Bacterial resistance represents a rising problem in public healthcare, consequently the key factor is the development of new antibacterial drugs, that would inhibit new therapeutic targets or existing targets with novel mechanisms of action. Bacterial DNA gyrase, consisting of two subunits A and two subunits B is a validated target for the development of new antibacterial drugs. In clinical practice fluoroquinolones are used as inhibitors of DNA gyrase A subunit, DNA gyrase B subunit inhibitors are not present in current clinical practice. In our thesis we have designed compounds with a potential inhibitory activity on the DNA gyrase B subunit. We have synthesized 8 compounds with aminopiperdine scaffold that was at the first terminal site expanded with dibromopyrrole or indole fragments. At the second terminal site we attached aliphatic fragment with a free carboxyl group and its methyl ester analogues, while piperdin-4-amine was substituted with an allyl or benzyl fragment. All final synthesized compounds were evaluated with an in vitro assay on the isolated enzyme. We have discovered that dibromopyrrole fragment is the most important for strong inhibitory activity. Compounds with a carboxyl group have formed stronger interactions with amino acid residue Arg136 at the entrance of the binding site. Substitution of piperdin-4-amine with lipophilic fragments disables optimal conformation in the active site of DNA gyrase B enzyme, because the key interactions with Asp73 and the conserved water molecule are discontinued. As reference we synthesized two unsubstituted compounds with 3,4-dichloro-5-methyl pyrrole fragment. They showed good inhibitory activity for enzyme DNA gyrase from E.coli. The results represent an important contribution to structure-activity relationship of these series of compounds.
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