Title:Design, Synthesis and Evaluation of Benzimidazole Hybrids to Inhibit Acetylcholinesterase
and COX for Treatment of Alzheimer’s Disease
Volume: 22
Issue: 1
Author(s): Sukhvir Kaur, Richa Minhas, Shivam Mishra, Birpal Kaur, Yogita Bansal*Gulshan Bansal
Affiliation:
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India
Keywords:
NsCOXi, Alzheimer’s disease, acetylcholinesterase inhibitor, hybrid, benzimidazole, ibuprofen, naproxen.
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.
