Kim, MinjaeNaik, Siddhi D.Choi, HongseokKim, Seung WooPark, Jung HoonJoung, MisukSong, JiyoonGaikwad, Vidyasagar B.Jeong, Lak Shin2026-05-262026-05-262025ACS Medicinal Chemistry Letters. 16(1); 2025; 149–156.1948-5875https://doi.org/10.1021/acsmedchemlett.4c00522http://khandolacollege.ndl.gov.in/handle/123456789/292The A3 Adenosine Receptor (A3AR) is an important therapeutic target due to its role in inflammation and immune response regulation. Herein, we synthesized and evaluated 5′-deoxy-adenosine derivatives with oxygen at the 4′-position, comparing them to previously studied 4′-thionucleosides. Compound 1h exhibited the highest binding affinity (Ki = 5.9 ± 1.1 nM), consistent with the trend observed in the 4′-thionucleosides. Notably, the 5′-deoxy-adenosine derivatives demonstrated enhanced agonistic activity. Docking studies with compound 1h revealed a shift in binding mode when oxygen replaced sulfur at the 4′-position. The compounds retained strong interactions with critical residues, such as Thr94, even without a hydrogen bond donor at the 5′-position. These results explain the increased agonistic effect observed when the ring heteroatom was changed from sulfur to oxygen.enNATURAL SCIENCES::ChemistryArticle