2. Academic Validation
  3. Design, synthesis, and biological evaluation of chalcone derivatives as selective Monoamine Oxidase-B inhibitors with potential neuroprotective effects

Design, synthesis, and biological evaluation of chalcone derivatives as selective Monoamine Oxidase-B inhibitors with potential neuroprotective effects

  • Eur J Med Chem. 2025 Nov 15:298:117990. doi: 10.1016/j.ejmech.2025.117990.
Giorgio Facchetti 1,  Sara Marchese 2,  Valentina Coccè 3,  Luisa Doneda 3,  Giulio Alessandri 3,  Francesca Paino 3,  Augusto Pessina 3,  Luca Pinzi 4,  Giulio Rastelli 4,  Claudia Binda 5,  Michael S Christodoulou 6,  Isabella Rimoldi 1
Affiliations

Affiliations

  • 1 CRC StaMeTec, Department of Pharmaceutical Science, University of Milan, Via Golgi 19, 20133, Milan, Italy.
  • 2 Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9, 27100, Pavia, Italy.
  • 3 CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, 20133, Milan, Italy.
  • 4 Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi, 103, Modena, Italy.
  • 5 Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9, 27100, Pavia, Italy. Electronic address: claudia.binda@unipv.it.
  • 6 Department of Food, Environmental and Nutritional Sciences, University of Milan, Via Celoria 2, 20133 Milano, Italy. Electronic address: michail.christodoulou@unimi.it.
PMID: 40738081 DOI: 10.1016/j.ejmech.2025.117990
Abstract

A series of chalcone derivatives was synthesized via Claisen-Schmidt condensation and further modified through selective reductions and amide couplings to explore their potential as Monoamine Oxidase B (MAO-B) inhibitors. Screening against recombinant human MAO-B identified compounds 4a, 4b, 4e, and 5a as potent inhibitors, showing submicromolar inhibition constants (Ki). Structure-activity relationship (SAR) analysis emphasized the relevance of a planar α,β-unsaturated carbonyl and specific aromatic substitutions for activity. Crystallographic studies showed conserved binding modes in the MAO-B active site, while computational analyses confirmed favourable interactions and conformational flexibility of compound 5a. Cytotoxicity assays in normal and Cancer cell lines indicated minimal toxicity for 5a. Notably, 5a also exhibited neuroprotective effects in SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA), a model of Parkinson's disease. These findings demonstrated the importance of structural fine-tuning within the chalcone scaffold to achieve MAO-B selectivity and identify compound 5a as a promising, non-toxic candidate for neurodegenerative disease treatment.

Keywords

Chalcones; Crystal structure; Human monoamine oxidase; Inhibitor; Neuroprotective drugs; SH-SY5Y neuroblastoma cell line.

Figures
Products