title: Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2 R Ligands To Combat Neurodegenerative Disorders.
abstract: A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB2 R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro- or sub-micromolar activities at both targets and excellent selectivity over hCB1 and AChE, respectively. Computational studies of the first- and second-generation lead structures by applying molecular dynamics (MD) on the active hCB2 R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual-acting compounds with "balanced" affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Dolles
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Nimczick
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheiner
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramler
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Stadtmüller
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Sawatzky
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Antonios
authors.initials: A
authors.lastname: Drakopoulos
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sotriffer
authors.affiliation: Pharmaceutical and Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, 95053, Regensburg, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wittmann
authors.affiliation: Pharmaceutical and Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, 95053, Regensburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany. michael.decker@uni-wuerzburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000595:Amino Acid Sequence; D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D017434:Protein Structure, Tertiary; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016415:Sequence Alignment; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D002800:Cholinesterase Inhibitors; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D002091:Butyrylcholinesterase
keywords: Alzheimer′s disease; butyrylcholinesterase; cannabinoid receptor ligands; molecular dynamics; multitarget compounds