Design, Synthesis and in silico Study of Diarylsulfide Piperazine-Amide Hybrids as Antibacterial Motifs

Novel antimicrobial drugs are required to fight the serious global health challenge of antibiotic resistance. In this study, 12 hybrids of diarylsulfide (DAS) piperazine-amide 8a-l were synthesized. All the 12 compounds were assessed for the antibacterial study against Gram-positive and Gram-negative bacteria. Antibacterial structure-activity relationship (SAR) analysis revealed that disubstituted compounds, particularly 8h (3,4-dinitro) and 8j (2,4-dichloro), exhibited superior antibacterial activity and also states that ortho-substituted compounds performing better than para-substituted ones. Molecular docking studies further strengthened antibacterial efficacy of disubstituted compounds 8h (-7.58 kcal/mol) and 8j (7.14 kcal/mol) exhibited the highest binding affinity to the DNA gyr. A enzyme, interacting with essential residues critical for bacterial DNA replication. It was concluded that strong binding, alongside favourable lower RMSD values, allows these compounds to effectively inhibit DNA gyrase. Therefore, these DAS piperazine-amide compounds represent promising lead compounds for further study as antibacterial agents.