| Avtor/Urednik | Panek, Dawid; Więckowska, Anna; Pasieka, Anna; Godyń, Justyna; Jończyk, Jakub; Bajda, Marek; Knez, Damijan; Gobec, Stanislav; Malawska, Barbara | |
| Naslov | Design, synthesis, and biological evaluation of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones derivatives as potential disease-modifying multifunctional anti-Alzheimer agents | |
| Tip | članek | |
| Vol. in št. | Letnik 23, št. 2 | |
| Leto izdaje | 2018 | |
| Obseg | str. 1-15 | |
| ISSN | 1420-3049 - Molecules (Basel, Switzerland) | |
| Jezik | eng | |
| Abstrakt | 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. | |
| Deskriptorji | Alzheimerjeva bolezen | |
| Proste vsebinske oznake | isoindoline-1,3-dione derivatives cholinesterase inhibitors BACE-1 inhibitors Abeta-aggregation molecular modeling multiple anti-Alzheimer's ligands |