Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer's Disease

  • ACS Omega. 2022 Aug 30;7(36):32131-32152. doi: 10.1021/acsomega.2c03368.
Nan Wang  1  2 ,  Wenjie Liu  3 ,  Lijun Zhou  2 ,  Wenwu Liu  3 ,  Xu Liang  2 ,  Xin Liu  2 ,  Zihua Xu  1 ,  Tianming Zhong  1 ,  Qiong Wu  1 ,  Xinming Jiao  2 ,  Jiangxia Chen  2 ,  Xinyue Ning  2 ,  Xiaowen Jiang  1  2  4 ,  Qingchun Zhao  1  2
Affiliations
  • 1. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang110840, People's Republic of China.
  • 2. School of Life Sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang110016, People's Republic of China.
  • 3. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang110016, People's Republic of China.
  • 4. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang110016, People's Republic of China.
PMID: 36120034 DOI: 10.1021/acsomega.2c03368
Abstract

The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from Notopterygium) is a dual BACE1/GSK3β inhibitor. In this study, we designed and synthesized 48 notopterol derivatives with furacoumarin as a scaffold in order to enhance their balanced AChE/BACE1/GSK3β inhibitory activity. Fortunately, 1c showed effective inhibitory activity against AChE (58.7% at 1.0 μM), BACE1 (48.3% at 20 μM), and GSK3β (40.3% at 10 μM). Furthermore, 1c showed good blood-brain barrier penetrability, suitable bioavailability, and oral safety. More importantly, 1c could ameliorate the impaired learning and memory in Aβ-induced AD mice. In conclusion, we reported the triple inhibitor of AChE/BACE1/GSK3β lead compounds based on a furocoumarin scaffold of notopterol for the first time, which provides a potential new strategy for the treatment of AD.

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