Microtiter Plate-based Chemistry and in Situ Screening: SuFEx-enabled Lead Discovery of Selective AChE Inhibitors

Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSOF) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound was identified as a reversible, competitive, and selective AChE inhibitor ( = 22 nM). The drug-like evaluation showed that had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. behavioural study showed that treatment improved the Aβ-induced cognitive impairment, significantly prevented the effects of Aβ toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.