Author/Editor     Panek, Dawid; Więckowska, Anna; Pasieka, Anna; Godyń, Justyna; Jończyk, Jakub; Bajda, Marek; Knez, Damijan; Gobec, Stanislav; Malawska, Barbara
Title     Design, synthesis, and biological evaluation of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones derivatives as potential disease-modifying multifunctional anti-Alzheimer agents
Type     članek
Vol. and No.     Letnik 23, št. 2
Publication year     2018
Volume     str. 1-15
ISSN     1420-3049 - Molecules (Basel, Switzerland)
Language     eng
Abstract     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.
Descriptors     Alzheimerjeva bolezen
Keywords     isoindoline-1,3-dione derivatives
cholinesterase inhibitors
BACE-1 inhibitors
Abeta-aggregation
molecular modeling
multiple anti-Alzheimer's ligands