title: Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase.
abstract: Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Peng
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Sheng-Gang
authors.initials: SG
authors.lastname: Yang
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China. Electronic address: tomyang@mail.ccnu.edu.cn.
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Yang
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China; Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 30071, PR China. Electronic address: gfyang@mail.ccnu.edu.cn.
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D004791:Enzyme Inhibitors; D013619:Tacrine; C030123:coumarin; D000110:Acetylcholinesterase; D002802:Cholinesterases; D053829:Amyloid Precursor Protein Secretases
keywords: Acetylcholinesterase inhibitor; Alzheimer’s disease; Butylcholinesterase inhibitor; Coumarin