Novel benzo[h]quinoline hybrids 4, 6, and 10 exhibit potent bactericidal and antibiofilm activity against S. aureus.

The escalating crisis of antimicrobial resistance (AMR) poses a severe global health threat, necessitating the urgent development of new therapeutic agents. A critical challenge in AMR is the formation of biofilms, which shield bacteria from antibiotics and host immune responses, rendering conventional treatments ineffective. Current antibiotics often struggle against these complex structures, highlighting a significant therapeutic gap. This research explores novel small molecules targeting bacterial Peptide Deformylase (PDF) enzyme, a crucial metalloenzyme involved in bacterial protein maturation, offering a promising, underexplored mechanism to overcome existing resistance pathways.

Researchers designed and synthesized a novel series of benzo[h]quinoline-based 2-thioxothiazolidin-4-one and thiazol-4-one hybrids (compounds 3-11), specifically engineered to enhance interactions with the bacterial Peptide Deformylase (PDF) enzyme. These compounds underwent comprehensive in vitro biological assessment, starting with initial inhibition zone (IZ) screening. This was followed by quantitative minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests against a diverse panel of Gram-positive, Gram-negative, and fungal strains. The anti-biofilm efficacy of the most promising candidates was then evaluated against S. aureus and S. typhi at sub-inhibitory doses, using a dose-dependent destruction assay.

The synthesized benzo[h]quinoline derivatives exhibited potent, primarily bactericidal activity across various microbial strains. Compounds 4, 6, and 10 emerged as particularly outstanding candidates, demonstrating significant activity against S. aureus with a MIC of 7.8 μg/mL. This potency was found to be equivalent to the standard reference antibiotic used in the study. Furthermore, the anti-biofilm efficacy of these leading compounds was rigorously assessed. Compound 6 distinguished itself as a prominent dual-action agent, combining strong bactericidal effects with significant dose-dependent biofilm destruction. > Compound 6 exhibited considerable biofilm inhibition against S. aureus by 56.76% and against S. typhi by 65.93%, even at substantially diluted sub-lethal concentrations (25% MBC). These findings strongly confirm the substituted benzo[h]quinoline core as a highly promising pharmacophore for developing next-generation antimicrobial medicines effective against both free-floating planktonic cells and resilient structured biofilms.