School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, China.
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, China.
Eur J Med Chem. 2019 Nov 1;181:111598. doi: 10.1016/j.ejmech.2019.111598. Epub 2019 Aug 6.
A class of novel δ-sulfonolactone-fused pyrazole scaffold was prepared via sulfur (VI) fluoride exchange (SuFEx) chemistry using aryl sulfonyl fluorides and pyrazolones. Enzyme screening revealed their cholinesterase inhibitory activity, among them, compounds 4a, 5a and 5d were identified as highly selective submicromolar BuChE inhibitors (IC = 0.20, 0.46 and 0.42 μM, respectively), which exhibited nontoxicity, lipophilicity and remarkable neuroprotective activity. Kinetic studies showed that BuChE inhibition of compounds 5a and 5d was reversible, mixed-type and non-competitive inhibition against BuChE (K = 145 nM and 60 nM, respectively). Compound 5d can be accommodated into hBuChE via π-S interaction and hydrophobic interactions. The title compounds are potentially symptomatic treatment in progressive Alzheimer's disease.
通过使用芳基磺酰氟和吡唑酮的硫（VI）氟交换（SuFEx）化学，制备了一类新型的 δ-磺酰内酯融合吡唑骨架。酶筛选显示了它们对胆碱酯酶的抑制活性，其中化合物 4a、5a 和 5d 被鉴定为高选择性亚毫摩尔 BuChE 抑制剂（IC=0.20、0.46 和 0.42μM），它们表现出非毒性、亲脂性和显著的神经保护活性。动力学研究表明，化合物 5a 和 5d 对 BuChE 的抑制作用是可逆的、混合型和非竞争性的（K=145nM 和 60nM）。化合物 5d 可以通过π-S 相互作用和疏水相互作用容纳到 hBuChE 中。标题化合物可能是进行性阿尔茨海默病的对症治疗方法。
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