Strategic Design and Synthesis of a Piperazine-Coupled 1,3-diketone as a Potential Antibacterial Agent Against MRSA

Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant healthcare challenge due to its strong antibiotic resistance. In this study, a piperazine-coupled 1,3-diketone derivative, compound-1d ((2E,2′E)-2,2′-(piperazine-1,4-diylbis(methaneylylidene))bis(1-phenylbutane-1,3-dione)), was strategically designed, synthesized, and characterized using FT-IR, 1H-NMR, and 13C-NMR techniques. The compound exhibited significant antibacterial activity, with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 125 µg/mL and 250 µg/mL, respectively, against MRSA (ATCC 43300). Computational analyses, including ADMET prediction, DFT calculations, molecular docking, and molecular dynamics simulations, confirmed strong and stable interactions with PBP2a (1MWT) and glycosyltransferase (6FTB) proteins, showing binding energies of -8.8 and -7.1 kcal/mol, respectively. The results demonstrate that the piperazine bridge plays a pivotal role in enhancing antibacterial activity, highlighting compound-1d as a promising lead scaffold that disrupts PBP2a- and glycosyltransferase-mediated cell wall synthesis in MRSA.