Theoretical and Experimental Investigations of N‐ and O‐Alkylated Sulfonamides: Density Functional Theory, Hirshfeld Surface Analysis, and Molecular Docking Studies

The current article is based on the synthesis of new N‐ and O‐alkylated sulfonamides; 4‐{[Ethyl‐(naphthalene‐2‐sulfonyl)‐amino]‐methyl}‐cyclohexanecarboxylic acid ethyl ester (IV), 4‐[(2‐nitrobenzene‐1‐sulfonylamino)‐methyl]‐cyclohexanecarboxylic acid ethyl ester (V) and 4‐[(Cyclohexa‐1,5‐dienesulfonylamino)‐methyl]‐cyclohexanecarboxylic acid methyl ester (VI). These compounds were characterized by FT‐IR spectroscopy, ESI‐MS spectrometry, and X‐ray crystallography. Density functional theory (DFT) of sulfonamide esters was carried out through the Gaussian‐09 program to optimize structures. Hirshfeld surface analysis has been performed to understand the intermolecular interactions. Biological evaluation of all compounds was done to check their application for antibacterial (Halomonas halophila, Shigella sonnei, Bacillus subtilis, Chromohalobacter salexigens, Staphylococcus aureus Escherichia coli, Serratia marcescens, Chromohalobacter israelensis, Nesseria gonorrhoeae, Klebsiella pneumonia, and Halomonas salina), anti‐fungal (Aspergillus niger), enzyme inhibition activity (Acetylcholine esterase and butyrylcholine esterase) and anti‐oxidant activity (DPPH (2,2‐diphenyl‐1‐picrylhydrazyl) scavenging method, were carried out. Molecular docking was performed to check the interaction modes of these sulfonamide esters. N‐ and O‐alkylated sulfonamides were prepared and confirmed through spectroscopic techniques and X‐ray crystallography. The crystal structures indicated that the most important contributions for the crystal packing were H−H intercontact. The O‐alkylated sulfonamide (VI) showed greater hardness and lower softness characteristics and tended to be more stable compound. The N‐alkylated sulfonamide (IV) showed better results in all biological applications. Molecular docking of compounds were also supported the experimental enzyme inhibition results.