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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.

Author information

1
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
2
Biomedical Research Centre, University Hospital Hradec Kralove, Czech Republic.
3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
4
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland. Electronic address: mfmalaws@cyf-kr.edu.pl.

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 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.

KEYWORDS:

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

PMID:
27721153
DOI:
10.1016/j.ejmech.2016.09.078
[Indexed for MEDLINE]

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