Design, Synthesis, Biological Evaluation and Molecular Docking of New Acid-Functionalized Carbazole Derivatives as Potential Antibiotic Agents

Abstract

The emergence of antibiotic resistance necessitates the discovery of new scaffolds with improved efficacy and drug-like properties. In this work, a new series of acid-functionalized carbazole derivatives was designed, synthesized, and comprehensively evaluated for their antibacterial potential. The incorporation of acidic functionalities into the carbazole framework enhanced physicochemical properties and biological interactions, yielding distinct strain-specific antibacterial activities. Minimum inhibitory concentration (MIC) studies demonstrated that 3-methyl-1,4-dioxo-4,9-dihydro-1H-carbazole-6-carboxylic acid (2) exhibited broad-spectrum potency, particularly against S. aureus and E. coli, while 6-methyl-9H-carbazole-3-carboxylic acid (3) showed selectivity against B. cereus and (E)-3-methyl-1-(2-tosylhydrazono)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid (1) displayed strong activity toward S. typhimurium. Molecular docking studies revealed favourable binding affinities of all derivatives toward bacterial dihydrofolate reductase (DHFR), with compound 1 showing the highest docking scores. Molecular dynamics simulations further confirmed the broad conformational adaptability of compound 1, the target-specific stability of compound 3, and protein-dependent binding behaviour of compound 2. Complementary ADMET predictions indicated that all compounds adhered to Lipinskis rules, with compound 3 displaying the most favourable pharmacokinetic profile, including high oral bioavailability and low toxicity risk. Together, these experimental and computational findings establish acid-functionalized carbazole scaffolds as promising antibacterial candidates.