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 (K_i = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aβ_1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aβ_1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.

 抽象的

为了发现抗痴呆的新型支架，我们对一系列具有 α-卤素、α-芳基和 α-炔基的 δ-芳基-1,3-二烯磺酰氟进行了 ChE 抑制活性测定，其中化合物A10被鉴定为选择性BuChE 抑制剂（对于 eqBChE，IC ₅₀ = 0.021 μM；对于 hBuChE，IC 50 = 3.62 μM）。 BuChE 抑制的 SAR 显示：(i) o - > m - > p -； –OCH ₃ > –CH ₃ > –Cl (–Br) 对于δ -芳基； (ii) α-Br > α-Cl、α-I。化合物A10表现出神经保护作用、BBB 渗透作用、对 BuChE ( K _i = 29 nM) 的混合竞争抑制作用以及良性神经和肝脏安全性。 A10治疗几乎可以将Aβ1-42_诱导的认知功能障碍完全恢复至正常水平，并且Aβ1-42总量的评估证实了_其抗淀粉样蛋白生成特性。因此，潜在的BuChE抑制剂A10是治疗AD的有希望的有效先导药物。