Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer’s disease

Abstract

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer’s disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC₅₀ = 4.68 nM; huBuChE IC₅₀ = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD₅₀ > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.

Graphical Abstract

Keywords:

• Alzheimer’s disease
• butyrylcholinesterase inhibitors
• anti-neuroinflammation
• pyranone-carbamate derivatives
• cognitive improvement

Authors contributions

Chuanyu Yu designed and synthesised compounds, conducted in vitro and in vivo activity evaluation, and wrote the manuscript; Xueyan Liu conducted in vivo activity evaluation and molecular docking; Bingxiang Ma conducted in vitro activity evaluation and ADME calculations; Jiexin Xu assisted in the synthesis of compounds; Yiquan Chen and Chaoxian Dai assisted in animal experiments; Huaping Peng guided the design and implementation of the project; Daijun Zha designed and guided the entire project and edited the manuscript.

Disclosure statement

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

Additional information

Funding

This work was supported by the Research Foundation for the National Natural Science Foundation of China (Grant number: 22374021), the Natural Science Foundation of Fujian Province (Grant number: 2021J01693), and the Talented Scholars of Fujian Medical University (Grant number: XRCZX2018014).