Design, synthesis and biological evaluation of novel carbamates as potential inhibitors of acetylcholinesterase and butyrylcholinesterase

Jie Wu; Marco Pistolozzi; Siyu Liu; Wen Tan

doi:10.1016/j.bmc.2020.115324

Design, synthesis and biological evaluation of novel carbamates as potential inhibitors of acetylcholinesterase and butyrylcholinesterase

Bioorg Med Chem. 2020 Mar 1;28(5):115324. doi: 10.1016/j.bmc.2020.115324. Epub 2020 Jan 18.

Authors

Jie Wu¹, Marco Pistolozzi², Siyu Liu³, Wen Tan⁴

Affiliations

¹ School of Pharmacy, Jinan University, Guangzhou 510632, China; YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China.
² School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
³ Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
⁴ Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China; Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia. Electronic address: went@gdut.edu.cn.

PMID: 32008882
DOI: 10.1016/j.bmc.2020.115324

Abstract

Rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), has been approved by U.S. Food and Drug Administration to treat Alzheimer's disease (AD) and Parkinson's disease (PD) dementia. In the current work, a bambuterol derivative lacking one of the carbamoyloxy groups on the benzene ring (BMC-1) and its analogues were synthesized using 1-(3-hydroxyphenyl) ethan-1-one and 1-(4-hydroxyphenyl) ethan-1-one as starting materials. In-vitro cholinesterase assay established that nine compounds were more potent to inhibit both electric eel AChE and equine serum BChE than rivastigmine under the same experimental conditions. Further study confirmed that among the nine carbamates, BMC-3 (IC_50(AChE) = 792 nM, IC_50(BChE) = 2.2 nM) and BMC-16 (IC_50(AChE) = 266 nM, IC_50(BChE) = 10.6 nM) were excellent cholinesterase inhibitors with potential of permeating through the blood-brain barrier. These carbamates could be used as potential dual inhibitors of AChE and BChE and to discover novel drugs for the treatment of AD and PD dementia.

Keywords: Acetylcholinesterase; Bambuterol; Butyrylcholinesterase; Carbamates; Inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / metabolism*
Animals
Butyrylcholinesterase / metabolism*
Carbamates / chemical synthesis
Carbamates / chemistry
Carbamates / pharmacology*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Electrophorus
Horses
Molecular Structure
Structure-Activity Relationship

Substances

Carbamates
Cholinesterase Inhibitors
Acetylcholinesterase
Butyrylcholinesterase