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

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.

Automated summary

Compound A10, as a selective BuChE inhibitor, exhibits neuroprotective effects, good safety profile, and can effectively restore Aβ (1-42)-induced cognitive dysfunction.