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

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

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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