title: Design, synthesis, biological evaluation, and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors.
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 IC50to 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.
authors.affiliation: 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.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yiguang
authors.initials: Y
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Jinling
authors.initials: J
authors.lastname: Shang
authors.affiliation: 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.
authors.forename: Xiaoou
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D002091:Butyrylcholinesterase / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068836:Rivastigmine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D047188:Chalcones; D002800:Cholinesterase Inhibitors; D017382:Reactive Oxygen Species; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000068836:Rivastigmine
keywords: Alzheimer’s disease; Antioxidative; Chalcone-rivastigmine hybrids; Cholinesterase inhibition; Molecular docking