Antibacterial agents are substances that inhibit bacterial growth and their reproduction. Their effectiveness relies on selective toxicity and appropriate pharmacokinetic properties. The spread of bacterial resistance and the escalation of severe infections compel us to develop new antibacterial agents. One of the antibiotic classes is also monocyclic beta-lactams or 2-azetidinones. These are four-membered cyclic amides, that contain two carbon atoms, a carbonyl group and a nitrogen atom. Monobactams, like other groups of beta-lactams, target bacterial cell wall synthesis. Specifically, they inhibit the activity of penicillin-binding proteins, which are essential for the processes of transglycosylation and transpeptidation steps involved in forming the glycosidic and peptide bonds of peptidoglycan.
In our work, we focused on the synthesis and biological evaluation of 3-amido substituted monocyclic beta-lactams. In the first part we optimized the synthetic reaction conditions. We selected carbonylimidazole (CDI) as the coupling reagent, a reaction temperature of 50 °C, and a reaction time of 16 hours. Subsequently, we synthesized 3-amido-substituted monocyclic beta-lactams from 13 starting acids. In the final phase of our work, we performed biochemical and biological evaluations of the synthesized compounds. We determined the inhibitory activity of 18 compounds on PBP1b from Streptococcus pneumoniae by measuring the fluorescence anisotropy and determined the antibacterial activity of the compounds. Compound 13a exhibited the best residual activity, while compound 6a required the lowest concentration to achieve 50% inhibition (IC50). We further tested our compounds on 10 different bacterial strains. Compound 14 showed the most potent activity against Gram-negative bacterial strains, which has a thiophene in its structure. Compound 5a showed the most potent activity against Gram-positive bacterial strains, which has a 3-nitrophenyl side chain. Compound 6a, which containes a 2,6-dichloro substituted benzene ring, showed activity against both Gram-negative and Gram-positive bacterial strains. The most promising compound against Gram-negative bacteria was identified as compound 12, which has a low IC50 value and shows the best inhibitory activity against Gram-negative bacteria. Against Gram-positive bacteria, the best results were observed with compound 5a. Compound 6a was also interesting as it is a nanomolar inhibitor of PBP1b.
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