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

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.