title: Multiple Ligands Targeting Cholinesterases and β-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore.
abstract: Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50  = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent.
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Szałaj
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Dudek
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001596:Benzylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002199:Capillary Permeability; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D011487:Protein Conformation; D012439:Saccharin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D058851:GPI-Linked Proteins; D006571:Heterocyclic Compounds; D008024:Ligands; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C548244:ACHE protein, human; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D012439:Saccharin
keywords: Alzheimer's disease; Beta amyloid aggregation inhibitors; Cholinesterase inhibitors; Multitarget-directed ligand