title: Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines.
abstract: The study presents the discovery of novel butyrylcholinesterase (BuChE) inhibitors among derivatives of azaphenothiazines by application of in silico and in vitro screening methods. From an in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand - AChE and ligand - BuChE). Five compounds displayed moderate AChE and good BuChE inhibitory activity at screening concentrations of 10 µM. The IC50 values for active BuChE inhibitors were in the 11.8-122.2 nM range. Three of the most active inhibitors are tetra- or pentacyclic derivatives of azaphenothiazines with the same N-methyl-2-piperidinethyl substituent.
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Medical College, Jagiellonian University , Kraków , Poland and.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Lodarski
authors.forename: Jakub
authors.initials: J
authors.lastname: Jończyk
authors.forename: Natalia
authors.initials: N
authors.lastname: Guzior
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.forename: Joanna
authors.initials: J
authors.lastname: Gładysz
authors.forename: Joanna
authors.initials: J
authors.lastname: Walczyk
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Jeleń
authors.forename: Beata
authors.initials: B
authors.lastname: Morak-Młodawska
authors.forename: Krystian
authors.initials: K
authors.lastname: Pluta
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000302:isolation & purification; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000302:isolation & purification; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D055808:Drug Discovery; D004593:Electrophorus; D057075:Enzyme Assays; D057166:High-Throughput Screening Assays; D006736:Horses; D007700:Kinetics; D062105:Molecular Docking Simulation; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D001372:Aza Compounds; D002800:Cholinesterase Inhibitors; D010640:Phenothiazines; D010880:Piperidines; D054852:Small Molecule Libraries; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Azaphenothiazines; butyrylcholinesterase inhibitors; cholinesterases; molecular docking; virtual screening