Abstract
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 (IC50 = 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 (Ki = 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.
Structure-based design and synthesis of a class of novel δ-sultone-fused pyrazole scaffolds were achieved. Compounds 4a, 5a and 5d were discovered to be highly selective submicromolar BuChE inhibitors (IC50 = 0.20, 0.46 and 0.42 μM, respectively), exhibiting remarkable neuroprotective activity. [Display omitted]
•δ-Sultone-fused pyrazoles showed selective BuChE inhibitory activity.•Novel scaffolds were synthesized by SuFEx click chemistry.•IC50 values of 4a, 5a and 5d are 0.20, 0.46 and 0.42 μM, respectively.•5a and 5d exhibited remarkable neuroprotective activity.