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

Abstract

Novel scaffolds are expected to treat Alzheimer’s disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1–K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC₅₀ = 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 hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (K_i = 0.77 μM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aβ_1 − 42-induced cognitive impairment, and significantly prevented the effects of Aβ_1 − 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.

Keywords:

• Pyrazole
• sulphonyl fluoride
• cholinesterase inhibitor
• SuFEx
• anti-amyloid

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Financial support was provided by the National Natural Science Funding of China [22071190], Natural Science Fundation of Anhui provincial Department of Education [KJ2019ZD21], and Anhui Provincial Natural Science Foundation [2008085MH272].