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

Abstract

AbstractLate‐stage diversification of drug molecules is an important strategy in drug discovery that can be facilitated by reaction screening using high‐throughput experimentation. Here we present a rapid method for functionalizing bioactive molecules based on accelerated reactions in microdroplets. Reaction mixtures are nebulized at throughputs better than 1 reaction/second and the accelerated reactions occurring in the microdroplets are followed by desorption electrospray ionization mass spectrometry (DESI‐MS). Because the accelerated reactions occur on the millisecond timescale, they allow an overall screening throughput of 1 Hz working at the low nanogram scale. Using this approach, an opioid agonist (PZM21) and an antagonist (naloxone) were diversified using three reactions important in medicinal chemistry: sulfur fluoride exchange (SuFEx) click reactions, imine formation reactions, and ene‐type click reactions. Some 269 functionalized analogs of naloxone and PZM21 were generated and characterized by tandem mass spectrometry (MS/MS) after screening over 500 reactions.