title: Design, synthesis, and evaluation of 7H-thiazolo-[3,2-b]-1,2,4-triazin-7-one derivatives as dual binding site acetylcholinesterase inhibitors.
abstract: New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as a new drug candidate for the treatment of Alzheimer's disease (AD) through the binding to both catalytic and peripheral sites of the enzyme. Therefore, a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives 6a-j were synthesized and investigated for their ability to inhibit the activity of human AChE (hAChE) in comparison with huperzine-A. All the compounds were found to inhibit AChE activity, especially compounds 6c and 6i with the inhibition value of 76.10% and 77.82%, respectively. The molecular docking study indicated that they were nicely accommodated by AChE. The molecular docking study revealed that 6c and 6i possessed a more optimal binding conformation than 6a and can perfectly fit into the active and peripheral site of hAChE, and consequently exhibited highly improved inhibitor potency to hAChE.
authors.affiliation: College of Chemical Engineering, Shijiazhuang University, Shijiazhuang, 050035, China.
authors.forename: Sijie
authors.initials: S
authors.lastname: Liu
authors.forename: Ruofeng
authors.initials: R
authors.lastname: Shang
authors.forename: Lanxiang
authors.initials: L
authors.lastname: Shi
authors.forename: Ran
authors.initials: R
authors.lastname: Zhou
authors.forename: Jingyu
authors.initials: J
authors.lastname: He
authors.forename: David Chi-Cheong
authors.initials: DC
authors.lastname: Wan
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D014227:Triazines; C093444:1,2,4-triazine; D000110:Acetylcholinesterase
keywords: 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives; Alzheimer's disease; acetylcholinesterase; docking; inhibitors; synthesis