Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors.
J Enzyme Inhib Med Chem
; 38(1): 2237213, 2023 Dec.
Article
en En
| MEDLINE
| ID: mdl-37501629
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 (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 Aß1 - 42-induced cognitive impairment, significantly prevented the effects of Aß1 - 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Compuestos de Azufre
/
Fluoruros
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2023
Tipo del documento:
Article