2. Academic Validation
  3. Development of novel rivastigmine derivatives as selective BuChE inhibitors for the treatment of AD

Development of novel rivastigmine derivatives as selective BuChE inhibitors for the treatment of AD

  • Bioorg Chem. 2025 Feb 6:157:108245. doi: 10.1016/j.bioorg.2025.108245.
Yuting Li 1,  Qiyao Zhang 2,  Xinxin Wang 3,  Zhengwei Liu 4,  Hongsong Chen 5,  Zhenhui Su 3,  Yidan Xu 3,  Weichang Zhang 3,  Yulu Du 3,  Zhenghuai Tan 6,  Shuheng Huang 7,  Wenmin Liu 8,  Zhipei Sang 9
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228 China; School of Life and Health Sciences, Hainan University, Haikou 570228 China.
  • 2 Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228 China; School of Food Science and Engineering, Hainan University, Haikou 570228 China.
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228 China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228 China; College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061 China.
  • 5 College of Animal Science and Technology. Inner Mongolia Minzu University, Tongliao, Inner Mongolia 028000, China.
  • 6 Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China.
  • 7 Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228 China. Electronic address: shhuang@hainanu.edu.cn.
  • 8 College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061 China. Electronic address: liuwm1969@163.com.
  • 9 Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228 China. Electronic address: sangzhipei@hainanu.edu.cn.
PMID: 39954353 DOI: 10.1016/j.bioorg.2025.108245
Abstract

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder among the elderly, and there are currently no effective treatment options available. Selective inhibition of butyrylcholinesterase (BuChE) has emerged as a promising strategy for AD therapeutics. In this study, we identified compound 6a as a lead candidate derived from the structural modification of rivastigmine. Our findings indicated that 6a acts as a potent selective BuChE inhibitor, demonstrating an IC50 value of 0.33 μM (SI > 151.5). Furthermore, compound 6a displayed favorable neuroprotective properties, along with excellent blood-brain barrier (BBB) permeability and drug-like characteristics. In vivo investigations utilizing an AlCl3-induced zebrafish model of AD revealed that compound 6a significantly improved cognitive function, which was further supported by its ability to mitigate memory impairment induced by scopolamine. Overall, these results highlight compound 6a as a promising selective BuChE inhibitor with potential therapeutic implications for the treatment of Alzheimer's disease.

Keywords

AlCl(3)-induced zebrafish model; Alzheimer’s disease; BuChE inhibitors; Rivastigmine derivatives; Scopolamine-induced memory impairment.

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