Methylpiperazine-Based 1,2,4-Triazole Derivatives as Potent DNA Gyrase B Inhibitors with Promising Broad-Spectrum Antimicrobial Activity

The emergence of antimicrobial resistance (AMR) poses a critical threat to global health, underscoring the need for new antimicrobial agents. In this study, a novel series of 1,2,4-triazole derivatives was synthesized from methylpiperazine intermediates via esterification, hydrazide formation, thiourea condensation, and Mannich-type reactions. Structural characterization was performed using FT-IR, 1H, 13C NMR, and EI-MS techniques. Antimicrobial activities of the synthesized compounds were evaluated via broth microdilution. One derivative displayed remarkable broad-spectrum activity with MIC values <0.24 µg/mL against E. coli, S. aureus, M. smegmatis, and C. albicans. Molecular docking against E. coli DNA gyrase B (PDB: 4PRV) revealed strong binding affinities for two derivatives (–9.9 and –9.8 kcal/mol), correlating well with in vitro results. Key interactions included hydrogen bonding, π–π stacking, and halogen bonding. SAR analysis emphasized the role of electron-withdrawing and hydrophobic groups in enhancing activity. These triazole derivatives show promise as potent antimicrobial candidates targeting DNA gyrase B.