title: Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and β-amyloid aggregation inhibitors with neuroprotective properties.
abstract: The presented study describes the synthesis, pharmacological evaluation (AChE and BuChE inhibition, beta amyloid anti-aggregation effect and neuroprotective effect), molecular modeling and crystallographic studies of a novel series of isoindoline-1,3-dione derivatives. The target compounds were designed as dual binding site acetylcholinesterase inhibitors with an arylalkylamine moiety binding at the catalytic site of the enzyme and connected via an alkyl chain to a heterocyclic fragment, capable of binding at the peripheral anionic site of AChE. Among these molecules, compound 15b was found to be the most potent and selective AChE inhibitor (IC50EeAChE = 0.034 μM). Moreover, compound 13b in addition to AChE inhibition (IC50 EeAChE = 0.219 μM) possesses additional properties, such as the ability to inhibit Aβ aggregation (65.96% at 10 μM) and a neuroprotective effect against Aβ toxicity at 1 and 3 μM. Compound 13b emerges as a promising multi-target ligand for the further development of the therapy for age-related neurodegenerative disorders.
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Guzior
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: Mirosław
authors.initials: M
authors.lastname: Skrok
authors.affiliation: Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kurpiewska
authors.affiliation: Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Kraków, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Lewiński
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 Biology, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Anja
authors.initials: A
authors.lastname: Pišlar
authors.affiliation: Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia; Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
authors.forename: Janko
authors.initials: J
authors.lastname: Kos
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. Electronic address: mfmalaws@cyf-kr.edu.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: C000602797:2-(5-(3-chlorobenzylamino)pentyl)isoindoline-1,3-dione; C000602796:2-(5-(4-fluorobenzylamino)pentyl)isoindoline-1,3-dione; D016229:Amyloid beta-Peptides; D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D010797:Phthalimides; D066329:Protein Aggregates; D000110:Acetylcholinesterase
keywords: Alzheimer's disease; Cholinesterase inhibitors; Multi-target-directed ligands; Neuroprotection; β-amyloid aggregation inhibitors