2. Academic Validation
  3. Synthesis, in vitro and in vivo biological evaluation of novel graveolinine derivatives as potential anti-Alzheimer agents

Synthesis, in vitro and in vivo biological evaluation of novel graveolinine derivatives as potential anti-Alzheimer agents

  • Bioorg Med Chem. 2020 Jan 1;28(1):115190. doi: 10.1016/j.bmc.2019.115190.
Wen Luo 1,  Jian-Wu Lv 1,  Ting Wang 1,  Zhi-Yang Zhang 1,  Hui-Yan Guo 1,  Zhi-Yi Song 2,  Chao-Jie Wang 1,  Jing Ma 3,  Yi-Ping Chen 4
Affiliations

Affiliations

  • 1 Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China.
  • 2 Institute for Innovative Drug Design and Evaluation, Henan University, Kaifeng 475004, People's Republic of China.
  • 3 Institute for Innovative Drug Design and Evaluation, Henan University, Kaifeng 475004, People's Republic of China. Electronic address: [email protected].
  • 4 School of Pharmaceutical Sciences, Guangxi University of Chinese Medicine, Nanning 530001, People's Republic of China. Electronic address: [email protected].
PMID: 31744779 DOI: 10.1016/j.bmc.2019.115190
Abstract

A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC50 values of 0.72 μM and 0.16 μM, respectively. The results from Lineweaver-Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced β-amyloid (Aβ) aggregation inhibition. Moreover, 5f didn't show obvious toxicity against PC12 and HepG2 cells at 50 μM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer's disease.

Keywords

Acetylcholinesterase; Alzheimer’s disease; Butyrylcholinesterase; Graveolinine; β-amyloid.

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