Molecules (Aug 2024)

Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists

  • Amélie Laversin,
  • Robin Dufossez,
  • Raphaël Bolteau,
  • Romain Duroux,
  • Séverine Ravez,
  • Sergio Hernandez-Tapia,
  • Martin Fossart,
  • Mathilde Coevoet,
  • Maxime Liberelle,
  • Saïd Yous,
  • Nicolas Lebègue,
  • Patricia Melnyk

DOI
https://doi.org/10.3390/molecules29163847
Journal volume & issue
Vol. 29, no. 16
p. 3847

Abstract

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The adenosine A2A receptor (A2AR) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new A2AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 (Ki (hA2AR) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound 5m showed a high affinity for hA2AR with a Ki value of 5 nM and demonstrated antagonist activity with an IC50 of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities (9x, Ki = 21 nM; 10d, Ki = 15 nM) and functional antagonist activities (9x, IC50 = 9 µM; 10d, IC50 = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A2AR antagonists for therapeutic applications.

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