Due to the rapidly increasing bacterial resistance, there is an urgent need to find new antibacterial drugs and the corresponding drug targets. One of the most promising new classes of drugs are novel bacterial topoisomerase inhibitors (NBTIs). Topoisomerases, which include bacterial DNA gyrase and topoisomerase IV, mantain topological state of DNA and enable normal flow of processes such as replication and transcription. NBTIs can inhibit both enzymes and thus cause the death of bacterial cell. NBTIs are composed of bicyclic left-hand side (LHS), which binds into DNA, the linker and an aromatic right-hand side (RHS), which binds into hydrophobic pocket in enzyme.
Within the framework of the master's degree we focused on the synthesis of novel bacterial topoisomerase inhibitors with preserved 1,5-naphthyrydine left-hand side, but distinct linkers and right-hand sides. For right-hand side we used two different types of differently substituted aromatic rings, phenyl and furan – thereby we tried to the effect of aromatic ring on the action of compounds. Using different functional groups we tried to find out whether various other interactions can adequately substitute halogen and halogen bonds bonds, which have thus far showed important effect on the action of NBTIs. We also modified the linker moiety. by piperidine and cyclohexaneto determine whether linker influences hERG inhibition, which hampers the further development of NBTIs.
Final compounds were first characterized with NMR, HRMS, IR spectroscopy and had their melting points measured and then biological tests were made. We determined IC50, minimal inhibitory concentration (MIC) values, and inhibition of hERG channels. Compound containing phenyl rings turned out to be more potent inhibitors of selected enzymes and the importance of halogen bonds was also verified, as the halogen-substituted compound showed the best results. MIC values exposed weaker effect of our compounds against gram-negative bacteria and the main problem appeared to be in lower permeability. Testing on hERG channels showed that the ciclohexan linker is a much safer choice than the piperidine one. The results clearly indicate that the use of proper linker is important in order to achieve lower cardiotoxicity and greater selectivity of compounds.
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