Design, synthesis, and biological evaluation of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones derivatives as potential disease-modifying multifunctional anti-Alzheimer agentsPanek, Dawid (Avtor) Więckowska, Anna (Avtor) Pasieka, Anna (Avtor) Godyń, Justyna (Avtor) Jończyk, Jakub (Avtor) Bajda, Marek (Avtor) Knez, Damijan (Avtor) Gobec, Stanislav (Avtor) Malawska, Barbara (Avtor) isoindoline-13-dione derivativescholinesterase inhibitorsBACE-1 inhibitorsAβ-aggregationmolecular modelingmultiple anti-Alzheimer's ligandsThe 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.20182021-10-05 09:08:05Članek v reviji131864sl