2-(2-(hydroxymethyl)phenyl)-N-methylacetamide | 218131-53-4

• 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-(2-(hydroxymethyl)phenyl)-N-methylacetamide
• 英文别名: 2-[2-(hydroxymethyl)phenyl]-N-methylacetamide
• CAS: 218131-53-4
• 化学式: C₁₀H₁₃NO₂
• 分子量: 179.219
• InChiKey: IDCQQTSBILIZPI-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：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  49.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(2-(hydroxymethyl)phenyl)-N-methylacetamide 在 sodium azide 、 1-羟基苯并三唑 、 甲基磺酰氯 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.5h， 生成 2,3-dihydroxy-N-(2-(2-(methylamino)-2-oxoethyl)benzyl)benzamide
  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：

  3-异色酮 、 甲胺 以 四氢呋喃 为溶剂， 反应 8.0h， 以99%的产率得到2-(2-(hydroxymethyl)phenyl)-N-methylacetamide
  参考文献：
  名称：

  IDO/TDO Inhibitor

  摘要：

  以下公式（I）给出的化合物或该化合物的药学上可接受的盐可用作IDO/TDO抑制剂。因此，公式（I）的化合物或该化合物的药学上可接受的盐可用作，例如，用于肿瘤、传染病、神经退行性疾病、白内障、器官移植排斥、自身免疫疾病、术后认知障碍以及与女性生殖健康相关的疾病的治疗剂。在以下公式（I）中，环A代表芳香环、脂环、杂环或两个或更多个选自芳香环、脂环和杂环的缩合环的环；X、R1和R2代表构成环A的环原子上的取代基；m代表0到6的整数；X代表例如卤素原子；R1和R2相同或不同，选自例如由公式（a）或公式（b）组成的基团，而在以下公式（a）和公式（b）中，Y选自O、S和Se组成的基团，Z选自O、S和Se组成的基团，n表示1到8的整数，r表示1到8的整数，s表示1到8的整数，R4代表例如—C(═NH)—HN2，R6代表例如取代或未取代的芳基。

  公开号：

  US20200239452A1

文献信息

• IDO/TDO Inhibitor
  申请人：GENERAL INCORPORATED ASSOCIATION PHARMA VALLEY PROJECT SUPPORTING ORGANIZATION

  公开号：US20200239452A1

  公开（公告）日：2020-07-30

  A compound of formula (I) given below or a pharmaceutically acceptable salt of the compound is useful as an IDO/TDO inhibitor. Thus, the compound of formula (I) or the pharmaceutically acceptable salt of the compound can be used as, for example, a therapeutic agent for a disease or a disorder selected from tumor, infectious disease, neurodegenerative disorder, cataract, organ transplant rejection, autoimmune disease, postoperative cognitive impairment, and disease related to women's reproductive health [in the following formula (I), ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from an aromatic ring, an aliphatic ring and a heterocyclic ring; X, R 1 and R 2 represent a substituent on a ring atom constituting ring A; m represents an integer of 0 to 6; X represents, for example, a halogen atom; and R 1 and R 2 are the same or different and are selected from, for example, the group consisting of groups of formula (a) or formula (b); and in the following formula (a) and formula (b), Y is selected from the group consisting of O, S, and Se, Z is selected from the group consisting of O, S, and Se, n represents an integer of 1 to 8, r represents an integer of 1 to 8, s represents an integer of 1 to 8, R 4 represents, for example, —C(═NH)—HN 2 , and R 6 represents, for example, a substituted or unsubstituted aryl group].

  以下公式（I）给出的化合物或该化合物的药学上可接受的盐可用作IDO/TDO抑制剂。因此，公式（I）的化合物或该化合物的药学上可接受的盐可用作，例如，用于肿瘤、传染病、神经退行性疾病、白内障、器官移植排斥、自身免疫疾病、术后认知障碍以及与女性生殖健康相关的疾病的治疗剂。在以下公式（I）中，环A代表芳香环、脂环、杂环或两个或更多个选自芳香环、脂环和杂环的缩合环的环；X、R1和R2代表构成环A的环原子上的取代基；m代表0到6的整数；X代表例如卤素原子；R1和R2相同或不同，选自例如由公式（a）或公式（b）组成的基团，而在以下公式（a）和公式（b）中，Y选自O、S和Se组成的基团，Z选自O、S和Se组成的基团，n表示1到8的整数，r表示1到8的整数，s表示1到8的整数，R4代表例如—C(═NH)—HN2，R6代表例如取代或未取代的芳基。
• 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.