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

  • ACS Med Chem Lett. 2026 Jan 16;17(2):510-519. doi: 10.1021/acsmedchemlett.5c00706.
Karol Biernacki  1 ,  Olga Ciupak  2 ,  Mateusz Daśko  2 ,  Agata Grobelna  1 ,  Artur Mirocki  3 ,  Janusz Rak  3 ,  Paweł Czubak  4 ,  Aleksandra Martyna  4 ,  Konrad Kubiński  4 ,  Maciej Masłyk  4 ,  Katarzyna Szwarc-Karabyka  5 ,  Mateusz Kwaśnik  4 ,  Janusz Rachoń  1 ,  Sebastian Demkowicz  1
Affiliations
  • 1. Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12 Street, 80-233 Gdańsk, Poland.
  • 2. Department of Inorganic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12 Street, 80-233 Gdańsk, Poland.
  • 3. Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63 Street, 80-308 Gdańsk, Poland.
  • 4. Department of Molecular Biology, Faculty of Medicine, The John Paul II Catholic University of Lublin, Konstantynów 1i Street, 20-708, Lublin, Poland.
  • 5. Nuclear Magnetic Resonance Laboratory, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12 Street, 80-233, Gdańsk, Poland.
PMID: 41704353 DOI: 10.1021/acsmedchemlett.5c00706
Abstract

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 IC50 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.

Keywords
1,2,4-oxadiazole; Steroid sulfatase; breast cancer; drug design; molecular modeling; structure−activity relationship.
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