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 δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound was identified as a selective BuChE inhibitor (IC = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) - > - > -; -OCH > -CH > -Cl (-Br) for -aryl; (ii) α-Br > α-Cl, α-I. Compound exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE ( = 29 nM), and benign neural and hepatic safety. Treatment with could almost entirely recover the A -induced cognitive dysfunction to the normal level, and the assessment of total amount of A confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor is a promising effective lead for the treatment of AD.