Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F17%3A10331701" target="_blank" >RIV/00179906:_____/17:10331701 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.1016/j.ejmech.2016.09.078" target="_blank" >http://dx.doi.org/10.1016/j.ejmech.2016.09.078</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2016.09.078" target="_blank" >10.1016/j.ejmech.2016.09.078</a>
Alternative languages
Result language
angličtina
Original language name
Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation
Original language description
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 mu M to 19.18 mu M. The target compounds displayed inhibition of human beta-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 mu M 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-l-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 mu M) and inhibitory activity against hBACE1 (33.61% at 50 mu M). Compound 52 is a selective AChE inhibitor (IC50 AchE = 6.47 mu M) with BACE1 inhibitory activity (26.3% at 50 mu M) and it displays the most significant A beta anti-aggregating properties among all the obtained compounds (39% at 10 mu M). 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.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
European Journal of Medicinal Chemistry
ISSN
0223-5234
e-ISSN
—
Volume of the periodical
125
Issue of the periodical within the volume
January
Country of publishing house
FR - FRANCE
Number of pages
20
Pages from-to
676-695
UT code for WoS article
000390496600054
EID of the result in the Scopus database
2-s2.0-84990026631