Infectious diseases have always been affecting the population throughout the world. When penicillin and other antibacterial agents were discovered in the beginning of the 20th century, and it appeared as if humans had finally controlled and destroyed pathogens, antibiotic-resistant bacterial strains began to develop. The resistance of bacteria to antibacterial agents is a major global problem, and is one of the biggest threat to the world's population. A very daunting fact is that more and more bacteria are becoming resistant to an increasing number of different active ingredients, however, the development of new antibacterial agents is a slow process and requires a lot of energy and resources. For this reason, the discovery of new agents that would work through new mechanisms of action or that would bind to yet-unused binding sites on already existing targets, is very important. For this master's thesis, we wanted to synthesize compounds that would inhibit bacterial growth with the mechanism of action on subunit B of DNA gyrase enzyme. Currently, there are no active substances on the market yet that would inhibit the growth of bacteria with a similar mechanism of action. Two series of compounds were synthesized, i.e. piperazine and piperidine derivatives, and their inhibitory activity was evaluated by an enzyme assay on DNA gyrase and topoisomerase IV enzymes from bacteria Escherichia coli and Staphylococcus aureus. We also carried out antibacterial testing on nine different Gram-positive and Gram-negative bacterial strains. The results of the tests allowed us to examine the structure-activity relationship of the compounds. We have discovered that, in general, piperidine derivatives exhibit better activity on the DNA gyrase enzyme from E. coli and S. aureus compared to piperazine derivatives. We assumed that derivatives possessing free carboxylic acid groups and hydrazide groups would be significantly more active than their methyl ester analogues due to the possibility of forming additional interactions with the enzyme, but this is not the case. Among all synthesized compounds, compound 11 containing a 5-oxo-4,5-dihydro-1,3,4-oxadiazole ring in its structure exhibits the highest activity. We assume that the reason for its high activity is the possibility of forming more hydrogen bonds, as well as the possibility of interactions with the salt bridge at the binding site of the enzyme. From the results of the antibacterial tests, it can be concluded that most compounds are more active against Gram-positive bacteria than against Gram-negative bacteria. Many compounds have shown very good antibacterial activity, however, compound 11 has proved to be the best, because at 50 μM concentration it inhibited bacterial growth in seven out of nine bacterial strains for more than 93 %.
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