4-chloro-2-(4-methoxyphenoxy)benzoic acid | 1274574-83-2

• 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-chloro-2-(4-methoxyphenoxy)benzoic acid
• CAS: 1274574-83-2
• 化学式: C₁₄H₁₁ClO₄
• 分子量: 278.692
• InChiKey: KWMYEKBAZIIIII-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 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：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-chloro-2-(4-methoxyphenoxy)benzoic acid 在 硫酸 、 potassium carbonate 、 potassium iodide 、 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 7.0h， 生成 6-chloro-2-(5-(4-methylpiperidin-1-yl)pentyloxy)-9H-xanthen-9-one
  参考文献：
  名称：

  Rational design of new multitarget histamine H3 receptor ligands as potential candidates for treatment of Alzheimer’s disease

  摘要：

  Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H₃ receptor (H₃R) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human H₃R (hH₃R) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hH₃R affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC₅₀ values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hH₃R (K_i = 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC₅₀ = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC₅₀ = 880 nM and 394 nM respectively) and hMAO B (IC₅₀ = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hH₃R, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.

  DOI：

  10.1016/j.ejmech.2020.112743
• 作为产物：
  描述：

  2,4-二氯苯甲酸 、 4-甲氧基苯酚 在 sodium methylate 、 铜 、 copper(II) oxide 作用下， 以 paraffin oil 为溶剂， 反应 2.0h， 以45%的产率得到4-chloro-2-(4-methoxyphenoxy)benzoic acid
  参考文献：
  名称：

  Rational design of new multitarget histamine H3 receptor ligands as potential candidates for treatment of Alzheimer’s disease

  摘要：

  Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H₃ receptor (H₃R) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human H₃R (hH₃R) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hH₃R affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC₅₀ values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hH₃R (K_i = 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC₅₀ = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC₅₀ = 880 nM and 394 nM respectively) and hMAO B (IC₅₀ = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hH₃R, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.

  DOI：

  10.1016/j.ejmech.2020.112743

文献信息

• Microwave-Assisted, Yb(OTf)3 /TfOH Cocatalyzed Synthesis of Xanthones and Thioxanthones by Intramolecular Friedel-Crafts Reaction under Solvent-Free Conditions
  作者：Weike Su、Jie Li、Can Jin

  DOI：10.3987/com-11-12136

  日期：——

  An efficient method for the synthesis of biologically interesting xanthones and thioxanthones was achieved using Yb(OTf)(3)/TfOH as co-catalysts by a microwave radiation-mediated reaction. Both electron-rich and electron-poor substrates could be cyclized in good yields.
• Rational design of new multitarget histamine H3 receptor ligands as potential candidates for treatment of Alzheimer’s disease
  作者：Dorota Łażewska、Marek Bajda、Maria Kaleta、Paula Zaręba、Agata Doroz-Płonka、Agata Siwek、Alaa Alachkar、Szczepan Mogilski、Ali Saad、Kamil Kuder、Agnieszka Olejarz-Maciej、Justyna Godyń、Dorota Stary、Sylwia Sudoł、Małgorzata Więcek、Gniewomir Latacz、Maria Walczak、Jadwiga Handzlik、Bassem Sadek、Barbara Malawska、Katarzyna Kieć-Kononowicz

  DOI：10.1016/j.ejmech.2020.112743

  日期：2020.12

  Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H₃ receptor (H₃R) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human H₃R (hH₃R) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hH₃R affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC₅₀ values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hH₃R (K_i = 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC₅₀ = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC₅₀ = 880 nM and 394 nM respectively) and hMAO B (IC₅₀ = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hH₃R, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.