Design, synthesis and biological activity evaluation of novel carbazole-benzylpiperidine hybrids as potential anti Alzheimer agents

Alzheimer's 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 b-secretase (BACE1) activity and metal chelation properties. Among the synthesized compounds, compounds 9b (IC50 - 16.5 mu M for AChE and IC50 - 0.59 mM for BuChE) and 9c (IC50 - 26.5 mM for AChE and IC50 = 0.18 mu M 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 50 mM). 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. (C) 2020 Published by Elsevier B.V.