Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 243, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114729
Keywords
Aromatic tertiary amine derivatives; BChE inhibitors; Alzheimer's disease
Categories
Funding
- National Natural Science Foundation of China [82173652, 81872728]
- Natural Science Foundation of Jiangsu Province [BK20191411, BK20221522)]
- Jiangsu Province 333 high-level talent training project
- Qing Lan project
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This study identified compounds 17c and 19c as potential drugs with selective inhibition of BChE, good blood brain barrier permeation, and cellular safety. The experimental results also showed that 17c and 19c were able to protect cells from AD-related damage and restore cognitive function in vivo.
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 mu M), good BBB permeation and primary cell safety. Besides, 17c can dose-response protect cell from A beta(1-42) 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.
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