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.
2018
2021-10-05 09:08:05
1033
isoindoline-1,3-dione derivatives, cholinesterase inhibitors, BACE-1 inhibitors, Aβ-aggregation, molecular modeling, multiple anti-Alzheimer's ligands
Alzheimerjeva bolezen
dk_c
Dawid
Panek
70
Anna
Więckowska
70
Anna
Pasieka
70
Justyna
Godyń
70
Jakub
Jończyk
70
Marek
Bajda
70
Damijan
Knez
70
Stanislav
Gobec
70
Barbara
Malawska
70
UDK
4
616.894:615
ISSN pri članku
9
1420-3049
DOI
15
10.3390/molecules23020347
COBISS_ID
3
4473713
RAZ_Panek_Dawid_2018.pdf
6598837
Predstavitvena datoteka
2021-10-05 09:11:24
0
Izvorni URL
2021-10-05 09:08:09