Design, synthesis and evaluation of 2-aryl benzoxazoles as promising hit for the A 2A receptor

J Enzyme Inhib Med Chem. 2017 Dec;32(1):850-864. doi: 10.1080/14756366.2017.1334648.


The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1 μm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 μm) without being cytotoxic at 100 μm. This compound, along with low-molecular weight compound D1 (Ki = 10 μm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation.

Keywords: A2A receptor; Benzoxazole; neurodegenerative disease; solubility.

MeSH terms

  • Adenosine A2 Receptor Antagonists / chemical synthesis
  • Adenosine A2 Receptor Antagonists / chemistry
  • Adenosine A2 Receptor Antagonists / pharmacology*
  • Benzoxazoles / chemical synthesis
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology*
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Receptor, Adenosine A2A / metabolism*
  • Solubility
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Adenosine A2 Receptor Antagonists
  • Benzoxazoles
  • Receptor, Adenosine A2A