Insights into novel benzo[h]quinoline-based 2-thioxothiazolidin-4-one and thiazol-4-one hybrids as potential antimicrobial, and antibiofilm candidates: Design, synthesis, molecular modeling, and in-silico ADME studies.

Abstract

The growing crisis of antimicrobial resistance urges the immediate development of new therapeutic pharmaceuticals that can overcome current resistance mechanisms, including biofilm formation. This study included the synthesis and strategic design of a novel set of quinoline-based scaffolds (3-11) to enhance interactions with the bacterial Peptide Deformylase (PDF) enzyme. The compounds underwent extensive in vitro biological assessment, comprising initial inhibition zone (IZ) screening, followed by quantitative minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests against a range of Gram-positive, Gram-negative, and fungal strains. The synthesized derivatives exhibited potent, primarily bactericidal activity, with compounds 4, 6, and 10 emerging as notably outstanding candidates. These three compounds exhibited significant activity against S. aureus (MIC = 7.8 μg/mL), demonstrating equivalent potency to the standard reference antibiotic. Additionally, the anti-biofilm efficacy of these leading candidates was assessed against S. aureus and S. typhi at sub-inhibitory doses. Compound 6 emerged as a prominent dual-action drug, demonstrating strong bactericidal activity and significant dose-dependent biofilm destruction. It exhibited considerable biofilm inhibition against both S. aureus (56.76%) and S. typhi (65.93%) even at substantially diluted sub-lethal concentrations (25% MBC). The findings strongly confirm the substituted benzo[h]quinoline core as a highly promising pharmacophore for the development of next-generation antimicrobial medicines effective against both free-floating planktonic cells and tough structured biofilms.