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

Authors

Changchun Ye, Zilu Chen, Jiantao Jiang, Jianzhong Li, Ranran Kong, Shiyuan Liu, Xin Chen, Zhengshui Xu

Published in

Journal of enzyme inhibition and medicinal chemistry. Volume 41. Issue 1. Pages 2627711. Epub Feb 23, 2026.

Abstract

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.

PMID:
41725379
Bibliographic data and abstract were imported from PubMed on 23 Feb 2026.

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