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Structure–activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease
- Source :
- Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1860-1873 (2021)
- Publication Year :
- 2021
- Publisher :
- Taylor & Francis Group, 2021.
-
Abstract
- To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; –OCH3 > –CH3 > –Cl (–Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aβ1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aβ1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.
Details
- Language :
- English
- ISSN :
- 14756366 and 14756374
- Volume :
- 36
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.7f8355becd94532881e4dcf903bb612
- Document Type :
- article
- Full Text :
- https://doi.org/10.1080/14756366.2021.1959571