Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists

A series of novel dual A(2A)/A(2B) AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A(2A) AR antagonist cAMP functional assay results were encouraging for most target compounds containing quinoline or its open-ring bioisosteres. In addition, compound 7i displayed better inhibitory activity on A(2B) AR (IC50 14.12 nM) and higher potency in IL-2 production than AB928. Moreover, molecular docking studies were carried out to explain the rationality of molecular design and the activity of compound 7i. Further studies on 7f and 7i revealed good liver microsomes stabilities and acceptable in vivo PK profiles. This study provides insight into the future development of dual A(2A)/A(2B) AR antagonists for cancer immunotherapy.