Design, synthesis and antiproliferative activity of oxadiazole derivatives as potent glycogen synthase kinase-3/histone deacetylase 6 dual inhibitors.

A series of oxadiazole-based dual inhibitors targeting GSK3 and HDAC6 were rationally designed by integrating key pharmacophores into a single molecule. Among these derivatives, 4-(((5-(benzo[d][1, 3]dioxol-5-yl)-1,3,4-oxadiazol-2-yl)thio)methyl)-N-hydroxybenzamide (15i) was identified as the most potent compound with IC₅₀ of 5.50, 69 nM and 88 nM against HDAC6, GSK3α and GSK3β, respectively. 15i also exhibited potent cytotoxicity against the AGS cancer cell line, with IC₅₀ values in the submicromolar range. Molecular docking simulation confirmed that 15i fitted well into the active sites of both HDAC6 and GSK3β. These findings establish compound 15i as a promising candidate for further evaluation.