title: Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives as dual-binding site acetylcholinesterase inhibitors.
abstract: A new series of 2-(diethylaminoalkyl)-isoindoline-1,3-dione derivatives intended as dual binding site cholinesterase inhibitors were designed using molecular modeling and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and the formation of the β-amyloid (Aβ) plaques. For AChE inhibitory activity, the spectrophotometric method of Ellman and the electrophoretically mediated microanalysis assay were used, giving good results. Most of the synthesized compounds had AChE inhibitory activity with IC(50) values ranging from IC(50) = 0.9 to 19.5 µM and weak Aβ anti-aggregation inhibitory activity. These results support the outcome of docking studies which tested compounds targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The most promising selective AChE inhibitors are compounds 10 (IC(50) = 1.2 µM) and 11 (IC(50) = 1.1 µM), with 6-7 methylene chains, which also inhibit Aβ fibril formation.
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Michalina
authors.initials: M
authors.lastname: Ignasik
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.forename: Natalia
authors.initials: N
authors.lastname: Guzior
authors.forename: Michaela
authors.initials: M
authors.lastname: Prinz
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D000110:Acetylcholinesterase; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004593:Electrophorus; D006736:Horses; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D002800:Cholinesterase Inhibitors; D054833:Isoindoles; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase