Solution Stability and ADME-Guided Prioritisation of S-Glycosyl Nrf2-Modulating Isothiocyanates

Introduction
Carbohydrate-derived isothiocyanates are valuable glycomimetic analogues of natural electrophilic redox modulators such as sulforaphane and iberin. Among them, C6-isothiocyanate S-glycosides offer a particularly attractive scaffold, combining the electrophilic N=C=S pharmacophore with a sugar framework able to modulate polarity, aqueous behavior and molecular recognition. Beyond Nrf2 potency, the selection of promising redox modulators requires consideration of chemical stability and predicted drug-like properties.

Methods
A focused set of C6-isothiocyanate S-glycosyl derivatives was evaluated by integrating Nrf2 activation, stability in aqueous DMSO and in silico pharmacokinetic descriptors. Stability was assessed by time-dependent ¹H NMR experiments in a (CD₃)₂SO:D₂O mixture, following diagnostic resonances over time. ADME descriptors and bioavailability radar plots were calculated using SwissADME to compare solubility, lipophilicity, size, polarity, saturation, flexibility and overall drug-likeness across representative derivatives.

Results
The combined analysis identified selected C6-isothiocyanate S-glycosides with a favorable balance between Nrf2-modulating activity, chemical robustness in aqueous DMSO and predicted ADME profile. The phenylsulfone β-S-glycosyl C6-isothiocyanate derivative showed no appreciable degradation after 24 h under the tested conditions, with only slow spectral evolution at longer incubation times. Bioavailability radar plots revealed how the nature of the anomeric sulfur substituent and its oxidation state influence the global developability profile.

Conclusions
C6-isothiocyanate S-glycosides constitute chemically robust carbohydrate-based Nrf2 modulators. Integrating biological activity, ¹H NMR-monitored stability in aqueous DMSO and predicted ADME descriptors provides a rational framework for prioritizing electrophilic glycomimetics beyond potency alone.

Acknowledgments: Project PID2022-138863OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU.