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

TL;DR

This paper introduces new compounds that target two key factors in Alzheimer's disease, potentially offering a more effective treatment approach.

Contribution

The study introduces ferulic acid carbamate derivatives as dual-targeting agents for BuChE and Nrf2 in Alzheimer’s disease.

Findings

Compound 5c and 5e showed over 150-fold selectivity for BuChE inhibition.

Three compounds reversed toxicity and oxidative stress in HT22 cells and improved outcomes in C. elegans models.

Compound 5c was shown to fit well into the active sites of BuChE and Keap1 with favorable CNS drugability.

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.

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