Design, green synthesis and biological evaluation of fluorinated N-acyl sulfonamides as novel anti-inflammatory agents: an in vivo and in silico study

Abstract

The N-acylsulfonamide functional group constitutes a key moiety in numerous successful drugs, primarily due to its high chemical stability and favorable human tolerance profile. Herein, we report the development of a new eco-friendly and highly efficient approach for the preparation of N-acylsulfonamides. This method involves the synthesis of N-sulfonyloxaziridines via oxidation of the corresponding N-sulfonylimines, followed by a facile rearrangement into N-acylsulfonamides under mild and green conditions. The methodology afforded a diverse range of N-acylsulfonamides in good yields and high atom economy (AE). The synthesized compounds were subsequently evaluated for their in vivo anti-inflammatory activity. Specifically, the fluorinated N-acylsulfonamides 3c, 3e, and 3f exhibited potent inhibitory activity against carrageenan-induced inflammation, surpassing the reference drug (diclofenac). Analysis of the structure-activity relationship (SAR) highlighted the critical role of fluorine in enhancing this anti-inflammatory potential. Molecular docking and ADME-T studies were undertaken to elucidate the molecular mechanisms of action and predict the pharmacokinetic profile of these compounds on their biological targets.