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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.

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.

Journal of enzyme inhibition and medicinal chemistry (2021-08-25)
Chengyao Wu, Guijuan Zhang, Zai-Wei Zhang, Xia Jiang, Ziwen Zhang, Huanhuan Li, Hua-Li Qin, Wenjian Tang
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Acetylcholinesterase human, recombinant, expressed in HEK 293 cells, lyophilized powder, ≥1,000 units/mg protein (Lowry)
Sigma-Aldrich
Butyrylcholinesterase human, vial of ≥4 units