Design, synthesis, and biological assessment of a novel series of coumarin-tethered thiazole derivatives as potential antibacterial agents

Résumé

Since the discovery of penicillin in the 1930s, antibiotics have been the primary treatment for bacterial infections. However, antimicrobial resistance (AMR) has escalated due to antibiotics overuse and misuse. To address this concern, a new series of coumarin-thiazole derivatives was synthesized and evaluated against Serratia fonticola, Campylobacter jejuni, Enterococcus faecalis, and Achromobacter xylosoxidans. Most compounds showed selective activity, with compounds 6a and 6c exhibiting potent effects against E. faecalis (MICs: 25, 12.5 μg/mL) and A. xylosoxidans (MICs: 50, 25 μg/mL), comparable to ciprofloxacin. Further studies revealed that 6a and 6c effectively disrupted bacterial biofilms with a low resistance risk. Mechanistically, they induced ROS production, thereby impairing redox homeostasis and reducing lipid peroxidation. Additionally, compound 6a inhibited E. coli DNA gyrase (IC50 = 23.75 μg/mL). Molecular docking studies (PDB ID: 4duh) and dynamics simulations confirmed the stable binding of these compounds to DNA gyrase, suggesting their potential as novel antibacterial agents. These findings highlight promising avenues for the development of new therapeutic agents to combat AMR.

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