Synthesis of Novel 1,2,4-Oxadiazole-isoxazoline Hybrids and Their in Silico Potential with Adenosine Receptors.

A concise and efficient synthetic route to novel 1,2,4-oxadiazole-isoxazoline hybrids 7 has been developed via regioselective 1,3-dipolar cycloaddition of in situ-generated nitrile oxides with 3-( p -substituted-aryl)-5-vinyl-1,2,4-oxadiazoles 6 . The target compounds 7a–ay were obtained in moderate to excellent yields (16–97%) and fully characterized by IR, NMR, and HRMS analyses. The reactions exhibited high regioselectivity, exclusively affording 5-isoxazoline derivatives, while substituent effects played a decisive role in modulating reaction efficiency. In silico studies revealed that all hybrids 7a–ay display strong binding affinities toward the adenosine A₁ receptor (−10.0 to −8.3 kcal/mol), surpassing the co-crystallized ligand and engaging in key stabilizing interactions within the binding pocket. Furthermore, ADMET predictions indicated favorable drug-likeness, high gastrointestinal absorption, and suitable physicochemical properties. Overall, these findings identify 1,2,4-oxadiazole-isoxazoline hybrids as promising and tunable scaffolds for the development of adenosine A₁ receptor-targeted agents; however, further structural optimization and comprehensive biological evaluation are required to fully validate their therapeutic potential.