Dawid Panek (Avtor), Anna Więckowska (Avtor), Anna Pasieka (Avtor), Justyna Godyń (Avtor), Jakub Jończyk (Avtor), Marek Bajda (Avtor), Damijan Knez (Avtor), Stanislav Gobec (Avtor), Barbara Malawska (Avtor)

Povzetek

The complex nature of Alzheimer's disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward beta-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human %-secretase (hBACE-1), and beta-amyloid (A beta-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC50 = 3.33 microM), hBACE-1 (43.7% at 50 microM), and A beta-aggregation (24.9% at 10 microM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes acetylcholinesterase and beta-secretase. In conclusion: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer's agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: beta-secretase and A beta-aggregation.

Ključne besede

isoindoline-1,3-dione derivatives;cholinesterase inhibitors;BACE-1 inhibitors;Abeta-aggregation;molecular modeling;multiple anti-Alzheimer's ligands;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 616.894:615
COBISS: 4473713 Povezava se bo odprla v novem oknu
ISSN: 1420-3049
Št. ogledov: 222
Št. prenosov: 173
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: Alzheimerjeva bolezen;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-15
Letnik: ǂVol. ǂ23
Zvezek: ǂiss. ǂ2
Čas izdaje: 2018
DOI: 10.3390/molecules23020347
ID: 13641446