20.500.12556/RUL-131864 Design, synthesis, and biological evaluation of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones derivatives as potential disease-modifying multifunctional anti-Alzheimer agents 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 β-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human β-secretase (hBACE-1), and β-amyloid (Aβ-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC$_{50}$ = 3.33 µM), hBACE-1 (43.7% at 50 µM), and Aβ-aggregation (24.9% at 10 µM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes acetylcholinesterase and β-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: β-secretase and Aβ-aggregation. isoindoline-1 3-dione derivatives cholinesterase inhibitors BACE-1 inhibitors Aβ-aggregation molecular modeling multiple anti-Alzheimer's ligands Alzheimerjeva bolezen true false true Angleški jezik Slovenski jezik Članek v reviji 2021-10-05 09:08:05 2021-10-05 09:08:08 2022-09-10 04:14:15 0000-00-00 00:00:00 2018 0 0 15 str. iss. 2, art. 347 Vol. 23 2018 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.894:615 1420-3049 10.3390/molecules23020347 4473713 RAZ_Panek_Dawid_2018.pdf RAZ_Panek_Dawid_2018.pdf 1 0DEC31C48C934B9B622C5A52A9E37F71 25b7d3cdb32bca93e48d494cb872131ae971c1f0683313ace087831d36c98f46 27b68070-25ab-11ec-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=149290 http://www.mdpi.com/1420-3049/23/2/347 0 b3c4c73a-25aa-11ec-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=149289 Fakulteta za farmacijo 0 0 0