2. Academic Validation
  3. Development of the "hidden" multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease

Development of the "hidden" multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2023 May 5;251:115253. doi: 10.1016/j.ejmech.2023.115253.
Rui Chen 1,  Xinjuan Li 2,  Hongsong Chen 3,  Keren Wang 2,  Teng Xue 4,  Jing Mi 2,  Yujuan Ban 1,  Gaofeng Zhu 1,  Yi Zhou 2,  Wu Dong 5,  Lei Tang 6,  Zhipei Sang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China.
  • 2 College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
  • 3 Inner Mongolia Key Laboratory of Toxicant Monitoring and Toxicology, College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao, 02800, China.
  • 4 School of Pharmaceutical Sciences, Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, Hainan University, Haikou, Hainan, 570228, China.
  • 5 Inner Mongolia Key Laboratory of Toxicant Monitoring and Toxicology, College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao, 02800, China. Electronic address: dongwu@imun.edu.cn.
  • 6 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China. Electronic address: tl1974@163.com.
  • 7 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China; School of Pharmaceutical Sciences, Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, Hainan University, Haikou, Hainan, 570228, China. Electronic address: sangzhipei@126.com.
PMID: 36921526 DOI: 10.1016/j.ejmech.2023.115253
Abstract

Accumulation of evidences suggested that excessive amounts of AChE and BuChE in the brain of AD patients at the different stage of AD, which could hydrolyze ACh and accelerated Aβ aggregation. To develop new "hidden" multifunctional agents through AChE/BuChE would be a promising strategy to treat AD. To this end, firstly, a series of chalcone derivatives with chelating property was designed and synthesized. The in vitro results showed that compound 3f indicated significant selective MAO-B inhibitory activity (IC50 = 0.67 μM) and remarkable anti-inflammatory property. It also significantly inhibited self-induced Aβ1-42 aggregation and showed remarkable neuroprotective effects on Aβ25-35-induced PC12 cell injury. Furthermore, compound 3f was a selective metal chelator and could inhibit Cu2+-induced Aβ1-42 aggregation. Based on this, the carbamate fragment was introduced to compound 3f to obtain carbamate derivatives. The biological activity results exhibited that compound 4b showed good BBB permeability, good AChE inhibitory potency (IC50 = 5.3 μM), moderate BuChE inhibitory potency (IC50 = 12.4 μM), significant MAO-B inhibitory potency, anti-inflammation potency on LPS-induced BV-2 cells and neuroprotective effects on Aβ25-35-induced PC12 cell injury. Compared with 3f, compound 4b did not show obvious chelation property. Significantly, compound 4b could be activated by AChE/BuChE following inhibition of AChE/BuChE to liberate an active multifunctional chelator 3f, which was consistent with our original intention. More importantly, compounds 3f and 4b presented favorable ADME properties and good stability in artificial gastrointestinal fluid, blood plasma and rat liver microsomes. The in vivo results suggested that compound 4b (0.0195 μg/mL) could significantly improve dyskinesia and reaction capacity of the AlCl3-induced zebrafish AD model by increasing the level of ACh. Together our data suggest that compound 4b was a promising "hidden" multifunctional agent by AChE/BuChE, and this strategy deserved further development for the treatment of AD.

Keywords

ADME properties; Alzheimer's disease; Multifunctional chelators; Site-activated prochelator; Zebrafish AD model.

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