Abstract
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•A series of novel quinoline-1,3,4-oxadiazole and quinoline-1,2,4-triazole hybrids has been designed and synthesized.•The new hybrids were tested against DNA gyrase and topoisomerase IV from Escherichia coli and Staphylococcus aureus.•Compounds 4c, 4e, 4f, and 5e were the most active ones.•Compound 4e showed IC50 values lower than reference novobiocin.•Some compounds have demonstrated superior antibacterial activity to ciprofloxacin.•Docking study revealed high binding affinities toward DNA gyrase and topoisomerase IV.
DNA gyrase and topoisomerase IV (topo IV) inhibitors are among the most interesting antibacterial drug classes without antibacterial pipeline representative. Twenty-four new quinoline-1,3,4-oxadiazole and quinoline-1,2,4-triazole hybrids were developed and tested against DNA gyrase and topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compounds 4c, 4e, 4f, and 5e displayed an IC50 of 34, 26, 32, and 90 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). The activities of 4c, 4e, 4f, and 5e on DNA gyrase from S. aureus were weaker than those on E. coli gyrase. Compound 4e showed IC50 values (0.47 µM and 0.92 µM) against E. coli topo IV and S. aureus topo IV, respectively in comparison to novobiocin (IC50 = 11, 27 µM, respectively). Antibacterial activity against Gram-positive and Gram-negative bacterial strains has been studied. Some compounds have demonstrated superior antibacterial activity to ciprofloxacin against some of the bacterial strain studied. The most active compounds in this study showed no cytotoxic effect with cell viability>86%. Finally, a molecular docking analysis was performed to investigate the binding mode and interactions of the most active compounds to the active site of DNA gyrase and topoisomerase IV (topo IV) enzymes.