The emergence of multi-drug-resistant bacteria has become a global challenge, necessitating the urgent development of novel antimicrobial agents. In our work, we focused on the optimization of synthetic pathways for the preparation of β-lactam antibiotics, specifically the subgroup of monobactams or 2-azetidinones, which were afterwards evaluated biologically. These types of drugs work by inhibiting peptidoglycan synthesis leading to the formation of structural weaknesses in the cell wall that subsequently succumb to osmotic pressure and result in bacterial cell death. The compounds were synthesized via various multi-step procedures and purified using liquid chromatography. In the end we prepared seven final and two control compounds, which were evaluated for their inhibitory activity against the PBP1b enzyme from Streptococcus pneumoniae using fluorescence anisotropy. Additionally, their minimal inhibitory concentrations were determined against four bacterial strains.
Out of three synthetical routes used to prepare the C3-substituted product, the pathway utilizing a tert-butyloxycarbonyl protecting group at C3 and an azide group at C4 exhibited the highest overall yield (1.4%). The synthetic pathway for the C4-substituted product proved comparably successful, achieving a 0.7% overall yield using a benzyloxycarbonyl protecting group instead of the tert-butyloxycarbonyl. despite the low yields, a sufficient amount of each product was isolated for biochemical and biological evaluation. The results indicated that none of the final compounds exhibited inhibitory activity towards the PBP1b enzyme, while both control compounds inhibited the enzyme, with compound 33 also achieving satisfactory results in the microdilution antimicrobial susceptibility test by inhibiting the growth of the Gram-negative bacterium E. coli.
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