2-(aminomethyl)-5-fluoro-N-methylbenzamide

• 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: 2-(aminomethyl)-5-fluoro-N-methylbenzamide
• 化学式: C₉H₁₁FN₂O
• 分子量: 182.198
• InChiKey: DVOHZSVOEPGUCR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  55.1
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(aminomethyl)-5-fluoro-N-methylbenzamide 、 苯甲酸,二羟基- 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 6.5h， 以61%的产率得到N-(4-fluoro-2-(methylcarbamoyl)benzyl)-2,3-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：

  5-fluoro-N,2-dimethylbenzamide 在 N-溴代丁二酰亚胺(NBS) 、 sodium azide 、 偶氮二异丁腈 、 三苯基膦 作用下， 以 四氢呋喃 、 四氯化碳 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 2-(aminomethyl)-5-fluoro-N-methylbenzamide
  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

• HIV INTEGRASE INHIBITORS
  申请人：Naidu B. Narasimhulu

  公开号：US20070129379A1

  公开（公告）日：2007-06-07

  The invention encompasses a series bicyclic pyrimidinone compounds of Formula I which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.

  这项发明涵盖了一系列公式I的双环嘧啶酮化合物，这些化合物抑制HIV整合酶并防止病毒整合到人类DNA中。这种作用使得这些化合物对治疗HIV感染和艾滋病有用。该发明还涵盖了用于治疗HIV感染者的药物组合物和方法。
• Bicyclic heterocycles as HIV integrase inhibitors
  申请人：Naidu Narasimhulu B.

  公开号：US20050267105A1

  公开（公告）日：2005-12-01

  The invention encompasses a series cyclic bicyclic pyrimidinone compounds of Formula I which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.

  这项发明涵盖了一系列环状嘧啶酮化合物，其化学式为I，可以抑制HIV整合酶并防止病毒整合到人类DNA中。这种作用使得这些化合物对治疗HIV感染和艾滋病有用。该发明还涵盖了用于治疗HIV感染者的药物组合物和方法。
• Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors
  作者：Manoj Patel、B. Narasimhulu Naidu、Ira Dicker、Helen Higley、Zeyu Lin、Brian Terry、Tricia Protack、Mark Krystal、Susan Jenkins、Dawn Parker、Chiradeep Panja、Richard Rampulla、Arvind Mathur、Nicholas A. Meanwell、Michael A. Walker

  DOI：10.1016/j.bmc.2020.115541

  日期：2020.7

  The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified

  描述了与一系列桥接三环嘧啶酮甲酰胺作为 HIV-1 整合酶链转移的有效抑制剂相关的设计、合成和结构-活性关系。对这些分子进行结构修饰是为了检查对野生型和临床相关抗性病毒的效力的影响。[3.2.2]-桥接三环系统被确定为一种有利的化学型，其代表对野生型病毒和 G140S/Q1​​48H 抗性病毒均表现出出色的抗病毒活性，这些病毒是响应拉特拉韦和艾维替拉韦治疗而产生的。
• HIV integrase inhibitors
  申请人：Naidu Narasimhulu B.

  公开号：US20070111984A1

  公开（公告）日：2007-05-17

  The invention encompasses a series bicyclic pyrimidinone compounds of Formula I which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.

  这项发明涵盖了一系列公式I的双环嘧啶酮化合物，它们能抑制HIV整合酶，防止病毒整合到人类DNA中。这一作用使得这些化合物对治疗HIV感染和艾滋病具有用处。该发明还涵盖了用于治疗HIV感染者的药物组合物和方法。
• Design, synthesis and SAR study of novel C2-pyrazolopyrimidine amides and amide isosteres as allosteric integrase inhibitors
  作者：Manoj Patel、Christopher Cianci、Christopher W. Allard、Dawn D. Parker、Jean Simmermacher、Susan Jenkins、Brian Mcauliffe、Beatrice Minassian、Linda Discotto、Mark Krystal、Nicholas A. Meanwell、B. Narasimhulu Naidu

  DOI：10.1016/j.bmcl.2020.127516

  日期：2020.11

  The design, synthesis and structure-activity relationships associated with a series of C2-substituted pyrazolopyrimidines as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) are described. Structural modifications to these molecules were made in order to examine the effect on potency and, for select compounds, pharmacokinetic properties. We examined a variety of C2-substituted pyrazolopyrimidines

  描述了与一系列作为HIV-1整合酶（ALLINIs）的有效变构抑制剂的C2取代的吡唑并嘧啶相关的设计，合成和构效关系。对这些分子进行结构修饰，以检查其对功效的影响，以及对于某些化合物而言，其药代动力学特性。我们检查了各种C2取代的吡唑并嘧啶，发现C2-酰胺衍生物在细胞培养中显示出最有效的抗HIV-1感染的抗病毒活性。