Stereoselective synthesis and antibacterial potential of C-3 chloro β-lactams: Insights into DNA gyrase inhibition using in silico molecular docking

This study explores the development of novel antibacterial agents through the stereoselective synthesis of eight C-3 chloro-substituted ortho-/meta-/para-(2-benzo[d]oxazolyl)phenyl-β-lactams. These compounds were obtained via the reaction of 2-chloroethanoic acid and 4-chlorophenylethanoic acid with isomeric ortho-, meta- and para-(2-benzo[d]oxazolyl)phenyl Schiff bases, exclusively yielding trans-β-lactams with high stereoselectivity (J = 1.8-2.6 Hz) and excellent yields (78-93 %). The antibacterial potential of these chloro β-lactams was further evaluated against S. aureus and E. coli, revealing significant activity across all tested compounds. Notably, compounds 5a and 5f exhibited the highest potency, with binding energies of -7.65 and -8.17 kcal/mol against E. coli and -7.35 and -8.29 kcal/mol against S. aureus. The IC₅₀ values further confirmed their strong inhibitory effects, with 5a and 5f displaying values of 39 ng/mL and 35 ng/mL against E. coli, and 32 ng/mL and 30 ng/mL against S. aureus. Molecular docking studies demonstrated strong hydrogen bonding interactions between the synthesized compounds and the active sites of DNA gyrase in E. coli (PDB ID: 1KZN) and S. aureus (PDB ID: 5BS3), indicating favourable binding affinity. These findings highlight the potential of stereoselective C-3 chloro β-lactams as promising antibacterial candidates targeting DNA gyrase.