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 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 sho...

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Bibliographic Details
Published in:Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.2099-2111
Main Authors: Li, Huan-Huan, Wu, Chengyao, Zhang, Shi-Long, Yang, Jian-Guo, Qin, Hua-Li, Tang, Wenjian
Format: Article
Language:English
Subjects:
Alzheimer's disease
anti-amyloid
Brief Report
Chemical engineering
Chemistry
cholinesterase inhibitor
Cognitive ability
Dementia
Enzymes
Fluorides
Life sciences
Neurodegenerative diseases
Neuroprotection
Pharmacy
Pyrazole
Pyrazoles
Research Paper
SuFEx
Sulfur
sulphonyl fluoride
Toxicity
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Summary: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 (Ki = 0.77 μM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aβ1 − 42-induced cognitive impairment, and significantly prevented the effects of Aβ1 − 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2022.2103553