Synthesis and Biological Evaluation of 3,5-Diaryl-Substituted 1,2,4-Oxadiazole Sulfamates as Potent Steroid Sulfatase Inhibitors

A novel series of 3,5-disubstituted 1,2,4-oxadiazole sulfamates was synthesized and evaluated as steroid sulfatase (STS) inhibitors. Molecular docking predicted high affinity (binding energies of up to −8.9 kcal·mol –1 ), often surpassing the reference Irosustat. Biological evaluation confirmed potent inhibition; compound 9n reduced enzymatic STS activity to 3.5% at 10 μM. In JEG-3 cells, the most potent derivative, 9j, exhibited an IC 50 of 6.64 nM, comparable to that of Irosustat (4.19 nM). Structure–activity relationship analysis revealed that the substitution pattern of the oxadiazole heterocycle plays a decisive role in determining biological activity. Shifting the aryl-sulphamate pharmacophore between positions 3- and 5- of the 1,2,4-oxadiazole heterocycle is crucial for maintaining high biological activity. These findings establish 3,5-disubstituted 1,2,4-oxadiazole sulfamates as promising leads for treating hormone-dependent cancers.