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-benzylpi...

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Bibliographic Details
Published in:Journal of molecular structure 2020-12, Vol.1221, p.128793, Article 128793
Main Authors: Sadeghian, Batool, Sakhteman, Amirhossein, Faghih, Zeinab, Nadri, Hamid, Edraki, Najmeh, Iraji, Aida, Sadeghian, Issa, Rezaei, Zahra
Format: Article
Language:English
Subjects:
Acetylcholinesterase
Alzheimer’s disease
Benzylpiperidine
Butyrylcholinesterase
Carbazole
Docking study
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Summary: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 β-secretase (BACE1) activity and metal chelation properties. Among the synthesized compounds, compounds 9b (IC50 = 16.5 μM for AChE and IC50 = 0.59 μM for BuChE) and 9c (IC50 = 26.5 μM for AChE and IC50 = 0.18 μM 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 μM). 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. [Display omitted] •Synthesis of novel carbazole-benzylpiperidine hybrids.•The synthesized compounds had inhibitory activity against AChE, BuChe, and BACE1.•These compounds could interact with Zn2+ Ion.•Kinetic and docking studies showed that these compounds were non-competitive inhibitors for AChE.
ISSN:0022-2860
1872-8014
DOI:10.1016/j.molstruc.2020.128793