Abstract: Natural sulfur-containing (SC) compounds have attracted increasing attention for their potential role as insulin sensitizers due to their unique redox-active properties. In this study, a structure-activity relationship (SAR) analysis was conducted by integrating quantitative structure-activity relationship (QSAR) predictions with structural motifs to elucidate the key determinants of insulin sensitizing activity. The results reveal a clear correlation between sulfur chain length, substitution pattern, and biological activity. Compounds containing linear trisulfide (–S–S–S–) scaffolds exhibit the highest predicted insulin sensitizing activity, along with strong apoptosis agonist and chemoprotective profiles, suggesting an optimal balance between redox reactivity and selectivity. In contrast, tetrasulfides (–S–S–S–S–) demonstrate enhanced overall reactivity and broader biological effects, but with reduced selectivity and increased likelihood of nonspecific or cytotoxic responses. Shorter sulfur chains, such as disulfides (–S–S–), and cyclic sulfur species show comparatively lower insulin-sensitizing activity, reflecting diminished redox potential and signaling modulation capacity. It is hypothesized that the presence of allyl substituents significantly enhances biological activity by increasing lipophilicity, membrane permeability, and electrophilic character, thereby facilitating interaction with redox-sensitive cellular targets. Mixed alkyl polysulfides provide intermediate activity profiles and offer tunable structures for optimizing the pharmacological balance. Overall, the results indicate that the insulin-sensitizing activity of natural sulfur-containing (SC) compounds is primarily governed by redox mechanisms dependent on the sulfur chain, which are further modulated by substituent chemistry and molecular architecture. These findings suggest that trisulfide-based structures particularly allyl-substituted derivatives are promising candidates for the rational design of more effective and selective insulin sensitizers. However, experimental data are required to confirm these results.

Cite: Dembitsky V.M. , Terent’ev A.O.
Small Molecules, Big Impact: Sulfur-Containing Natural Products in Insulin Sensitization.
Journal of Science and Mathematics Letters. 2026. V.14. N3. P.533-543. DOI: 10.37134/jsml.vol14.3.13.2026 OpenAlex

Dates:

Submitted:	Jun 7, 2026
Accepted:	Sep 2, 2026
Published online:	Sep 19, 2026

Identifiers:

≡ OpenAlex:

W7220396099

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