Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists.

The adenosine A _2A receptor (A _2A R) 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 A _2A R antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 ( K _i ( h A _2A R) = 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 h A _2A R with a K _i value of 5 nM and demonstrated antagonist activity with an IC ₅₀ of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities ( 9x , K _i = 21 nM; 10d , K _i = 15 nM) and functional antagonist activities ( 9x , IC ₅₀ = 9 µM; 10d , IC ₅₀ = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A _2A R antagonists for therapeutic applications.