Discovery of a Novel Template, N3‑1'-Homologated 4'-Truncated Thiosugar-Substituted Xanthine as an A3AR Antagonist via Conversion of an A1AR Antagonist.

Adenosine receptors (ARs) are G protein-coupled receptors involved in diverse physiological and pathological processes. Among them, the A3 subtype (A3AR) is an attractive therapeutic target due to its low basal expression and strong upregulation in inflamed or tumor tissues. Here, an A1AR-derived xanthine scaffold was repurposed toward A3AR antagonism by introducing a 1'-homologated 4'-truncated thiosugar at the N3 position. Structure-activity studies identified C8 substitution as the key determinant of subtype selectivity, while N1 groups modulated binding cooperatively. The optimized analogue 5p exhibited potent and selective A3AR binding (K i = 6.8 nM) with functional antagonism, showing an enhanced A1/A3 selectivity index (72) compared with that of the known xanthine-based A3AR antagonist I-ABOPX (4.5). These findings demonstrate that thiosugar homologation effectively redirects xanthine scaffolds toward selective A3AR antagonists and identify 5p as a promising lead compound.