Turning the Sulfur Dial: Strategic Oxidation-State Manipulation in Modern Drug Discovery

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Organic Chemistry

Background:

• Sulfur's unique electronic properties (polarizability, accessible oxidation states) enable diverse molecular geometries.
• Sulfur-containing motifs are increasingly prevalent in FDA-approved drugs, rising from 11% in 2020 to 20% in 2024.
• Sulfur offers tunable properties beyond lipophilicity for drug design.

Purpose of the Study:

• To advocate for sulfur oxidation state switching as a primary lead optimization strategy.
• To elucidate how varying sulfur oxidation states influence molecular geometry, polarity, and stability.
• To demonstrate the utility of sulfur's interconvertible oxidation states for fine-tuning drug properties.

Main Methods:

• Analysis of sulfur's electronic and geometric characteristics across different oxidation states.
• Mapping the impact of sulfur oxidation state changes on target engagement and ADMET properties.
• Review of synthetic methodologies enabling access to diverse sulfur motifs, including SuFEx click chemistry and DABSO-mediated sulfonylation.

Main Results:

• Sulfur's oxidation states (-2 to +6) provide a tunable platform for medicinal chemistry.
• Interconversion of sulfur oxidation states allows for rapid optimization of drug candidate properties.
• Synthetic innovations facilitate the practical application of sulfur-based drug design.

Conclusions:

• Sulfur oxidation state switching is a powerful, first-line strategy for lead optimization.
• A framework is proposed to integrate sulfur oxidation state as a dynamic variable in medicinal chemistry design.
• Leveraging sulfur's unique chemistry can accelerate the development of novel therapeutics.