Sadeghian_2020_J.Mol.Struct_1221_128793

Alzheimers disease (AD) as the most common form of dementia in aged people, is an intricate neurodegenerative disease. Therefore, a novel strategy so-called multi-target-directed ligand has received much attention for the effective treatment of AD. In this study a series of novel carbazole-benzylpiperidine hybrids 9a-m was designed, synthesized and evaluated as acetylcholinesterase and butyrylcholinesterase inhibitors. Moreover, some of these compounds were evaluated for anti -secretase (BACE1) activity and metal chelation properties. Among the synthesized compounds, compounds 9b (IC50=16.5M for AChE and IC50=0.59M for BuChE) and 9c (IC50=26.5M for AChE and IC50=0.18M for BuChE) showed the highest inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Furthermore, these compounds (9b and 9c) displayed interaction with Zn2+ ion and compound 9c showed moderate inhibitory activity against BACE1 (24.5% at 50M). Kinetic and docking studies exhibited that these compounds likely act as a non-competitive inhibitor able to interact with the catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase simultaneously.