Synthesis, Antimicrobial Activity and SAR of Indole–Oxazole–Azetidinone Hybrids

Abstract

To counter the quick development of resistance, new and effective therapeutic entities are very necessary. Regioselective chloroacetylation, oxazole cyclization, Schiff bases and Staudinger β-lactam cyclization were used in this study to explore and prepare a series of unprecedented indole-oxazole-aztidinone hybrids (5ae). All synthesized moieties were thoroughly identified by IR, ¹H-NMR, ¹³C-NMR, mass spectrometry and elemental analysis. The in vitro antimicrobial efficacy of these compounds against Gram +ve bacteria, Gram –ve bacteria and fungi was evaluated. The final βlactam derivatives (5a–e) displayed notably higher antibacterial activity than the intermediate Schiff base compounds (4a–e), with minimum inhibitory concentrations ranging from 1.56 to 12.5 µg /mL. Among all tested compounds, compound 5b showed the highest activity, with an MIC of 3.125 µg /mL against S. aureus and B. subtilis and an MIC of 1.56 µg /mL against C. krusei, similar to the activities of the reference drugs chloramphenicol and fluconazole. Structure-activity relationship (SAR) demonstrated that electron-withdrawing substituents, particularly para-chlorine group, significantly increased antibacterial activity by increasing lipophilicity and membrane permeability. Hydroxyl substitution provided discrimination in antifungal activity through hydrogen bonding interactions. These results indicate that indole-oxazol-azetidenone is a promising pharmacophore motif for the development of superior antibacterial drugs.