Benzopyrone represents a privilege scaffold to identify novel adenosine A/A receptor antagonists.

Adenosine receptor antagonists are under investigation as potential drug candidates for the treatment of certain cancers, neurological disorders, depression and potentially improve tumour immunotherapy. The benzo-γ-pyrone scaffold is well-known in medicinal chemistry with diverse pharmacological activities attributed to them, however, their therapeutic potential as adenosine receptor antagonists have not been investigated in detail. To expand on the structure-activity relationships, the present study explored the adenosine A and A receptor binding affinities of a selected series of benzo-γ-pyrone analogues. In vitro evaluation led to the identification of 5-hydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one with the best adenosine A receptor affinity among the test compounds and was found to be non-selective (AK = 0.956 µM; AK = 1.44 µM). Hydroxy substitution on ring A and/or B play a key role in modulating the binding affinity at adenosine A and A receptors. Adenosine A receptor affinity was increased to the nanomolar range with hydroxy substitution on C6 (ring A), while meta-hydroxy substitution on ring B governed adenosine A receptor affinity. The double bond between C2 and C3 of ring C as well as C2 phenyl substitution was shown to be imperative for both adenosine A and A receptor affinity. Selected benzo-γ-pyrone derivatives behaved as adenosine A receptor antagonists in the performed GTP shift assays. It may be concluded that benzo-γ-pyrone based derivatives are suitable leads for designing and identifying adenosine receptor antagonists as treatment of various disorders.