Synthesis and Antibacterial Activity of Novel Phosphonated CF(3)-β-lactams.

A new series of C-3 phosphonated 4-CF(3)-β-lactams was stereoselectively synthesized from corresponding 4-CF(3)-β-lactams, applying two different protocols for phosphonate group incorporation. The first method involved the direct incorporation of a phosphonate (V) moiety at the C-3 position although it was limited by steric hindrance. The second approach enabled the incorporation of a less bulky phosphonite (III), which was subsequently oxidized to the corresponding phosphonate (V). The synthesized β-lactam ring features both fluorinated and phosphonate substituents, which are known for their biological significance, such as enhancing membrane permeability, improving binding interactions, and inhibiting enzymes. Considering these properties, along with the inherent antibacterial potential of β-lactams, we evaluated the antibacterial activity of selected C-3 phosphonated 4-CF(3)-β-lactams against four bacterial strains (Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA), Neisseria gonorrheae, Escherichia coli (E. coli)). Applying the disk diffusion method, MIC measurements, and β-lactamase inhibition assays, compounds 11 and 16 emerged as the most promising candidates in this preliminary antibacterial evaluation.