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. Epub 2025 Mar 28.

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.

MeSH terms

  • Dose-Response Relationship, Drug
  • Glycogen Synthase Kinase 3 beta* / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta* / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Monoamine Oxidase Inhibitors* / chemical synthesis
  • Monoamine Oxidase Inhibitors* / chemistry
  • Monoamine Oxidase Inhibitors* / pharmacology
  • Monoamine Oxidase* / metabolism
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Quinazolinones* / chemical synthesis
  • Quinazolinones* / chemistry
  • Quinazolinones* / pharmacology
  • Structure-Activity Relationship

Substances

  • Monoamine Oxidase Inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Monoamine Oxidase
  • Quinazolinones
  • Protein Kinase Inhibitors
  • GSK3B protein, human