Design, synthesis and biological evaluation of novel pyrazolone derivatives as selective butyrylcholinesterase inhibitors with antioxidant activity against Alzheimer's disease.

• Novel pyrazolone-based compounds were designed and synthesized. • The pyrazolone structure was found a selective BuChE pharmacophore. • 5i displayed potent inhibitory activity and the highest selectivity against BuChE. • 5i could scavenge free radicals and cross the BBB. The butyrylcholinesterase (BuChE) has been a potent target for the treatment of the Alzheimer's disease (AD), but the selective BuChE inhibitor is still lacking in the market. In this study, the pyrazolone structure was found to be a promising pharmacophore targeting BuChE. Thus, a series of pyrazolone-based compounds 5a-p were designed, synthesized and evaluated in vitro for BuChE inhibitory activities, antioxidant activities and blood-brain barrier (BBB) permeabilities. Besides, the compounds 5g, 5h, 5i and 5o with submicromolar IC 50 values as well as good BuChE selectivity were chosen to assess their cytotoxicity in PC12 cells. Among them, compound 5i was the most selective BuChE inhibitor (SI: >200) and showed the good abilities to penetrate BBB, scavenge free radicals (1.04 trolox equivalent). Based on above results, compound 5i was selected for molecular docking studies to explain the BuChE selectivity and was considered as a promising lead compound for further investigation in the treatment of AD. [Display omitted] [ABSTRACT FROM AUTHOR]