Development of novel fluoro-substituted rivastigmine derivatives as selective AChE inhibitors for the treatment of AD

Abstract

The classic cholinergic hypothesis was considered as the successful hypothesis due to the marketed drugs (donepezil, rivastigmine, and galantamine). The development of selective AChE inhibitor still was a promising strategy for the treatment of Alzheimer’s disease (AD). Herein, 29 novel rivastigmine derivatives was rationally developed as selective AChE inhibitors for treating AD. The target compounds were designed and evaluated through AChE/BuChE inhibition, reversibility study, and neuroprotective effect. The results in vitro showed that compound 9a showed the best eeAChE inhibitory potency (IC₅₀ = 1.78 μM) and weak BuChE inhibitory potency, suggesting that compound 9a was a selective AChE inhibitor. The molecular docking offered possible mechanism for its high AChE inhibitory potency. The further study indicated that compound 9a was a pseudo-irreversible eeAChE inhibitor. Furthermore, 9a demonstrated significant neuroprotective effect on L-Glu-induced HT22 cells injury. Further, 9a presented favorable predicted drug-like property. Therefore, 9a was a promising selective AChE inhibitor for treating AD.