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Central Nervous System Agents in Medicinal Chemistry

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ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

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Research Article

Design, Synthesis and Evaluation of Benzimidazole Hybrids to Inhibit Acetylcholinesterase and COX for Treatment of Alzheimer’s Disease

Author(s): Sukhvir Kaur, Richa Minhas, Shivam Mishra, Birpal Kaur, Yogita Bansal* and Gulshan Bansal

Volume 22, Issue 1, 2022

Published on: 13 June, 2022

Page: [68 - 78] Pages: 11

DOI: 10.2174/1871524922666220428134001

Price: $65

Abstract

Background: A simultaneous administration of an acetylcholinesterase (AChE) inhibitor and a NSAID as a drug cocktail has been documented to exhibit significantly protective effects in AD patients. But it suffers from poor patent compliance, pharmacodynamics and pharmacokinetic issues.

Objective: The present study is aimed to design and synthesize a hybrid molecule capable of exhibiting both AChE inhibition and anti-inflammatory activities for de-accelerating the progression of AD. The synthesized molecules will be evaluated for in vitro and in vivo models.

Methods: The present study involves the coupling of ibuprofen or naproxen to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05. The synthesized compounds were characterized using FTIR, 1H-NMR, 13C-NMR and MS. All compounds were evaluated for in vitro AChE inhibitory and COX inhibitory activities. The most active compound was taken for in vivo evaluation.

Results: Compounds of series IB01-IB05 are found more potent as compared to NP01-NP05. The maximally potent compound IB04 in in vitro evaluation is selected for in vivo evaluation of memory restoration activity using scopolamine-induced amnesia model in mice. It significantly reverses the scopolamine-induced changes (i.e., escape latency time, mean time spent in target quadrant, brain AChE activity and oxidative stress) in a dose-dependent manner. IB04 at 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil.

Conclusion: The findings indicate that Benzimidazole hybrids utilizing ibuprofen and pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.

Keywords: NsCOXi, Alzheimer’s disease, acetylcholinesterase inhibitor, hybrid, benzimidazole, ibuprofen, naproxen.

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