of action was hypothesized to involve the chelation of the divalent metal ions inside the IN active site. Furthermore, the inhibitor of IN-LEDGF/p75 interaction was properly bound to the LEDGF/p75 binding site on IN. This work provides a new and efficient approach to evolve novel HIV-1 IN inhibitors from rational integration and optimization of previously reported inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.06.058
• 作为产物：
  描述：

  2,4-二羟基苯甲酸 、 4-氟溴苄 在 sodium hydride 、 盐酸 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 、 水 为溶剂， 反应 8.0h， 以53%的产率得到4-(4-fluorobenzyloxy)-2-hydroxybenzoic acid
  参考文献：
  名称：

  Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups

  摘要：

  HIV-1 integrase (IN) is a validated therapeutic target for antiviral drug design. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands the discovery of novel inhibitors that are structurally as well mechanistically different. Herein, we describe the design and discovery of novel IN inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75, which is essential for the HIV-1 integration as an IN cofactor. By merging the pharmacophores of salicylate and catechol, the 2,3-dihydroxybenzamide (5a) was identified as a new scaffold to inhibit the strand transfer reaction efficiently. Further structural modifications on the 2,3-dihydroxybenzamide scaffold revealed that the heteroaromatic functionality attached on the carboxamide portion and the piperidin-1-ylsulfonyl substituted at the phenyl ring are beneficial for the activity, resulting in a low micromolar IN inhibitor (5p, IC(50) = 5 mu M) with more than 40-fold selectivity for the strand transfer over the 3'-processing reaction. More significantly, this active scaffold remarkably inhibited the interaction between IN and LEDGF/p75 cofactor. The prototype example, N-(cyclohexylmethyl)-2,3-dihydroxy-5-(piperidin-1-ylsulfonyl) benzamide (5u) inhibited the IN-LEDGF/p75 interaction with an IC(50) value of 8 mu M. Using molecular modeling, the mechanism of action was hypothesized to involve the chelation of the divalent metal ions inside the IN active site. Furthermore, the inhibitor of IN-LEDGF/p75 interaction was properly bound to the LEDGF/p75 binding site on IN. This work provides a new and efficient approach to evolve novel HIV-1 IN inhibitors from rational integration and optimization of previously reported inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.06.058

文献信息

• Kcnq channel modulating compounds and their pharmaceutical use
  申请人：Brown Dalby William

  公开号：US20060173058A1

  公开（公告）日：2006-08-03

  This invention relates to novel compounds useful as modulators of the KCNQ channel, to pharmaceutical compositions comprising these compounds, and to methods of treatment herewith.

  本发明涉及一种作为KCNQ通道调节剂有用的新化合物，涉及包含这些化合物的制药组合物，以及使用这些化合物进行治疗的方法。
• KCNQ CHANNEL MODULATING COMPOUNDS AND THEIR PHARMACEUTICAL USE
  申请人：NEUROSEARCH A/S

  公开号：EP1603858A2

  公开（公告）日：2005-12-14
• US7741352B2
  申请人：——

  公开号：US7741352B2

  公开（公告）日：2010-06-22
• [EN] NOVEL KCNQ CHANNEL MODULATING COMPOUNDS AND THEIR USE<br/>[FR] NOUVEAUX COMPOSES MODULANT LE CANAL KCNQ ET LEUR UTILISATION
  申请人：NEUROSEARCH AS

  公开号：WO2004080377A2

  公开（公告）日：2004-09-23

  This invention relates to compounds of the general formula (I) useful as modulators of the KCNQ channel, to pharmaceutical compositions comprising these compounds, and to methods of treatment herewith.