期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 36, 期 1, 页码 1860-1873出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.1959571
关键词
Acetylcholinesterase; butyrylcholinesterase; sulphonyl fluoride; anti-amyloid; Alzheimer's disease
资金
- National Natural Science Funding of China [22071190]
- Natural Science Foundation of Anhui provincial Department of Education [KJ2019ZD21]
- Anhui Provincial Natural Science Foundation [2008085MH272]
Compound A10, as a selective BuChE inhibitor, exhibits neuroprotective effects, good safety profile, and can effectively restore Aβ (1-42)-induced cognitive dysfunction.
To discover novel scaffolds as leads against dementia, a series of delta-aryl-1,3-dienesulfonyl fluorides with alpha-halo, alpha-aryl and alpha-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 mu M for eqBChE, 3.62 mu M for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH3 > -CH3 > -Cl (-Br) for delta-aryl; (ii) alpha-Br > alpha-Cl, alpha-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (K (i) = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the A beta (1-42)-induced cognitive dysfunction to the normal level, and the assessment of total amount of A beta (1-42) confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.
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