Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry.

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Small-molecule optimization is typically a slow, resource-intensive process.
• Current methods often lack automation and rely heavily on expert medicinal chemists.

Purpose of the Study:

• To develop a high-throughput, automated hit-to-lead process for small-molecule drug discovery.
• To leverage sulfur(VI) fluoride exchange (SuFEx) click chemistry for rapid analog diversification and screening.

Main Methods:

• A high-throughput screening hit was modified with a SuFExable motif.
• Rapid diversification of the modified compound into 460 analogs via overnight reactions.
• Direct screening of reaction products to identify potent inhibitors.

Main Results:

• Achieved a 480-fold increase in inhibitor potency against bacterial cysteine protease SpeB (from 8 μM to 18 nM).
• Developed drug-like inhibitors with significantly improved efficacy.
• Demonstrated activity of the optimized molecule in a bacteria-host coculture model.

Conclusions:

• The SuFEx click chemistry methodology enables rapid, automated optimization of small-molecule probes and drug candidates.
• This approach can accelerate the development of novel therapeutics and biological tools.
• The picomole-scale reaction efficiency facilitates direct screening and further optimization.