Discovery of novel A3 adenosine receptor ligands based on chromone scaffold

Abstract

A project focused on the discovery of new chemical entities (NCEs) as AR ligands that incorporate a benzo-γ-pyrone [(4H)-1-benzopyran-4-one] substructure has been developed. Accordingly, two series of novel chromone carboxamides placed at positions C2 (compounds 2–13) and C3 (compounds 15–26) of the γ-pyrone ring were synthesized using chromone carboxylic acids (compounds 1 or 14) as starting materials. From this study and on the basis of the obtained structure–activity relationships it was concluded that the chromone carboxamide scaffold represent a novel class of AR ligands. The most remarkable chromones were compounds 21 and 26 that present a better affinity for A3AR (Ki=3680nM and Ki=3750nM, respectively). Receptor-driven molecular modeling studies provide information on the binding/selectivity data of the chromone. The data so far acquired are instrumental for future optimization of chromone carboxamide as a selective A3AR antagonist.