C3 amino-substituted chalcone derivative with selective adenosine A receptor affinity in the micromolar range.

Abstract: To identify novel adenosine receptor (AR) ligands based on the chalcone scaffold, herein the synthesis, characterization and in vitro and in silico evaluation of 33 chalcones (- and -) and structurally related compounds (-) are reported. These compounds were characterized by radioligand binding and GTP shift assays to determine the degree and type of binding affinity, respectively, against rat () A and A ARs. The chalcone derivatives , , and possessed selective A affinity below 10 µM, and thus, are the most active compounds of the present series; compound was the most potent selective A AR antagonist ( () = 1.6 µM). The structure-affinity relationships (SAR) revealed that the NH-group at position C3 of ring A of the chalcone scaffold played a key role in affinity, and also, the Br-atom at position C3' on benzylidene ring B. Upon in vitro and in silico evaluation, the novel C3 amino-substituted chalcone derivative -that contains an α,ß-unsaturated carbonyl system and easily allows structural modification-may possibly be a synthon in future drug discovery.

Graphic Abstract: C3 amino-substituted chalcone derivative () with C3' Br substitution on benzylidene ring B possesses selective adenosine A receptor affinity in micromolar range.