Pharmacophore-based design and discovery of (−)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis. (1st January 2017)

• Record Type: Journal Article
• Authors: Xie, Qiong; Zheng, Zhaoxi; Shao, Biyun; Fu, Wei; Xia, Zheng; Li, Wei; Sun, Jian; Zheng, Wei; Zhang, Weiwei; Sheng, Wei; Zhang, Qihong; Chen, Hongzhuan; Wang, Hao; Qiu, Zhuibai
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 32:Number 1(2017)
• Page Start: 659
• Page End: 671
• Publication Date: 2017-01-01
• Subjects: Pharmacophore -- carbamates -- (−)-meptazinol -- acetylcholinesterase -- amyloidogenesis; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2016.1265521
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (−)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate43 was highly potent (IC50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism.43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ42 ) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP695 cells at 50 µ M. The dual actions of43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.