Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease

Zonghua Luo; Liang Liang; Jianfei Sheng; Yanqing Pang; Jianheng Li; Ling Huang; Xingshu Li

doi:10.1016/j.bmc.2013.12.066

Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease

Bioorg Med Chem. 2014 Feb 15;22(4):1355-61. doi: 10.1016/j.bmc.2013.12.066. Epub 2014 Jan 9.

Authors

Zonghua Luo¹, Liang Liang², Jianfei Sheng¹, Yanqing Pang¹, Jianheng Li¹, Ling Huang¹, Xingshu Li³

Affiliations

¹ Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
² School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China.
³ Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: xsli219@yahoo.com.

PMID: 24461494
DOI: 10.1016/j.bmc.2013.12.066

Abstract

A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC₅₀ values of 0.76 and 0.46 μM, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD.

Keywords: Alzheimer’s disease; Cholinesterase inhibitors; GPx mimics.

Publication types

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

MeSH terms

Acetylcholinesterase / chemistry*
Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy
Antioxidants / chemical synthesis*
Antioxidants / metabolism
Antioxidants / therapeutic use
Azoles / chemical synthesis*
Azoles / chemistry*
Azoles / metabolism
Azoles / therapeutic use
Biocompatible Materials / chemical synthesis*
Biocompatible Materials / metabolism
Biocompatible Materials / therapeutic use
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / metabolism
Cholinesterase Inhibitors / therapeutic use
Glutathione Peroxidase / chemistry
Glutathione Peroxidase / metabolism
Humans
Isoindoles
Organoselenium Compounds / chemical synthesis*
Organoselenium Compounds / chemistry*
Organoselenium Compounds / metabolism
Organoselenium Compounds / therapeutic use
Protein Binding

Substances

5,6-dimethoxy-2-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzo(d)(1,2)selenazol-3(2H)-one
5,6-dimethoxy-2-(4-(piperidin-1-ylmethyl)phenyl)benzo(d)(1,2)selenazol-3(2H)-one
Antioxidants
Azoles
Biocompatible Materials
Cholinesterase Inhibitors
Isoindoles
Organoselenium Compounds
ebselen
Glutathione Peroxidase
Acetylcholinesterase
Butyrylcholinesterase