title: Novel ferulic amide derivatives with tertiary amine side chain as acetylcholinesterase and butyrylcholinesterase inhibitors: The influence of carbon spacer length, alkylamine and aromatic group.
abstract: Based on our recent investigations on chalcone derivatives as AChE inhibitors, a series of ferulic acid (FA) tertiary amine derivatives similar to chalcone compounds were designed and synthesized. The results of bioactivity evaluation revealed that most of new synthesized compounds had comparable or more potent AChE inhibitory activity than the control drug Rivastigmine. The alteration of carbon chain linking tertiary amine groups and ferulic acid scaffold markedly influenced the inhibition activity against AChE. Among them the inhibitory activity of compound 6d (IC50: 0.71 ± 0.09 μmol/L) and 6e (IC50: 1.11 ± 0.17 μmol/L) was equal to 15-fold and 9-fold than that of Rivastigmine against AChE (IC50: 10.54 ± 0.86 μmol/L), respectively. Moreover, compound 6d shows the highest selectivity for AChE over butyrylcholinesterase(BuChE) (ratio: 18.3). The kinetic study suggested that compound 6d revealed a mixed-type inhibition against AChE. The result of molecular docking showed that compound 6d combines to AChE with three amino acid sites(Trp84, Tyr334 and Trp279), while combines to BuChE with two amino acid sites (Tyr67 and Gly66) in enzyme domains, respectively. Compound 6d might act as a potential agent for the treatment of Alzheimer's diseases (AD).
authors.affiliation: College of Chemistry and Chemical Engineering, Hu'nan University, Changsha 410082, China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Liu
authors.affiliation: College of Chemistry and Chemical Engineering, Hu'nan University, Changsha 410082, China.
authors.forename: Linbo
authors.initials: L
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Hu'nan University of Chinese Medicine, Changsha 410208, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Gao
authors.affiliation: College of Medicine, Hu'nan Normal University, Changsha 410013, China. Electronic address: liuyingzi111@sina.com.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Medicine, Hu'nan Normal University, Changsha 410013, China.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Xu
authors.affiliation: College of Medicine, Hu'nan Normal University, Changsha 410013, China.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: College of Medicine, Hu'nan Normal University, Changsha 410013, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: College of Chemistry and Chemical Engineering, Hu'nan University, Changsha 410082, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Tang
authors.affiliation: College of Chemistry and Chemical Engineering, Hu'nan University, Changsha 410082, China.
authors.forename: Haoqun
authors.initials: H
authors.lastname: Fan
authors.affiliation: College of Pharmacy, Hu'nan University of Chinese Medicine, Changsha 410208, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Xia
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000577:Amides / Q000737:chemistry*; D000588:Amines / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003373:Coumaric Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000588:Amines; D002800:Cholinesterase Inhibitors; D003373:Coumaric Acids; C004999:ferulic acid; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterases; Alzheimer's disease; Ferulic acid; Molecular docking; α,β-Unsaturated carbonyl