Glycogen synthase kinase 3 β (GSK-3β) has a central role in Alzheimer's disease (AD). Selective inhibitors which avoid τ hyperphosphorylation may represent an effective therapeutical approach to the AD pharmacotherapy and other neurodegenerative disorders. Here, we describe the synthesis, biological evaluation, and SAR of the small heterocyclic thiadiazolidinones (TDZD) as the first non-ATP competitive inhibitor of GSK-3β. Their synthesis is based on the reactivity of sulfenyl chlorides. In GSK-3β assays, TDZD derivatives showed IC₅₀ values in the micromolar range, whereas in other protein kinases assays they were devoid of any inhibitory activity. SAR studies allowed the identification of the key structural features. Finally, a possible enzymatic binding mode is proposed.