Design, synthesis and evaluation of benzimidazole-NsCOXis hybrids for the treatment of Alzheimer’s disease

Abstract Usage of an acetylcholinesterase (AChE) inhibitor and a non-selective COX inhibitor (NsCOXi) have been documented to exhibit significantly protective and recuperative effects in AD patients. Therefore, it is hypothesised that a compound capable of exhibiting both AChE inhibition and anti-inflammatory activities can be potential pluripotent drug candidate for de-accelerating the progression of AD, as well as for providing relief from the associated inflammatory pathological indications. The present study involves the coupling of ibuprofen (IB) or naproxen (NP) to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05 as pluripotent anti-AD compounds. All target compounds are evaluated for in vitro AChE inhibitory and COX inhibitory activities. Compounds IB01-IB05 are found more potent as compared to NP01-NP05. Compound IB04 being the most active in in vitro evaluation is selected for in vivo evaluation of memory restoration 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 higher dose i.e. 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil. The findings indicate that Benzimidazole-NsCOXi derivatives having pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.