1. Academic Validation
  2. Discovery of novel β-carboline derivatives as selective AChE inhibitors with GSK-3β inhibitory property for the treatment of Alzheimer's disease

Discovery of novel β-carboline derivatives as selective AChE inhibitors with GSK-3β inhibitory property for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2022 Feb 5;229:114095. doi: 10.1016/j.ejmech.2021.114095.
Wenwu Liu 1 Xin Liu 2 Wenjie Liu 3 Yaping Gao 2 Limeng Wu 3 Yaoguang Huang 3 Huanhua Chen 3 Deping Li 4 Lijun Zhou 2 Nan Wang 5 Zihua Xu 6 Xiaowen Jiang 7 Qingchun Zhao 8
Affiliations

Affiliations

  • 1 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China.
  • 2 School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 3 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 4 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 5 School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China.
  • 6 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China.
  • 7 School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China. Electronic address: jxwphu@syphu.edu.cn.
  • 8 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China. Electronic address: zhaoqingchun1967@163.com.
Abstract

The natural product harmine, a representative β-carboline alkaloid from the seeds of Peganum harmala L. (Zygophyllaceae), possesses a broad spectrum of biological activities. In this study, a novel series of harmine derivatives containing N-benzylpiperidine moiety were identified for the treatment of Alzheimer's disease (AD). The results showed that all the derivatives possessed significant anti-acetylcholinesterase (AChE) activity and good selectivity over butyrylcholinesterase (BChE). In particular, compound ZLWH-23 exhibited potent anti-AChE activity (IC50 = 0.27 μM) and selective BChE inhibition (IC50 = 20.82 μM), as well as acceptable glycogen synthase kinase-3 (GSK-3β) inhibition (IC50 = 6.78 μM). Molecular docking studies and molecular dynamics simulations indicated that ZLWH-23 could form stable interaction with AChE and GSK-3β. Gratifyingly, ZLWH-23 exhibited good selectivity for GSK-3β over multi-kinases and very low cytotoxicity towards SH-SY5Y, HEK-293T, HL-7702, and HepG2 cell lines. Importantly, ZLWH-23 displayed efficient reduction against tau hyperphosphorylation on Ser-396 site in Tau (P301L) 293T cell model. Collectively, harmine-based derivatives could be considered as possible drug leads for the development of AD therapies.

Keywords

AChE; Alzheimer's disease; GSK-3β; Harmine; β-Carboline.

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