title: Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta.
abstract: Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer's disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention--compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM), and it inhibits amyloid beta aggregation (35.8% at 10 μM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer's agents.
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. hebdamichalina@gmail.com.
authors.forename: Michalina
authors.initials: M
authors.lastname: Hebda
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. marek.bajda@uj.edu.pl.
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. anna.wieckowska@uj.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Więckowska
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. natalia.szalaj@uj.edu.pl.
authors.forename: Natalia
authors.initials: N
authors.lastname: Szałaj
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. anna.pasieka@uj.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Pasieka
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. dawid.panek@uj.edu.pl.
authors.forename: Dawid
authors.initials: D
authors.lastname: Panek
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. justyna.godyn@uj.edu.pl.
authors.forename: Justyna
authors.initials: J
authors.lastname: Godyń
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. tomasz.wichur@doctoral.uj.edu.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wichur
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana 1000, Slovenia. damijan.knez@ffa.uni-lj.si.
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana 1000, Slovenia. Stanislav.Gobec@ffa.uni-lj.si.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland. mfmalaws@cyf-kr.edu.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D008024:Ligands; D008958:Models, Molecular; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; C110621:Isoindol-1-one; D054833:Isoindoles; D008024:Ligands; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; PAMPA-BBB assay; cholinesterase inhibitors; molecular modelling; multi-target-directed ligands (MTDL); β-amyloid aggregation inhibitors