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  2. Design, synthesis, and biological activity of 2-aroylbenzofuran-3-ols and 2-aroylbenzofuran derivatives: A new route towards hMAO-B inhibition

Design, synthesis, and biological activity of 2-aroylbenzofuran-3-ols and 2-aroylbenzofuran derivatives: A new route towards hMAO-B inhibition

  • Eur J Med Chem. 2025 Nov 5:297:117983. doi: 10.1016/j.ejmech.2025.117983.
Paolo Guglielmi 1 Michele Coluccia 1 Guya Diletta Marconi 2 Francesco Ortuso 3 Francesca Procopio 4 Simone Carradori 5 Jacopo Pizzicannella 2 Francesca Arrighi 1 Anna Troiani 1 Chiara Salvitti 1 Fernanda Borges 6 Daniel Chavarria 7 Paola Chimenti 8 Daniela Secci 9 Francesca Diomede 2
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • 2 Department of Innovative Technologies in Medicine & Dentistry, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.
  • 3 Department of Health Sciences, University "Magna Graecia" of Catanzaro, Campus Universitario "S. Venuta", Catanzaro, Italy; Net4Science Academic Spin-Off, Università"Magna Græcia" di Catanzaro, Campus "S. Venuta", Catanzaro, Italy.
  • 4 Department of Health Sciences, University "Magna Graecia" of Catanzaro, Campus Universitario "S. Venuta", Catanzaro, Italy.
  • 5 Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.
  • 6 MedInUP, Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal; Department of Chemistry and Biochemistry, Faculty of Sciences/Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Porto, Portugal.
  • 7 CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
  • 8 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy. Electronic address: paola.chimenti@uniroma1.it.
  • 9 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy. Electronic address: daniela.secci@uniroma1.it.
Abstract

The crucial role of human monoamine oxidases (hMAOs), particularly the B isoform, in the pathogenesis of neurodegenerative diseases has been extensively studied. Alongside numerous Other factors, the clinical use of hMAO-B inhibitors to alleviate symptoms of Parkinson's disease is well-established. In order to develop novel hMAO-B inhibitors as potential candidates for the treatment of these conditions, we have designed and synthesized two libraries of compounds based on the 2-aroylbenzofuran-3-ol and the 2-aroylbenzofuran scaffolds. The hMAO inhibitory activity and selectivity of these compounds was thoroughly investigated. In general, the 2-aroylbenzofuran-3-ols were unable to inhibit hMAO isoforms. In contrast, 2-aroylbenzofuran derivatives acted as potent and selective hMAO-B inhibitors, showing IC50 values within the nanomolar range and as low as 8.2 nM. The best compounds exhibited broad safety ranges in human gingival fibroblasts (hGFs) and SH-SY5Y neuroblastoma cells. A preliminary evaluation of the compounds' neuroprotective effects was conducted through the co-exposure of the cells to the neurotoxic agent 6-hydroxydopamine (6-OHDA) and the synthesized compounds, whose activity was comparable to that of (R)-(-)-deprenyl, the reference hMAO-B inhibitors. The characterization of the compounds was enriched with the in silico prediction of the drug-likeness of the most active compounds among the 2-aroyl benzofurans using the free web tool SwissADME. All compounds were predicted to have high gastrointestinal absorption and to permeate the blood-brain barrier and molecular modelling studies provided insights into the molecular mechanisms responsible for the high hMAO-B inhibitory potency and selectivity of 2-aroylbenzofurans.

Keywords

2-aroylbenzofurans; Human monoamine oxidase (hMAO); Neurodegenerative diseases; Parkinson's disease; hMAO-B selective inhibitors.

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