School of Pharmacy, Anhui Medical University, Hefei, China.
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, China.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):2099-2111. doi: 10.1080/14756366.2022.2103553.
Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds were assayed for ChE inhibitory activity, amongst them, compound showed potent BuChE and BuChE inhibition (IC = 0.79 μM and 6.59 μM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of BuChE through π-sulphur interaction. Compound was a reversible, mixed and non-competitive BuChE inhibitor ( = 0.77 μM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. behavioural study showed that treatment improved the A-induced cognitive impairment, and significantly prevented the effects of A toxicity. Therefore, selective BuChE inhibitor has potential to be further developed as AD therapeutics.
新型支架有望治疗阿尔茨海默病，研究发现吡唑-5-氟硫酸盐是选择性 BuChE 抑制剂。对化合物进行了 ChE 抑制活性测试，其中化合物 对 BuChE 和 BuChE 具有很强的抑制作用（IC = 0.79 μM 和 6.59 μM）。SAR 分析表明，吡唑环的 1-、3-、4-取代基和 5-氟硫酸盐影响 BuChE 抑制活性。分子对接表明，氟硫酸盐通过 π-硫相互作用增加了 BuChE 的结合亲和力。化合物 是一种可逆的、混合的和非竞争性的 BuChE 抑制剂（ = 0.77 μM），表现出显著的神经保护作用、安全的毒理学特征和 BBB 穿透性。行为学研究表明， 治疗可改善 A 诱导的认知障碍，并显著预防 A 毒性的影响。因此，选择性 BuChE 抑制剂 具有进一步开发为 AD 治疗药物的潜力。
