Design, synthesis, in vitro and in vivo 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, 15b and 15j showed submicromolar IC₅₀ values (15b, eeAChE IC₅₀ = 0.39 ± 0.11 µM; 15j, eqBChE IC₅₀ = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j 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 in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.

Keywords:

• Alzheimer’s disease
• cholinesterase inhibitor
• 1,3-dimethylbenzimidazolinone derivatives
• molecular docking
• structural modification
• structure-activity relationship

Acknowledgements

The authors gratefully thank the support from the grants of National Natural Science Foundation of China. The authors also thank the support from “Double First-Class” initiative Innovation team project of China Pharmaceutical University.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by the grants [Nos. 81872728 and 81573281] of National Natural Science Foundation of China and “Double First-Class” initiative Innovation team project of China Pharmaceutical University [Nos. CPU2018GF11 and CPU2018GY34].