Targeting Alzheimer's pathology: Tetralone- and thiochromanone-based benzyl pyridinium derivatives as promising multi-target-directed ligands

The lack of therapeutics that can fully halt the progression of Alzheimer's disease (AD) has prompted us to design and synthesize a series of tetralone/thiochromanone-based benzyl pyridinium salts (4a-4s) aimed at modulating multiple pathological targets associated with AD. Preliminary screening for cholinesterase and monoamine oxidase inhibition identified compounds 4e and 4g as the most potent inhibitors (AChE IC₅₀: 2.17 ± 0.13 μM and 2.29 ± 0.15 μM; MAO-B IC₅₀: 0.89 ± 0.07 μM and 0.92 ± 0.16 μM, respectively). Both compounds also demonstrated anti-neuroinflammatory activity by reducing pro-inflammatory cytokines (TNF-α and IL-6) and downregulating COX-2 and NF-κB signalling pathways. Additionally, 4e exhibited significant ROS scavenging ability by mitigating oxidative stress and conferred neuroprotection in SH-SY5Y cells by attenuating Aβ₁₋₄₂-induced mitochondrial dysfunction and apoptosis. Collectively, these findings position compound 4e as a promising multi-target-directed ligand (MTDL) for the treatment of AD.