De Lorenzi, E., Seghetti, F., Tarozzi, A., Pruccoli, L., Contardi, C., Serra, M., Bisi, A., Gobbi, S., Vistoli, G., Gervasoni, S., Argentini, C., Ghirardo, G., Guarato, G., Orso, G., Belluti, F., Di Martino, R.M.C., Zusso, M. (2023). Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold.  Eur. J. Med. Chem. 252(): 115297.

FBrf0256293

Research paper

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.