Structure-activity and structure-property relationships in CARBAZOLE-based AZETIDIN-2-one: Synthesis, antimicrobial evaluation, DFT, docking, ADME, and toxicity studies.

In response to the increasing global threat of antimicrobial resistance and the reduced efficacy of current antibiotics, this study reports the synthesis, structural characterization, and combined experimental and computational evaluation of 12 novel carbazole-based 2-azetidinone derivatives (5a-f and 6a-f) for their antimicrobial activities. The compounds were synthesized using conventional, ultrasonic, and microwave-assisted methods, with microwave irradiation giving yields up to 98.6% within only 5 min. Biological evaluations identified compounds 5b, 5e, 6b, and 6e as active carbazole-based β-lactams. Compounds 6b and 6e showed activity against Escherichia coli (25.3 and 24.1 mm) and Pseudomonas aeruginosa (23.0 and 22.0 mm), outperforming streptomycin (20.8 and 20.3 mm), with MICs of 78 μg/mL. For Gram-positive strains, 6b inhibited Enterococcus faecalis (22.9 mm, MIC 78 μg/mL), while Staphylococcus aureus suppressed by 6b (MIC 78 μg/mL) and 5e/6e (MIC 312 μg/mL). In antifungal assays, compound 6e showed remarkable activity against Candida albicans, producing a 28.4 mm inhibition zone and an MIC of 78 μg/mL, comparable to fluconazole (26.0 mm), and was also effective against Aspergillus brasiliensis (MIC 78 μg/mL). Density functional theory analyses revealed that compounds 5e and 6e display the smallest HOMO-LUMO gaps and the highest global electrophilicity indices. Molecular docking confirmed their superior binding affinities toward β-lactamase and penicillin-binding protein targets, with energies of -10.5 to -11.6 kcal/mol. ADME predictions indicated favorable drug-likeness and high gastrointestinal absorption. Overall, experimental and theoretical findings highlight compounds 5b, 5e, 6b, and 6e as promising leads for antimicrobial drug development and preclinical evaluation.