2. Academic Validation
  3. Design, synthesis, and biological evaluation of aromatic tertiary amine derivatives as selective butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease

Design, synthesis, and biological evaluation of aromatic tertiary amine derivatives as selective butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2022 Sep 2;243:114729. doi: 10.1016/j.ejmech.2022.114729.
Xin Lu 1,  Nan Qin 2,  Yijun Liu 3,  Chenxi Du 3,  Feng Feng 4,  Wenyuan Liu 3,  Yao Chen 5,  Haopeng Sun 6
Affiliations

Affiliations

  • 1 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China; Department of Pharmacy, College of Medicine, Institute of Translational Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China.
  • 2 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 3 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 4 Jiangsu Drug Development Engineering Research Center for Central Degenerative Disease, Jiangsu Food and Pharmaceuticals Science College, 223005, People's Republic of China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 5 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China. Electronic address: [email protected].
  • 6 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China; Jiangsu Drug Development Engineering Research Center for Central Degenerative Disease, Jiangsu Food and Pharmaceuticals Science College, 223005, People's Republic of China. Electronic address: [email protected].
PMID: 36084535 DOI: 10.1016/j.ejmech.2022.114729
Abstract

Butyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17-1001) was screened and validated as a selective BChE Inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, neurotoxicity assay and neuroprotective effects assay indicated two optimal compounds 17c and 19c. Both compounds showed selective BChE inhibitory (hBChE < 20 nM, eeAChE > 10 μM), good BBB permeation and primary cell safety. Besides, 17c can dose-response protect cell from Aβ1-42 induced damage. It also demonstrated that 17c and 19c were able to restore cognitive impairment in vivo test. These data suggest that 17c and 19c represent promising candidate for follow-up in the drug-discovery process against AD.

Keywords

Alzheimer's disease; Aromatic tertiary amine derivatives; BChE inhibitors.

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