Novel multipotent conjugate bearing tacrine and donepezil motifs with dual cholinergic inhibition and neuroprotective properties targeting Alzheimer's disease.

ABSTRACT: In this work, we developed potential multifunctional agents to combat Alzheimer's disease. According to our strategy, fragments of tacrine and donepezil were merged in a unique hybrid structure. After successfully synthesizing the compounds, they were evaluated for their dual AChE/BuChE inhibitor potential and neuroprotector response using a glutamate-induced excitotoxicity model. Most of the compounds showed promising activity. Among them, the hybrid with 2,5-dimetoxysubstitution (3b) was the most potent analogue, triggering dual potent AChE/BuChE inhibition with low nanomolar affinity (IC₅₀ ∼ 300 nM) and low toxicity to human liver cancer cells (HepG2). This analogue prevented the glutamate excitotoxic stimulus during pre/post treatment testing, maintained ATP levels, possesse

SUBMITTER: Yepes AF 

PROVIDER: S-EPMC11756598 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature