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[<i>d</i>][1, 3]dioxol-5-yl)-1,3,4-oxadiazol-2-yl)thio)methyl)-<i>N</i>-hydroxybenzamide (<b>15i</b>) was identified as the most potent compound with IC₅₀ of 5.50, 69 nM and 88 nM against HDAC6, GSK3<i>α</i> and GSK3<i>β</i>, respectively. <b>15i</b> also exhibited potent cytotoxicity against the AGS cancer cell line, with IC₅₀ values in the submicromolar range. Molecular docking simulation confirmed that <b>15i</b> fitted well into the active sites of both HDAC6 and GSK3<i>β</i>. These findings establish compound <b>15i</b> as a promising candidate for further evaluation.