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

• Published in: European journal of medicinal chemistry 2023-04, Vol.252, p.115297-115297, Article 115297
• Main Authors: De Lorenzi, Ersilia, Seghetti, Francesca, Tarozzi, Andrea, Pruccoli, Letizia, Contardi, Cecilia, Serra, Massimo, Bisi, Alessandra, Gobbi, Silvia, Vistoli, Giulio, Gervasoni, Silvia, Argentini, Carla, Ghirardo, Giulia, Guarato, Giulia, Orso, Genny, Belluti, Federica, Di Martino, Rita Maria Concetta, Zusso, Morena
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta oligomers; Amyloid beta-Peptides - metabolism; Curcumin - pharmacology; Curcumin - therapeutic use; Curcumin analogues; Drosophila Melanogaster model; Humans; Natural products; Neuroinflammation; Neuroinflammatory Diseases; Oxidative Stress
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115297

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.