Beyond Nrf2 Potency: Oxidation-State-Guided Stability and Drug-Likeness Profiling of N-Glycosyl Iberin Analogues

Introduction

N-glycosyl isothiocyanates bearing sulfur-containing substituents at C3 constitute a well-defined family of carbohydrate-based iberin analogues. In this scaffold, the electrophilic N=C=S group is located at the anomeric position, while the sulfur substituent can be modulated through a thioether–sulfoxide–sulfone redox sequence. This provides a useful framework to examine how sulfur oxidation influences chemical stability and predicted drug-like behavior beyond Nrf2 potency.

Methods

A structurally matched set of N-glycosyl iberin analogues was comparatively profiled according to the oxidation state of the C3 sulfur substituent. Nrf2 activation was used as the biological reference parameter. Stability was assessed by time-dependent ¹H NMR experiments in a DMSO-d₆/D₂O mixture, monitoring diagnostic resonances over time. Predicted ADME and drug-likeness descriptors were calculated using SwissADME, including bioavailability radar plots to compare polarity, lipophilicity, solubility, flexibility and size.

Results

Sulfur oxidation had a marked impact on biological and developability profile of the series. Thioether derivatives showed negligible Nrf2 modulation, whereas the corresponding sulfoxides and sulfones displayed low-micromolar activity, with phenyl-substituted oxidized analogues giving the most favorable responses. However, ¹H NMR monitoring showed that the isothiocyanate group at the anomeric position reduces chemical robustness in DMSO-d₆/D₂O medium. SwissADME radar plots revealed oxidation-dependent changes in polarity, lipophilicity, solubility, and global drug-likeness.

Conclusions

Sulfur oxidation state acts as a key activity-switching and developability-modulating element in N-glycosyl iberin analogues. Integrating Nrf2 activity, ¹H NMR-monitored solution stability and SwissADME descriptors provide a rational basis for prioritizing carbohydrate-based electrophilic redox modulators.