High‐Throughput Drug Derivatization and Bioassay by Desorption Electrospray Ionization Mass Spectrometry

Adapting high-throughput (HT) synthetic methods to the modification of drugs and to testing of their bioactivity should expedite drug discovery. Herein, the applicability of HT desorption electrospray ionization mass spectrometry (DESI MS) to achieve late-stage functionalization (LSF) and rapidly generate a modified opioid library is demonstrated. Specifically, aza-Michael addition and sulfur (VI) fluoride exchange reactions are used for functionalization. The modified drugs are both synthesized and characterized using an automated HT-DESI MS platform, with the reaction occurring during the droplet flight. Analysis by MS characterizes reaction products at a throughput of >1 reaction per second. With this platform, multiple nor-opioid scaffolds and functionalization reagents are screened and a selection of the hits obtained is subjected to HT label-free bioassays using the same DESI-MS platform. This combination of accelerated LSF reactions to rapidly create a diverse library of functionalized drugs with direct bioassays of the crude reaction mixtures for structure-activity relationship evaluation, both using the same platform, is anticipated to help expedite the early drug discovery process.