Fluorosulfate-containing pyrazole heterocycles as selective BuChE inhibitors: structure-activity relationship and biological evaluation for the treatment of Alzheimer's disease.

Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds were assayed for ChE inhibitory activity, amongst them, compound showed potent BuChE and BuChE inhibition (IC = 0.79 μM and 6.59 μM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of BuChE through π-sulphur interaction. Compound was a reversible, mixed and non-competitive BuChE inhibitor ( = 0.77 μM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. behavioural study showed that treatment improved the A-induced cognitive impairment, and significantly prevented the effects of A toxicity. Therefore, selective BuChE inhibitor has potential to be further developed as AD therapeutics.