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, A beta 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 A beta 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 A beta 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.
De Lorenzi, E., Seghetti, F., Tarozzi, A., Pruccoli, L., Contardi, C., Serra, M., et al. (2023). Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 252, 1-15 [10.1016/j.ejmech.2023.115297].
Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold
Seghetti, Francesca;Tarozzi, Andrea;Pruccoli, Letizia;Bisi, Alessandra;Gobbi, Silvia;Belluti, Federica
;Di Martino, Rita Maria Concetta;
2023
Abstract
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, A beta 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 A beta 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 A beta 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.File | Dimensione | Formato | |
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