Synthesis, Antibacterial Activity, and In Silico Analysis of Hydroxyxanthone Derivatives Targeting Gram-Positive and Gram-Negative Bacteria

The global rise of antibiotic-resistant bacteria poses a critical health challenge, necessitating the discovery of new antibacterial agents. In this study, three hydroxyxanthone derivatives, 1,5-dihydroxyxanthone (HX1), 1,6-dihydroxyxanthone (HX2), and 1,7-dihydroxyxanthone (HX3) were synthesized in 3.5, 38.2, and 17.54% yields, respectively. In vitro assays revealed that all compounds were inactive against Escherichia coli (MIC > 1000 µg/mL) but exhibited potent inhibition of Pseudomonas aeruginosa (MIC 15.62 µg/mL). Compounds HX1 and HX3 also demonstrated strong activity against Staphylococcus aureus and Bacillus subtilis (MICs of 15.62 µg/mL), while HX2 showed moderate activity (MIC of 31.25 µg/mL). Molecular docking indicated favorable binding energies (–6.23 to –6.68 kcal/mol) toward DHFR from E. coli and S. aureus, surpassing those of trimethoprim and tetracycline. Molecular dynamics simulations confirmed stable ligand–protein interactions, and ADMET analyses potential drug-likeness and pharmacokinetic profiles. Overall, HX1 and HX3 emerge as promising lead scaffolds for the development of novel DHFR-targeted antibacterial agents against both Gram-positive and Gram-negative pathogens.