Structure–activity relationship, <i>in vitro</i> and <i>in vivo</i> evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease

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 <b>A10</b> was identified as a selective BuChE inhibitor (IC₅₀ = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) <i>o</i>- > <i>m</i>- > <i>p</i>-; -OCH₃ > -CH₃ > -Cl (-Br) for <i>δ</i>-aryl; (ii) α-Br > α-Cl, α-I. Compound <b>A10</b> exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (<i>K</i>_i = 29 nM), and benign neural and hepatic safety. Treatment with <b>A10</b> could almost entirely recover the A<i>β</i>_1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of A<i>β</i>_1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor <b>A10</b> is a promising effective lead for the treatment of AD.