Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1, 3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer's disease. (1st January 2020)

• Record Type: Journal Article
• Authors: Mo, Jun; Chen, Tingkai; Yang, Hongyu; Guo, Yan; Li, Qi; Qiao, Yuting; Lin, Hongzhi; Feng, Feng; Liu, Wenyuan; Chen, Yao; Liu, Zongliang; Sun, Haopeng
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 35:Number 1(2020)
• Page Start: 330
• Page End: 343
• Publication Date: 2020-01-01
• Subjects: Alzheimer's disease -- cholinesterase inhibitor -- 1, 3-dimethylbenzimidazolinone derivatives -- molecular docking -- structural modification -- structure-activity relationship; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1699553
• Languages: English
• ISSNs: 1475-6366

Abstract

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 H2 O2 -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.