Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold

Simultaneous modulation of multifaceted toxicity arising from neuroinflammation, oxidative stress, and mitochondrial dysfunction represents a valuable therapeutic strategy to tackle Alzheimer's disease. Among the significant hallmarks of the disorder, Aβ protein and its aggregation products are well-recognised triggers of the neurotoxic cascade. In this study, by tailored modification of the curcumin-based lead compound 1, we aimed at developing a small library of hybrid compounds targeting Aβ protein oligomerisation and the consequent neurotoxic events. Interestingly, from in vitro studies, analogues 3 and 4, bearing a substituted triazole moiety, emerged as multifunctional agents able to counteract Aβ aggregation, neuroinflammation and oxidative stress. In vivo proof-of-concept evaluations, performed in a Drosophila oxidative stress model, allowed us to identify compound 4 as a promising lead candidate. [Display omitted] •A small library of curcumin-based analogues was designed as multi-functional tools for AD.•Compounds 3 and 4 reduced pro-inflammatory cytokine release from microglia cells.•Compounds 3 and 4 decreased oxidative stress in SH-SY5Y cells by inducing Nrf2.•Compounds 3 and 4 hampered Aβ oligomers formation.•Compound 4, in vivo oxidative stress model, exerted a consistent neuroprotective effect by modulating the redox-sensitive signalling pathways.•Compound 4 emerged as a promising multi-function lead for AD treatment.