Antibiotics are critical agents for treating bacterial infections; however, their excessive and inappropriate use leads to the emergence of resistant bacterial strains, necessitating the development of new antimicrobial compounds. Bacterial DNA gyrase, a type IIA topoisomerase that regulates DNA topological changes during replication and transcription, is an established target for antibacterial agents. Inhibitors of the GyrB subunit, which competitively bind to the ATP-binding site, represent a promising class due to their specificity and efficacy.
The aim of this master’s thesis was to design and synthesize three intermediates for the preparation of novel N-phenylpyrroleamide GyrB inhibitors bearing aminoalkyl substituents, along with one alcohol fragment for future research. The synthesis followed a three-step procedure involving a Mitsunobu reaction, catalytic hydrogenation, and amide bond formation. The identity and purity of the compounds were confirmed using NMR, IR, HRMS, and HPLC analyses. From the synthesized intermediates, the final compounds PP1-156, PP1-157-2, and PP1-159 were prepared.
Their inhibitory activity against Escherichia coli DNA gyrase and antibacterial efficacy were evaluated on selected Gram-positive and Gram-negative bacterial strains. Compound PP1-157-2 exhibited the highest inhibitory activity (IC₅₀ = 1.0 nM), while compound PP1-159 achieved the lowest minimum inhibitory concentration (MIC₉₀ = 0.125–0.25 µg/mL) against Staphylococcus aureus, including resistant MRSA and VISA strains. Activity against Gram-negative bacteria was lower, attributed to limited penetration through the outer membrane.
N-phenylpyrroleamide-based GyrB inhibitors represent a promising foundation for the development of new antibiotics, particularly against Gram-positive bacteria, while highlighting the need for further optimization to enhance efficacy against Gram-negative pathogens.
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