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
  • 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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