2. Academic Validation
  3. 2-(Phenylamino)-7,8-dihydroquinazolin-5(6H)-one, a promising scaffold for MAO-B inhibitors with potential GSK3β targeting

2-(Phenylamino)-7,8-dihydroquinazolin-5(6H)-one, a promising scaffold for MAO-B inhibitors with potential GSK3β targeting

  • Eur J Med Chem. 2025 Jul 5:291:117580. doi: 10.1016/j.ejmech.2025.117580.
Maria Luisa Di Paolo 1,  Silvia Salerno 2,  Giulia Nordio 3,  Francesco Piazzola 4,  Stefania Sarno 5,  Giuliana Sarno 6,  Benito Natale 7,  Valeria Poggetti 8,  Antonella Borreca 9,  Emma Baglini 10,  Elisabetta Barresi 11,  Federico Da Settimo 12,  Sandro Cosconati 13,  Sabrina Castellano 14,  Sabrina Taliani 15,  Lisa Dalla Via 16
Affiliations

Affiliations

  • 1 Department of Molecular Medicine, University of Padova, 35131, Padova, Italy. Electronic address: marialuisa.dipaolo@unipd.it.
  • 2 Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address: silvia.salerno@unipi.it.
  • 3 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy. Electronic address: giulia.nordio.1@phd.unipd.it.
  • 4 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy. Electronic address: francesco.piazzola@phd.unipd.it.
  • 5 Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy. Electronic address: stefania.sarno@unipd.it.
  • 6 Department of Pharmacy, University of Salerno, Fisciano, SA, 84084, Italy. Electronic address: gisarno@unisa.it.
  • 7 DiSTABiF, University of Campania Luigi Vanvitelli, 81100, Caserta, Italy. Electronic address: benito.natale@unicampania.it.
  • 8 Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address: valeria.poggetti@phd.unipi.it.
  • 9 Institute of Neuroscience (IN-CNR), Consiglio Nazionale delle Ricerche, Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, Milan, 20089, Italy. Electronic address: antonella.borreca@cnr.it.
  • 10 Institute of Clinical Physiology, National Research Council of Italy, CNR Research Area, 56124, Pisa, Italy. Electronic address: emma.baglini@cnr.it.
  • 11 Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address: elisabetta.barresi@unipi.it.
  • 12 Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address: federico.dasettimo@unipi.it.
  • 13 DiSTABiF, University of Campania Luigi Vanvitelli, 81100, Caserta, Italy. Electronic address: sandro.cosconati@unicampania.it.
  • 14 Department of Pharmacy, University of Salerno, Fisciano, SA, 84084, Italy.
  • 15 Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address: sabrina.taliani@unipi.it.
  • 16 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy. Electronic address: lisa.dallavia@unipd.it.
PMID: 40186896 DOI: 10.1016/j.ejmech.2025.117580
Abstract

Neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, constitute pathological conditions of great relevance on health span and quality of life. The identification of novel therapeutic options, able to modulate the processes involved in the insurgence and progression of neurodegenerative disorders, represents an intriguing challenge of current research. Herein, a library of 36-membered 2-(phenylamino)-7,8-dihydroquinazolinone derivatives was synthesized and biologically evaluated as human MAO inhibitors. Some compounds able to inhibit MAO-B potently and selectively (Ki in the nanomolar range) were identified, and robust structure-activity relationships were drawn, supported by computational studies. Further biological assays revealed a safe profile for all derivatives and, for compounds selected as the best MAO-B inhibitors (4, 5, 13, 14) the following properties also emerged: (i) the ability to inhibit MAO-B activity in whole cells, with an effectiveness comparable or slight lower with respect to the reference safinamide; (ii) physicochemical parameters suggesting drug-likeness properties; (iii) the ability to inhibit, albeit weakly, GSK3β kinase (for compound 4). Within the whole series, compound 4 stood out as a promising lead for future optimization campaigns aimed to obtain useful drugs for the treatment of Alzheimer's and Parkinson's diseases.

Keywords

2-(phenylamino)-7,8-dihydroquinazolin-5(6H)-one; GSK3β kinase; MAO enzymes; Neurodegenerative diseases.

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