Discovery of ferulic acid carbamate derivatives as dual-targeting agents of BuChE and Nrf2 for Alzheimer's disease.

Abstract

Given the multifactorial aetiology of Alzheimer's disease, multi-target strategies have emerged as a promising therapeutic approach. In this study, we designed and synthesised a series of ferulic acid carbamate derivatives to selectively inhibit BuChE and stimulate Nrf2 pathway. The biological evaluation revealed that compound 5c and 5e were the most potent, exhibiting over 150-fold selectivity for BuChE. Also, 5c, 5g and 5h significantly reversed both H2O2- and Aβ-induced toxicity in HT22 cells. These compounds were further shown to eliminate ROS accumulation induced by Aβ and upregulated HO-1 and GCLM by promoting the nuclei translocation of Nrf2. In Aβ transgenic C. elegans, three lead compounds alleviated Aβ-induced paralysis and cognitive deficits. In silico study revealed that compound 5c fitted well into the active sites of BuChE and Keap1 while maintaining favourable CNS drugability. This dual strategy of cholinesterase inhibition and oxidative stress mitigation is a promising approach for novel AD therapeutics.

Key Findings

• Ferulic acid carbamate derivatives were designed to selectively inhibit BuChE and activate the Nrf2 pathway.
• Compounds 5c and 5e showed over 150-fold selectivity for BuChE and reversed H2O2- and Aβ-induced toxicity in neuronal cells.
• Lead compounds alleviated Aβ-induced paralysis and cognitive deficits in Aβ transgenic C. elegans and promoted Nrf2 nuclear translocation, increasing antioxidant enzyme expression.

Clinical Significance

Citation

Lao Kejing, Li Yingze, Xiao Yueyanet al.. Discovery of ferulic acid carbamate derivatives as dual-targeting agents of BuChE and Nrf2 for Alzheimer's disease. Journal of enzyme inhibition and medicinal chemistry. 2026-Dec.