title: Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation.
abstract: The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50values ranging from 0.83 μM to 19.18 μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50= 0.83 μM) and inhibitory activity against hBACE1 (33.61% at 50 μM). Compound 52 is a selective AChE inhibitor (IC50 AChE= 6.47 μM) with BACE1 inhibitory activity (26.3% at 50 μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10 μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Panek
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Więckowska
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wichur
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: Justyna
authors.initials: J
authors.lastname: Godyń
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Jończyk
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Mika
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Janockova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
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: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000187:drug effects; D002802:Cholinesterases / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010446:Peptide Fragments / Q000378:metabolism; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D066263:Protein Aggregation, Pathological; D011485:Protein Binding / Q000187:drug effects; D012439:Saccharin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000588:Amines; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010797:Phthalimides; C444321:amyloid beta-protein (1-34); C037431:phthalimide; D002802:Cholinesterases; D053829:Amyloid Precursor Protein Secretases; D012439:Saccharin
keywords: Acetylcholinesterase inhibitors; Alzheimer's disease; Aβ aggregation; BACE1 inhibitors; Molecular docking; Multifunctional agents