The structure-based optimization of δ-sultone-fused pyrazoles as selective BuChE inhibitors

Abstract

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 (IC₅₀ = 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_i = 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.

Keywords: Alzheimer’s disease; Cholinesterase; Pyrazole; Structural optimization; SuFEx; Sultone.