The antimicrobal resistance represents a significant public health problem. An increasing number of bacteria is also resistant to fluoroquinolones, which are considered one of the most successful classes of antibiotics. The upsurge of resistance has thus created a need for the design of new antibacterial agents. Novel bacterial topoisomerase inhibitors have a similar mechanism of action as fluoroquinolones, but due to the different binding mode within the binding site, they work on bacterial strains that are resistant to fluoroquinolones. They act as dual inhibitors, as they inhibit two enzymes: DNA gyrase and topoisomerase IV. Both enzymes are classified as type II topoisomerases, which regulate the DNA topology during replication. Novel bacterial topoisomerase inhibitors consist of a right-hand side moiety that binds to the non-catalytic binding pocket of the enzyme, a left-hand side moiety that intercalates between the central base pairs of DNA, and a connecting part, the linker, whichs ensures the correct spatial orientation of the ligand, affects the physicochemical properties, pharmacological properties, safety profile, and inhibitory activity of the molecules.
As part of the master’s thesis, we synthesized structurally novel bacterial topoisomerase inhibitors. We synthesized a series of 1,2,3-triazoles and a 3-fluoro-6-methoxy-1,5-naphthyridine inhibitor with an oxazolidin-2-one linker. We assumed that these structural modifications would improve the antibacterial effect of the active compounds known in the literature. The antibacterial activity was evaluated in biological assays. The final compounds were characterized by various chromatographic and spectroscopic methods.
A series of synthesized 1,2,3-triazoles did not inhibit bacterial growth. On the other hand, oxazolidin-2-one derivative 33 showed potent minimal inhibitory concentrations for E. coli, mutated strains of E. coli, S. aureus and other ESKAPE class bacteria. The efficacy of inhibition of bacterial enzymes was confirmed by residual activities of DNA gyrase and topoisomerase IV from E. coli and S. aureus in the presence of the ligand. Therefore, we believe that derivative 33 represents a promising lead compound for the synthesis of novel bacterial topoisomerase inhibitors.
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