2. Academic Validation
  3. 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: [email protected].
  • 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: [email protected].
PMID: 34995924 DOI: 10.1016/j.ejmech.2021.114095
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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