Structural characterization, cytotoxicity, antibiofilm activity, and synergistic potential with molecular docking analysis of ibuprofen-derived hydrazide against bacterial pathogens.

The study investigates the synthesis, characterization, and antibacterial activity of an ibuprofen-derived hydrazide (HIDZ). It was synthesized and characterized using NMR spectroscopy, DFT Calculations, and ADMET studies. Furthermore, HIDZ cytotoxicity on L929 cells was evaluated using the MTT reduction assay. Antibacterial activity was assessed against Gram-positive and Gram-negative strains through the microdilution method. The combinatory potential of HIDZ was performed using the checkerboard test with β-lactam antibiotics, oxacillin (OXA), meropenem (MER), and cefepime (CPM). Antibiofilm activity was evaluated for biofilm inhibition and disruption, particularly in combination with OXA. Molecular docking analysis examined HIDZ interactions with Thymidylate kinase, DNA Gyrase B, and DNA Topoisomerase IV subunit B. The global chemical reactivity descriptors analysis revealed significant variations in the atomic centers' susceptibility, highlighting the environment's importance in determining the reactive behavior of HIDZ. Pharmacokinetic predictions indicated efficient permeability across biological membranes, suggesting favorable bioavailability. MTT experiment showed that HIDZ caused cytotoxicity on higher concentrations over L929 fibroblasts. HIDZ exhibited superior activity against Gram-positive strains compared to ibuprofen, with lower MIC and MBC values. Both compounds were ineffective against Gram-negative strains. However, HIDZ was able to inhibit the biofilm formation of the most tested strains. The combinatory effect shows an additive effect between HIDZ and β-lactams. However, the HIDZ/OXA combination improved biofilm disruption, achieving up to a 92 % reduction in residual biofilm and cell viability compared to the control. Molecular docking simulations showed that HIDZ may interact with bacterial enzymes, improving antibiotic efficiency. The study suggests that HIDZ has promising potential as an antibacterial and antibiofilm agent, particularly against Gram-positive bacteria and in combination with β-lactam antibiotics.