Fluorosulfate-containing pyrazole heterocycles as selective BuChE inhibitors: structure-activity relationship and biological evaluation for the treatment of Alzheimer’s disease
| Autor: | Huan-Huan Li, Chengyao Wu, Shi-Long Zhang, Jian-Guo Yang, Hua-Li Qin, Wenjian Tang |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 37, Iss 1, Pp 2099-2111 (2022) |
| Druh dokumentu: | article |
| ISSN: | 14756366 1475-6374 1475-6366 |
| DOI: | 10.1080/14756366.2022.2103553 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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