N-(4-fluorobenzyl)-2,3-dihydroxybenzamide | 1003850-04-1

• 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: N-(4-fluorobenzyl)-2,3-dihydroxybenzamide
• 英文别名: N-[(4-fluorophenyl)methyl]-2,3-dihydroxybenzamide
• CAS: 1003850-04-1
• 化学式: C₁₄H₁₂FNO₃
• 分子量: 261.253
• InChiKey: LCKHAWSKODCNGK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(4-fluorobenzyl)-2,3-dihydroxybenzamide 在 sodium hydroxide 、 magnesium(II) chloride hexahydrate 作用下， 以 甲醇 、 水 为溶剂， 以43%的产率得到
  参考文献：
  名称：

  Metal-Chelating 2-Hydroxyphenyl Amide Pharmacophore for Inhibition of Influenza Virus Endonuclease

  摘要：

  The influenza virus PA endonuclease is an attractive target for development of novel anti-influenza virus therapeutics. Reported PA inhibitors chelate the divalent metal ion(s) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In this work, a series of 2-hydroxybenzamide-based compounds have been synthesized and biologically evaluated in order to identify the essential pharmacophoric motif, which could be involved in functional sequestration of the metal ions (probably Mg2+) in the catalytic site of PA. By using HL1, H2L2, and HL3 as Model ligands with Mg2+ ions, we isolated and fully characterized a series of complexes and tested them for inhibitory activity toward PA-Nter endonuclease. H2L2 and the corresponding Mg2+ complex showed an. interesting inhibition of the endonuclease activity. The crystal structures of the uncomplexed HL1 and H2L2 and of the isolated magnesium complex [Mg(L-3)(2)(MeOH)(2)] 2MeOH were solved by X-ray diffraction analysis. Furthermore, the speciation models for HL1, H2L2, and HL3 with Mg2+ were obtained, and the formation constants of the complexes were measured. Preliminary docking calculations were conducted to-investigate the interactions of the title compounds with essential amino acids in the PA-Nter active site. These findings supported the "two-metal" coordination of divalent ions by a donor triad atoms chemotype as a powerful strategy to develop more potent PA endonuclease inhibitors.

  DOI：

  10.1021/mp400482a
• 作为产物：
  描述：

  苯甲酸,二羟基- 在 盐酸 、 水 、 potassium carbonate 、 1-羟基苯并三唑 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 120.0h， 生成 N-(4-fluorobenzyl)-2,3-dihydroxybenzamide
  参考文献：
  名称：

  [EN] HIV INTEGRASE INHIBITORS
  [FR] INHIBITEURS DE L'INTÉGRASE DU VIH

  摘要：

  公开号：

  WO2012106534A3

文献信息

• HIV INTEGRASE INHIBITORS
  申请人：National Institutes of Health

  公开号：US20140142137A1

  公开（公告）日：2014-05-22

  Provided herein, inter alia, are novel compounds for the inhibition of HIV integrase. The compounds disclosed herein are useful for methods of treating HIV infection in a subject in need thereof.

  本文提供了一些新的化合物，用于抑制HIV整合酶。本文所披露的化合物可用于治疗需要治疗HIV感染的人体内的方法。
• 2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based HIV-1 Integrase Inhibitors
  作者：Xue Zhi Zhao、Elena A. Semenova、B. Christie Vu、Kasthuraiah Maddali、Christophe Marchand、Stephen H. Hughes、Yves Pommier、Terrence R. Burke

  DOI：10.1021/jm070715d

  日期：2008.1.1

  The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3'-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors.
• 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
  作者：Xing Fan、Feng-Hua Zhang、Rasha I. Al-Safi、Li-Fan Zeng、Yumna Shabaik、Bikash Debnath、Tino W. Sanchez、Srinivas Odde、Nouri Neamati、Ya-Qiu Long

  DOI：10.1016/j.bmc.2011.06.058

  日期：2011.8

  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.
• Metal-chelating properties and antiviral activity of some 2-hydroxyphenyl amides
  作者：M. Carcelli、E. Fisicaro、C. Compari、L. Contardi、D. Rogolino、C. Solinas、A. Stevaert、L. Naesens

  DOI：10.1016/j.poly.2017.03.032

  日期：2017.6

  Influenza virus is an hot topic in medicinal chemistry and great efforts are ongoing for the discover of new antivirals able to overcome problems related to resistant strains and adverse side effects of current drugs. Influenza virus endonuclease is an attractive target for antiviral drug development and in particular the strategy to chelate the metal ion(s) within the active site proved to be an efficient mode to inhibit enzymatic activity. Our previous findings revealed that 2-hydroxyamide derivatives are able to chelate Mg2+ ions, forming complexes with different stoichiometric ratios. Here we report on the activity of the three ligands N-(4-fluorobenzy1)-2-hydroxybenzamide, N-(4-fluorobenzyl)-2,3-dihydroxybenzamide, and N1, N3-bis(4-fluorobenzyI)-2-hydroxyisophthalamide, containing the salicylic group, and their Mg2+ complexes (7)-(9), evaluated by means of virus yield assay in influenza virus-infected MDCK cells and vRNP reconstitution assay in HEK293T cells. In some cases, promising anti-influenza activities with EC50 values in the low micromolar range were found. As a contribute to clarify the activity in cells of the ligands, here we also present a study on the their coordinating properties towards the other essential metal ion Cu(II), carried out by potentiometric and calorimetric measurements. (C) 2017 Elsevier Ltd. All rights reserved.
• [EN] HYDRAZIDE, AMIDE, PHTHALIMIDE AND PHTHALHYDRAZIDE ANALOGS AS INHIBITORS OF RETROVIRAL INTEGRASE<br/>[FR] ANALOGUES D'HYDRAZIDE, D'AMIDE, DE PHTALIMIDE ET DE PHTALHYDRAZIDE EN TANT QU'INHIBITEURS DE L'INTÉGRASE RÉTROVIRALE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2009026248A2

  公开（公告）日：2009-02-26

  The present invention provides catechol-containing hydrazides, amides, phthalimide and phthalhydrazide analogs. These compounds are inhibitors of retroviral integrase, an essential enzyme for the proliferation of retroviruses such as HIV-1. Also provided are pharmaceutical compositions comprising at least one of the catechol-containing hydrazides, amides, phthalimide or phthalhydrazide analogs and a method of using the hydrazide, amide, phthalimide and phthalhydrazide analogs to inhibit retroviral proliferation and as therapeutics for the treatment of AIDS.