An inexpensive, metal-free and one-pot approach towards N-sulfonyl amidines: Identification of a chorismate mutase inhibitor with activities against S. aureus

Abstract

The simple yet innovative synthetic approaches for the direct access to the diversity based unique class of compounds of potential biological interest are of considerable interest as that can greatly facilitate the efforts in bioorganic / medicinal chemistry and drug discovery. In our efforts, we have developed a metal-free, inexpensive and one-pot method for the facile and direct synthesis of N-sulfonyl amidines that were designed as inhibitors of chorismate mutase. The methodology involved POCl3-SOCl2 promoted reaction of amide with sulphonamide to afford an array of new and unique class of compounds in good to acceptable yields. The methodology is free from the use of additional organic reaction media and amenable for scale-up. Based on in vitro and in silico studies, 3g has been identified as a first example of chorismate mutase inhibitor with selective and promising activities on a range of S. aureus strains. Indeed, the docking of 3g into AlphaFold predicted structure S. aureus CM I (UniProt ID: A0A380DU97) revealed good interactions with stabilization mostly via π-anion interactions in addition to a halogen (fluorine) bond. Compound 3g is of further pharmacological interest.