2. Academic Validation
  3. Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold

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

  • Eur J Med Chem. 2023 Apr 5;252:115297. doi: 10.1016/j.ejmech.2023.115297.
Ersilia De Lorenzi 1,  Francesca Seghetti 2,  Andrea Tarozzi 3,  Letizia Pruccoli 3,  Cecilia Contardi 1,  Massimo Serra 1,  Alessandra Bisi 2,  Silvia Gobbi 2,  Giulio Vistoli 4,  Silvia Gervasoni 4,  Carla Argentini 5,  Giulia Ghirardo 5,  Giulia Guarato 5,  Genny Orso 5,  Federica Belluti 6,  Rita Maria Concetta Di Martino 2,  Morena Zusso 5
Affiliations

Affiliations

  • 1 Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
  • 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro, 6, 40126 Bologna, Italy.
  • 3 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • 4 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy.
  • 5 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo Meneghetti 2, 35131 Padua, Italy.
  • 6 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro, 6, 40126 Bologna, Italy. Electronic address: [email protected].
PMID: 36996713 DOI: 10.1016/j.ejmech.2023.115297
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, 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.

Keywords

Alzheimer's disease; Amyloid beta oligomers; Curcumin analogues; Drosophila Melanogaster model; Natural products; Neuroinflammation; Oxidative stress.

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