Design, Synthesis, Computational Study, and Biological Evaluation of Sulphonyl and Amide Tethered Indole‐Piperazine Derivatives as Antimicrobial Agents

Abstract Piperazine derivatives are essential scaffolds in medicinal chemistry because they can be structurally modified to explore their novel biological activities. In this study, two new series of derivatives were synthesized that are (( S )‐5‐chloro‐l‐methyl‐1 H ‐indol‐2‐yl) (2‐methyl(phenyl sulphonyl)piperazin‐l‐yl)methadone derivatives ( 9a–f ) and ( S )‐4‐(benzoyl‐2‐methylpiperazin‐l‐yl)l(5‐chloro‐1‐methyl‐l H ‐indol‐2‐yl)methanone derivatives ( l0a–f ). FTIR, 1 H NMR, 13 C NMR, and mass spectrometry confirmed their structures. In vitro antimicrobial assays (MIC, µg/mL) revealed that compounds 9b ( Bacillus subtilis 94, Staphylococcus aureus 94.8, Escherichia coli 100, Proteus vulgaris 96, Aspergillus niger 120, Candida albicans 99.5), 9d (93.4, 98, 102, 118; 98, 98), 9f (94.2, 94.6, 132, 98; 122, 104), 10a (98, 124, 154, 140, 144, 106), and 10c (96, 96.5, 122, 126; 120, 102) displayed notable antibacterial and antifungal activities, comparable to standard drugs. Computational docking supported these findings, showing strong binding affinities and molecular dynamics simulations confirmed the stability of the protein–ligand complexes (0–100 ns). Among them, ( S )‐(4‐((4‐(tert‐butyl)phenyl)sulfonyl)‐2‐methylpiperazin‐1‐yl)(5‐chloro‐1‐methyl‐1 H ‐indol‐2yl)methanone ( 9f ) has emerged as the most promising molecule because of its thermodynamic stability and strong molecular interactions. ADMET predictions further suggested favorable pharmacokinetic properties, highlighting the potential of indole–piperazine derivatives as antimicrobial agents.