Chalcone-based derivatives as new scaffolds for hA3 adenosine receptor antagonists

Objectives With the aim of finding new adenosine receptor (AR) ligands based on the chalcone scaffold, we report the synthesis of a new series of coumarin–chalcone hybrids and the pharmacological characterization of their actions at four subtypes of AR. Methods The synthesized compounds 5–10 were characterized in radioligand binding (A1, A2A and A3) and adenylyl cyclase activity assays (A2B) to determine the affinity of the compounds for the four human AR (hAR) subtypes. Key findings Coumarin–chalcone hybrids were found to be ligands with a novel structure, not reported thus far, that showed varying affinity and selectivity for AR subtypes. Conclusions The coumarin–chalcone hybrids in which ring B of the chalcone scaffold was a thiophene (compounds 5 and 9) were found to be the most potent compounds of the series. Compound 9, in which ring A of the chalcone moiety was the phenyl ring of the coumarin, showed similar activity against hA1, hA2A and hA3 ARs, while compound 5, in which ring A of the chalcone was substituted by the benzopyrone ring of the coumarin moiety, showed similar activity only at the hA3 AR and, therefore, was deemed to be selective (Ki (dissociation constant) = 5160 nm). A new series of chalcone‐based derivatives, including a coumarin moiety in their structures, have been synthesized and binding assays for the hA1, hA2A, and hA3 adenosine receptors were employed to assess the affinity for receptor subtypes. Isosterical substitutions of one or both phenyl rings of the chalcone moiety reveal that thiophene‐containing compounds 5 and 9 have good binding affinity for ARs. Compound 5, in which both phenyl rings of the original chalcone scaffold (rings A and B) were substituted for a thiophene and pyrone rings, resulted selective for the hA3 adenosine receptor (Ki = 5,160 nM). Based on the obtained results, a preliminary structure‐activity relationship (SAR) study showed a high selectivity and good potency of these thiophene‐containing compounds.