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. 2020 Sep 1;201:112273. doi: 10.1016/j.ejmech.2020.112273. Epub 2020 Jun 12.
Structure-based optimization was conducted to improve the potency and selectivity of BuChE inhibitors with δ-sulfonolactone-fused pyrazole scaffold. By mimicking the hydrophobic interactions of donepezil at PAS, the introduction of a tertiary benzylamine at 5-position can significantly increase BuChE inhibitory activity. Compounds C4 and C6 were identified as high selective nanomolar BuChE inhibitors (IC = 8.3 and 7.7 nM, respectively), which exhibited mild antioxidant capacity, nontoxicity, lipophilicity and neuroprotective activity. Kinetic studies showed that BuChE inhibition of compound C6 was mixed-type against BuChE (K = 24 nM) and >2000-fold selectivity for BuChE over AChE. The proposed binding mode of new inhibitors was consistent with the results of structure-activity relationship analysis.
通过基于结构的优化，对具有 δ-磺内酯融合吡唑骨架的 BuChE 抑制剂进行了优化，以提高其效力和选择性。通过模拟多奈哌齐在 PAS 处的疏水相互作用，在 5 位引入叔丁基胺可以显著提高 BuChE 抑制活性。化合物 C4 和 C6 被鉴定为高选择性纳摩尔 BuChE 抑制剂（IC 分别为 8.3 和 7.7 nM），它们表现出温和的抗氧化能力、低毒性、亲脂性和神经保护活性。动力学研究表明，化合物 C6 对 BuChE 的抑制作用是混合类型（K 为 24 nM），对 BuChE 的选择性比 AChE 高 2000 多倍。新抑制剂的结合模式与构效关系分析的结果一致。
