Lao_2026_J.Enzyme.Inhib.Med.Chem_41_2645483

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 H(2)O(2)(-) and Abeta-induced toxicity in HT22 cells. These compounds were further shown to eliminate ROS accumulation induced by Abeta and upregulated HO-1 and GCLM by promoting the nuclei translocation of Nrf2. In Abeta transgenic C. elegans, three lead compounds alleviated Abeta-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.