Design, synthesis, biological evaluation, and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors

Ling Wang; Yu Wang; Yiguang Tian; Jinling Shang; Xiaoou Sun; Hongzhuan Chen; Hao Wang; Wen Tan

doi:10.1016/j.bmc.2016.11.002

Design, synthesis, biological evaluation, and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors

Bioorg Med Chem. 2017 Jan 1;25(1):360-371. doi: 10.1016/j.bmc.2016.11.002. Epub 2016 Nov 5.

Authors

Ling Wang¹, Yu Wang², Yiguang Tian³, Jinling Shang³, Xiaoou Sun³, Hongzhuan Chen², Hao Wang⁴, Wen Tan⁵

Affiliations

¹ Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Pre-Incubator for Innovative Drugs & Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China. Electronic address: lingwang@scut.edu.cn.
² Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
³ Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Pre-Incubator for Innovative Drugs & Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
⁴ Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: angela_wanghao@hotmail.com.
⁵ Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Pre-Incubator for Innovative Drugs & Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China. Electronic address: went@scut.edu.cn.

PMID: 27856236
DOI: 10.1016/j.bmc.2016.11.002

Abstract

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC₅₀ to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer's disease (AD) treatment.

Keywords: Alzheimer’s disease; Antioxidative; Chalcone-rivastigmine hybrids; Cholinesterase inhibition; Molecular docking.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy
Butyrylcholinesterase / metabolism
Catalytic Domain
Cell Line, Tumor
Chalcones / chemical synthesis
Chalcones / pharmacology*
Chalcones / toxicity
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / pharmacology*
Cholinesterase Inhibitors / toxicity
Humans
Hydrogen Bonding
Kinetics
Molecular Docking Simulation
Molecular Dynamics Simulation
Oxidative Stress / drug effects
Reactive Oxygen Species / metabolism
Rivastigmine / analogs & derivatives*
Rivastigmine / chemical synthesis
Rivastigmine / pharmacology*
Rivastigmine / toxicity
Structure-Activity Relationship

Substances

Chalcones
Cholinesterase Inhibitors
Reactive Oxygen Species
Acetylcholinesterase
Butyrylcholinesterase
Rivastigmine