title: Inhibition of acetylcholinesterase by coumarins: the case of coumarin 106.
abstract: In this contribution, from a coumarin library consisting of 29 compounds including natural and synthetic derivatives, an active acetylcholinesterase (AChE) inhibitor (coumarin 106) was found. This circumstance leaded us to continue with the pharmacological characterization of coumarin 106. The first study with the coumarin library was performed using a 96-microtiter well plate assay based on Ellman's reaction. Coumarins were assayed at 5 and 30 microM, and coumarin 106 was found the most active inhibitor at both concentrations. The follow-up analysis using kinetic studies demonstrated that coumarin 106 displays mixed-type AChE inhibition with a pIC(50)=4.97+/-0.09 and K(i)=2.36+/-0.17 microM. The ability of this molecule to interact with AChE was further confirmed through computational studies, in which a primary binding was proved to occur at the active gorge site, while a secondary binding was demonstrated at the peripheral anionic site. Also, coumarin 106 was shown to inhibit butyrylcholinesterase (BChE) with slightly lower potency (pIC(50)=4.56+/-0.06), and found to be non-toxic in Caco-2 cells. The combination of these findings makes coumarin 106 an attractive molecule for further investigation. This is the first report where AChE inhibitory activity has been associated with coumarin 106, and proof has been given of its convenience as a lead molecule.
authors.affiliation: Division of Pharmacy, Department of Biochemistry and Pharmacy, Faculty of Mathematics and Natural Sciences, Abo Akademi University, Artillerigatan 6A, FIN-20520 Turku, Finland.
authors.forename: Adyary
authors.initials: A
authors.lastname: Fallarero
authors.forename: Päivi
authors.initials: P
authors.lastname: Oinonen
authors.forename: Shikhar
authors.initials: S
authors.lastname: Gupta
authors.forename: Pia
authors.initials: P
authors.lastname: Blom
authors.forename: Anna
authors.initials: A
authors.lastname: Galkin
authors.forename: C Gopi
authors.initials: CG
authors.lastname: Mohan
authors.forename: Pia M
authors.initials: PM
authors.lastname: Vuorela
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000378:metabolism; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors; D002855:Chromatography, Thin Layer; D003374:Coumarins / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase