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

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 <b>5c</b> and <b>5e</b> were the most potent, exhibiting over 150-fold selectivity for BuChE. Also, <b>5c</b>, <b>5g</b> and <b>5h</b> 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 <i>C. elegans</i>, three lead compounds alleviated Aβ-induced paralysis and cognitive deficits. <i>In silico</i> study revealed that compound <b>5c</b> 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.