title: Amine substitution of quinazolinones leads to selective nanomolar AChE inhibitors with 'inverted' binding mode.
abstract: Selective and nanomolar acetylcholinesterase inhibitors were obtained by connecting tri- and tetracyclic quinazolinones-previously described as moderately active and unselective cholinesterase (ChE) inhibitors-via a hydroxyl group in para position to an anilinic nitrogen with different amines linked via a three carbon atom spacer. These tri- and tetracyclic quinazolinones containing different alicyclic ring sizes and connected to tertiary amines were docked to a high-resolution hAChE crystal structure to investigate the preferred binding mode in relation to results obtained by experimental structure-activity relationships. While the 'classical orientation' locating the heterocycle in the active site was rarely found, an alternative binding mode with the basic aliphatic amine in the active center ('inverted' orientation) was obtained for most compounds. Analyses of extended SARs based on this inverted binding mode are able to explain the compounds' binding affinities at AChE.
authors.affiliation: Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Fouad H
authors.initials: FH
authors.lastname: Darras
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wehle
authors.affiliation: Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany; Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Guozheng
authors.initials: G
authors.lastname: Huang
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.affiliation: Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany; Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany. Electronic address: michael.decker@uni-wuerzburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000588:Amines / Q000737:chemistry*; D001665:Binding Sites / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D002800:Cholinesterase Inhibitors; D052999:Quinazolinones; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Cholinesterase inhibitors; Computational study; Heterocycles; Quinazolinones