Multifunctional Agents in the Treatment of Alzheimer’s Disease: A Preliminary Investigational Study

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with a high incidence rate in older people worldwide.^[1] Apart from its widely recognized hallmarks, such as β-amyloid (Aβ) plaques and hyperphosphorylated tau proteins, neuroinflammation, oxidative stress, and metal ion accumulation were found to severely contribute to the disease's progression.^[2] Within this intricate framework, sirtuin-1 (SIRT1) has gained attention as a potential AD preventive factor, since it is involved in oxidative stress responses and brain homeostasis.^[3] AD's high degree of complexity seems to justify the limited success of current single-target therapies and the recent shift of the research programmes towards multifunctional agents able to target multiple mechanisms simultaneously, with additive or even synergistic effects to more effectively counteract disease progression.

In this study, we present a series of previously reported SIRT1 activators featuring a 2,6-diphenylimidazo[1,2-a]pyridine core^[4] for potential anti-AD applications. We expanded the compound library by decorating the phenyl rings with various methoxy and/or hydroxy groups. Due to their polyphenolic nature, they showed antioxidant properties in vitro, as assessed in vitro through DPPH and ABTS assays and TBARS using rat brain homogenate. Also, although with specific preferences, some compounds showed metal-chelating abilities towards Cu²⁺, Zn²⁺, and Fe²⁺.

Notably, in differentiated SH-SY5Y cells, a recognized AD model, compound CLM400 was demonstrated to reduce oxidative stress when tested at 2.5 nM, whereas a pro-oxidant effect was observed at higher concentrations. Interestingly, TEM analyses revealed the compound's ability to form larger, non-toxic off-pathway Aβ aggregates with a pro-aggregating behavior. This finding is particularly relevant and aligns with previous studies on resveratrol, while traditional anti-AD agents often focus on inhibiting aggregation into toxic soluble oligomers.

This preliminary study highlighted a new series of multifunctional agents as promising agents for AD treatment. However, in-depth studies are required to shed light on the formed aggregates.