Design, synthesis, <i>in vitro</i> and <i>in vivo</i> evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer’s disease

Abstract

Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer’s disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, <b>15b</b> and <b>15j</b> showed submicromolar IC₅₀ values (<b>15b</b>, eeAChE IC₅₀ = 0.39 ± 0.11 µM; <b>15j</b>, eqBChE IC₅₀ = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that <b>15b</b> and <b>15j</b> act in a competitive manner. <b>15b</b> and <b>15j</b> showed neuroprotective effect against H₂O₂-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay <i>in vitro</i>. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of <b>15b</b> and <b>15j</b> was lower than tacrine. In summary, these data suggest <b>15b</b> and <b>15j</b> are promising multifunctional agents against AD.