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Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.


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 phenylcarbamate 43 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-? (A?) lowering effects (51.9% decrease of A?42) superior to phenserine (31% decrease of total A?) in SH-SY5Y-APP695 cells at 50?µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.

SUBMITTER: Xie Q 

PROVIDER: S-EPMC6009976 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.

Xie Qiong Q   Zheng Zhaoxi Z   Shao Biyun B   Fu Wei W   Xia Zheng Z   Li Wei W   Sun Jian J   Zheng Wei W   Zhang Weiwei W   Sheng Wei W   Zhang Qihong Q   Chen Hongzhuan H   Wang Hao H   Qiu Zhuibai Z  

Journal of enzyme inhibition and medicinal chemistry 20171201 1


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  ...[more]

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