Rapid Exploration of\nChemical Space by High-Throughput\nDesorption Electrospray Ionization Mass Spectrometry

This study leverages accelerated reactions at the solution/air\ninterface of microdroplets generated by desorption electrospray ionization\n(DESI) to explore the chemical space. DESI is utilized to synthesize\ndrug analogs at an overall rate of 1 reaction mixture per second,\nworking on the low-nanogram scale. Transformations of multiple drug\nmolecules at specific functionalities (phenol, hydroxyl, amino, carbonyl,\nphenyl, thiophenyl, and alkenyl) are achieved using electrophilic/nucleophilic,\nredox, C–H functionalization, and coupling reactions. These\ntransformations occur under ambient conditions on the millisecond\ntime scale with direct detection of products being successful in all\nbut three of the reaction types studied. The large scope (22 bioactive\ncompounds, >20 chemical transformations, and >300 functionalization\nreagents) and high speed (>3000 reactions/hour) provide access\nto\na wide array of drug analogs that can be used for bioactivity testing.\nA total of ∼6800 unique reactions were examined through a data-driven\nworkflow, and more than 3000 unique derivatives (∼44%) were\nidentified tentatively by the <i>m</i>/<i>z</i> value and signal-to-control ratio in single-stage mass spectrometry\n(MS) analysis, with over 1000 being further characterized by tandem\nMS. The speed of the DESI-MS reaction screen provides potential advantages\nfor emerging machine learning-based predictions of organic synthesis,\nand it sets the stage for future online DESI-MS bioassays and scaled-up\nmicrodroplet synthesis before formal characterization of hit compounds\nis sought using traditional methods of drug discovery.