Design, synthesis, antimicrobial evaluation, in-silico molecular docking, and ADME-T evaluation of novel benzoxazole-piperazine hybrids with amide linkage

A series of benzoxazole-piperazine hybrids (9a–n) has been synthesized via a multistep approach incorporating the Mitsunobu reaction. These compounds were obtained in good yields using cost-effective and readily available starting materials under mild reaction conditions. Structural characterization was performed using ¹H NMR,¹³C NMR, LCMS, elemental analysis, and FTIR spectroscopy. The antimicrobial potential of 9a–n was assessed against bacterial strains Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli and fungal strains Aspergillus niger, and Candida albicans. Notably, compounds 9b, 9c and 9f exhibited potent antibacterial activity, comparable to chloramphenicol and gentamicin, and antifungal activity similar to nystatin. Molecular docking and dynamics simulations suggested that 9f inhibits E. coli DNA gyrase, forming a stable protein-ligand complex with strong binding interactions and low docking scores. Furthermore, in silico ADMET analysis indicated favorable pharmacokinetic properties with no significant toxicity concerns, highlighting their potential as promising antimicrobial agents.