3-[N-methyl-N-(3-hydroxybenzyl)amino]propoxyxanthen-9-one | 164934-44-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 3-[N-methyl-N-(3-hydroxybenzyl)amino]propoxyxanthen-9-one
• 英文别名: 3-[3-[(3-Hydroxyphenyl)methyl-methylamino]propoxy]xanthen-9-one
• CAS: 164934-44-5
• 化学式: C₂₄H₂₃NO₄
• 分子量: 389.451
• InChiKey: DALIQFSKLIXFTL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  异氰酸正丁酯 、 3-[N-methyl-N-(3-hydroxybenzyl)amino]propoxyxanthen-9-one 在 sodium hydride 作用下， 以 甲苯 为溶剂， 反应 24.0h， 以35%的产率得到3-{[methyl({3-[(9-oxo-9H-xanthen-3-yl)oxy]propyl})amino]methyl}phenyl N-butylcarbamate
  参考文献：
  名称：

  Acetylcholinesterase Inhibitors:  Synthesis and Structure−Activity Relationships of ω-[N-Methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl Derivatives

  摘要：

  Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyxanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.

  DOI：

  10.1021/jm9810046
• 作为产物：
  描述：

  N-benzyl-1-(3-methoxyphenyl)-N-methylmethanamine 在 palladium on activated charcoal 氢溴酸 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 反应 3.0h， 生成 3-[N-methyl-N-(3-hydroxybenzyl)amino]propoxyxanthen-9-one
  参考文献：
  名称：

  Valentini, Piero; Rampa, Angela; Bisi, Alessandra, Medicinal Chemistry Research, 1995, vol. 5, # 4, p. 255 - 264

  摘要：

  DOI：

文献信息

• Acetylcholinesterase Inhibitors:  SAR and Kinetic Studies on ω-[<i>N</i>-Methyl-<i>N</i>-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl Derivatives
  作者：Angela Rampa、Lorna Piazzi、Federica Belluti、Silvia Gobbi、Alessandra Bisi、Manuela Bartolini、Vincenza Andrisano、Vanni Cavrini、Andrea Cavalli、Maurizio Recanatini、Piero Valenti

  DOI：10.1021/jm010914b

  日期：2001.11.1

  In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetyleholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure-activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC50 value for the AChE inhibition of 0.32 +/- 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC50 value of 3.3 +/- 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.