title: Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors.
abstract: New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130.
authors.affiliation: a Pamukova Vocational High School, Sakarya University , Sakarya , Turkey.
authors.forename: Fatih
authors.initials: F
authors.lastname: Sonmez
authors.affiliation: b Department of Analytical and Pharmaceutical Chemistry, Faculty of Pharmacy , Bezmialem Vakif University , Istanbul , Turkey.
authors.forename: Belma
authors.initials: B
authors.lastname: Zengin Kurt
authors.affiliation: b Department of Analytical and Pharmaceutical Chemistry, Faculty of Pharmacy , Bezmialem Vakif University , Istanbul , Turkey.
authors.forename: Isil
authors.initials: I
authors.lastname: Gazioglu
authors.affiliation: c Department of Drug Sciences , University of Catania, Città Universitaria , Catania , Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.affiliation: b Department of Analytical and Pharmaceutical Chemistry, Faculty of Pharmacy , Bezmialem Vakif University , Istanbul , Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: Dag
authors.affiliation: c Department of Drug Sciences , University of Catania, Città Universitaria , Catania , Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cappello
authors.affiliation: d Molecular Modelling Laboratory, Department of Food Science , University of Parma , Parma , Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ginex
authors.affiliation: e Faculty of Arts and Science, Department of Chemistry , Sakarya University , Sakarya , Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Kucukislamoglu
authors.affiliation: c Department of Drug Sciences , University of Catania, Città Universitaria , Catania , Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects*; D000818:Animals; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003374:Coumarins / Q000494:pharmacology*; D015195:Drug Design; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D013057:Spectrum Analysis / Q000379:methods
chemical_list: D002800:Cholinesterase Inhibitors; D003374:Coumarins; D008024:Ligands; D000110:Acetylcholinesterase
keywords: Acetamide; Alzheimer’s disease; acetylcholinesterase; coumarin; selectivity