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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

The complexity of Alzheimer&apos;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.

Název v anglickém jazyce

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

Popis výsledku anglicky

The complexity of Alzheimer&apos;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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Svazek periodika

125

Číslo periodika v rámci svazku

January

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

20

Strana od-do

676-695

Kód UT WoS článku

000390496600054

EID výsledku v databázi Scopus

2-s2.0-84990026631