Nowadays bacterial resistance represents an increasing problem, since the existing drugs are no more that effective towards resistant bacteria. Therefore, it is necessary to discover drugs, against which bacteria would develop resistance more difficult. It makes sense to discover drugs acting on new targets in microorganism or targeting known targets, but with a different mode of action. Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and are validated antibacterial drug targets. The source of energy for both enzymes represents the ATP molecule. In this Master's thesis we will present the synthesis of novel pyrrolamide-based inhibitors of DNA gyrase and topoisomerase IV. Inhibitors were designed in a way to bind into the ATP-binding site. The pyrrole fragment mimics the adenine part of the ATP molecule. We have also attached electron withdrawing groups on the pyrrol moiety to achieve better interactions in the binding, introduced different side chains and studied structure-activty relationship. Final compounds were also tested for their enzyme inhibitory activity at 100 μM. If the residual activity of the enzyme was lower than 50%, we determined also the IC50 values on isolated enzymes DNA gyrase and topoisomerase IV from bacterial strains Escherichia coli and Staphylococcus aureus. The most potent compound on the isolated DNA gyrase from E. coli was compound 11 with an IC50value of 0,0418 μM. The compounds were also tested for antibacterial activity on two Gram positive (Enterococcus faecalis in S. aureus) and two Gram negative (E. coli in Pseudomonas aeruginosa) bacterial strains. Among all compounds only compound 12 showed activity against E. faecalis and S. aureus bacterial strains at MIC=50 μM.
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