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Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregationPanek, Dawid ...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, beta-secretase and beta-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 microM to 19.18 microM. The target compounds displayed inhibition of human beta-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 microM 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 microM) and inhibitory activity against hBACE1 (33.61 at 50 microM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 microM) with BACE1 inhibitory activity (26.3% at 50 microM) and it displays the most significant A(beta) anti-aggregating properties among all the obtained compounds (39 at 10 microM). 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.Source: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 125, Jan. 2017, str. 676-695)Type of material - article, component part ; adult, seriousPublish date - 2017Language - englishCOBISS.SI-ID - 4223601
Link(s):
http://www.sciencedirect.com/science/article/pii/S0223523416308169Dostop preko računalnikov UL
DOI
Author
Panek, Dawid |
Więckowska, Anna |
Wichur, Tomasz |
Bajda, Marek |
Godyń, Justyna |
Jończyk, Jakub |
Mika, Kamil |
Janockova, Jana |
Soukup, Ondrej, Biomedicinist |
Knez, Damijan, farmacevt |
Korabecny, Jan |
Gobec, Stanislav, 1970- |
Malawska, Barbara
Topics
Alzheimerjeva bolezen |
Alzheimer's disease |
multifunctional agents |
acetylcholinesterase inhibitors |
BACE1 inhibitors |
Aß aggregation |
molecular docking
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Database name | Field | Year |
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Panek, Dawid | |
Więckowska, Anna | |
Wichur, Tomasz | |
Bajda, Marek | |
Godyń, Justyna | |
Jończyk, Jakub | |
Mika, Kamil | |
Janockova, Jana | |
Soukup, Ondrej, Biomedicinist | |
Knez, Damijan, farmacevt | 36438 |
Korabecny, Jan | |
Gobec, Stanislav, 1970- | 15284 |
Malawska, Barbara |
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