Structure-activity and structure-property relationships in CARBAZOLE-based AZETIDIN-2-one: Synthesis, antimicrobial...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Computational Chemistry

Background:

• Rising global antimicrobial resistance necessitates novel therapeutic agents.
• Existing antibiotics face reduced efficacy, driving the search for new drug candidates.

Purpose of the Study:

• To synthesize and characterize novel carbazole-based 2-azetidinone derivatives.
• To evaluate the antimicrobial and antifungal activities of these compounds.
• To investigate their mechanisms of action using computational methods.

Main Methods:

• Synthesis of 12 carbazole-based 2-azetidinone derivatives (5a-f and 6a-f) via conventional, ultrasonic, and microwave-assisted techniques.
• Biological evaluation of antimicrobial activity against Gram-positive and Gram-negative bacteria using zone of inhibition and minimum inhibitory concentration (MIC) assays.
• Antifungal assays against Candida albicans and Aspergillus brasiliensis.
• Computational analysis including Density Functional Theory (DFT) and molecular docking studies.
• Absorption, Distribution, Metabolism, and Excretion (ADME) predictions.

Main Results:

• Microwave-assisted synthesis yielded up to 98.6% within 5 minutes.
• Compounds 5b, 5e, 6b, and 6e exhibited significant antimicrobial activity.
• Compounds 6b and 6e outperformed streptomycin against Escherichia coli and Pseudomonas aeruginosa.
• Compound 6e showed potent antifungal activity against Candida albicans and Aspergillus brasiliensis, comparable to fluconazole.
• DFT analysis indicated favorable electronic properties for compounds 5e and 6e.
• Molecular docking revealed strong binding affinities to β-lactamase and penicillin-binding protein targets.
• ADME predictions suggested good drug-likeness and gastrointestinal absorption.

Conclusions:

• Compounds 5b, 5e, 6b, and 6e are promising lead candidates for developing new antimicrobial agents.
• The synthesized carbazole-based β-lactams offer a potential solution to combat drug-resistant pathogens.
• Combined experimental and computational approaches effectively identified potent antimicrobial compounds.