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 in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO2F) 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 T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor (Ki = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Aβ1 - 42-induced cognitive impairment, significantly prevented the effects of Aβ1 - 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.
Keywords: SuFEx click chemistry; cholinesterase inhibitor; sulphonamide; sulphonyl fluoride.