Design, synthesis, and antibacterial efficacy of new methylene disalicylic acid/1,3,4-oxadiazole hybrids as dual inhibitors of DNA gyrase and topoisomerase IV.

DNA gyrase and topoisomerase IV enzymes are promising candidates for dual targeting with novel antibacterial agents, lowering the risk of bacterial resistance development. A new series of methylene disalicylic acid/1,3,4-oxadiazole hybrids (5a-l) was developed as dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity. The structures of the novel compounds were validated using 1H NMR, 13C NMR, and elemental microanalysis. Compounds 5a-l were tested for their inhibitory effect against E. coli DNA gyrase. Compounds 5g, 5h, 5j, and 5l exhibited the highest inhibitory activity against E. coli DNA gyrase, with IC50 values ranging from 164 to 179 nM. Compound 5h has the highest potency as an E. coli DNA gyrase inhibitor with an IC50 value of 164 nM, representing an enhanced potency compared to reference novobiocin. Compounds 5g, 5h, 5j, and 5l were tested against S. aureus DNA gyrase, E. coli, and S. aureus topoisomerase IV. The findings indicated that 5g, 5h, 5j, and 5l activities on DNA gyrase from S. aureus were predominantly less effective than those on E. coli gyrase, with IC50 values ranging from 44 to 56 nM. Compound 5h was the most efficient inhibitor of E. coli and S. aureus topoisomerase IV. Compound 5h showed significant antibacterial effectiveness against the multi-drug resistant (MDR) VRE-12201 and MRSA (EMRSA-15) strains, outperforming the reference drugs vancomycin and amoxicillin. This study used molecular docking to analyze compound 5h with E. coli DNA gyrase B. ADME analysis highlighted enhanced lipophilicity, making it a promising candidate for further optimization as a Gyrase B inhibitor.