The structure-based optimization of δ-sultone-fused pyrazoles as selective BuChE inhibitors
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 (Ki = 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.
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Conflict of interest statement
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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