High-Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets

Area of Science:

• Medicinal Chemistry
• Analytical Chemistry
• Chemical Engineering

Background:

• Late-stage diversification of drug molecules is crucial for drug discovery.
• High-throughput experimentation facilitates reaction screening for efficient drug development.

Purpose of the Study:

• To present a rapid method for functionalizing bioactive molecules using accelerated reactions in microdroplets.
• To enable high-throughput screening of chemical reactions for drug discovery.

Main Methods:

• Utilizing microdroplets for accelerated chemical reactions on a millisecond timescale.
• Employing desorption electrospray ionization mass spectrometry (DESI-MS) for reaction monitoring.
• Nebulizing reaction mixtures at a throughput exceeding 1 reaction/second.

Main Results:

• Generated and characterized 269 functionalized analogs of opioid agonist PZM21 and antagonist naloxone.
• Screened over 500 reactions using sulfur fluoride exchange (SuFEx) click, imine formation, and ene-type click reactions.
• Achieved an overall screening throughput of 1 Hz at the low nanogram scale.

Conclusions:

• The developed microdroplet reaction and DESI-MS method allows for rapid, high-throughput diversification of drug molecules.
• This approach significantly accelerates the screening of medicinal chemistry reactions for drug discovery.
• The method demonstrates efficiency in generating diverse analogs of bioactive compounds at a low scale.