Synthesis and Bioactivity of Novel 1,2,4‐Oxadiazole–Sulfonamide Hybrids as Potent Antibacterial Agents Against Klebsiella pneumoniae

To combat resistant bacterial strains, a series of compounds (8a-8n) were synthesized in moderate to excellent yields (32.8-94.0%). These analogs were subjected to preliminary screening against various bacterial strains, including Enterococcus faecalis, Escherichia coli, Bacillus subtills, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, to evaluate their effectiveness as antibacterial agents. Compounds 8f and 8i were the most effective derivatives, displaying their best antibacterial activity against K. pneumoniae with MIC values of 16 and 32 µg/mL, respectively. Additionally, compound 8f demonstrated a beneficial synergistic effect with ampicillin. The compound 8f was found to show good interactions with dihydropteroate synthase via hydrogen bonding, π-cation interaction and π-π stacking interactions. The binding free energy (BFE) value was calculated to be -63.91 Kcal/mol. The molecular dynamics simulation showed low RMSD values (0.6 to 2.2 Å) of DHPS-8f complex and apoprotein, suggesting a stronger binding affinity. Importantly, it exhibited no toxicity toward human red blood cells (hRBC). Furthermore, the absorption, distribution, metabolism, and excretion (ADME) profile of 8f indicated its favorable drug-like characteristics.