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Eur J Med Chem. 2017 Jan 5;125:676-695. doi: 10.1016/j.ejmech.2016.09.078. Epub 2016 Sep 26.

Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation.

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Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
Biomedical Research Centre, University Hospital Hradec Kralove, Czech Republic.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland. Electronic address:


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 IC50 values 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.


Acetylcholinesterase inhibitors; Alzheimer's disease; Aβ aggregation; BACE1 inhibitors; Molecular docking; Multifunctional agents

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