Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors

Abstract

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 (K_i = 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 Aβ_1 − 42-induced cognitive impairment, significantly prevented the effects of Aβ_1 − 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.

Keywords:

• SuFEx click chemistry
• sulphonyl fluoride
• sulphonamide
• cholinesterase inhibitor

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by the National Natural Science Funding of China under Grant 22071190; Natural Science Fundation of Anhui provincial Department of Education under Grant KJ2019ZD21; and Anhui Provincial Natural Science Foundation under Grant 2008085MH272.