Antibacterial activity of the structurally novel C-2 amine-substituted analogues based on quinoxaline.

Abstract

In the current study, we have designed and prepared a series of quinoxaline-based compounds, which were derived from o-phenylenediamine. Among them, compounds 5m-5p displayed good to moderate antibacterial activity with MICs of 4-16 μg mL^-1 against S. aureus, 8-32 μg mL^-1 against B. subtilis, 8-32 μg mL^-1 against MRSA and 4-32 μg mL^-1 against E. coli, respectively. Compound 5p, identified as a potent broad-spectrum antibacterial agent, demonstrated the strongest inhibitory effects against a range of bacterial strains and low cytotoxicity, thereby warranting further investigation. Compound 5p not only demonstrated the ability to disperse established bacterial biofilms but also induced a slower development of bacterial resistance compared to norfloxacin. Moreover, bactericidal time-kill kinetic studies revealed that at a high concentration of 3MIC, compound 5p was capable of directly killing MRSA cells. The subsequent postcontact effect (PCE) results showed that the growth rate of viable bacteria (MRSA) was greatly impacted and did not recover in less than 24 hours, even after antibacterial agent 5p was removed. The drug-like properties and ADME prediction exhibited that 5m-5p obeyed Lipinski's rule of five and therefore presumably maintained moderate to good bioavailability and human intestinal absorption rate when administered orally. Mechanistic investigations have elucidated that compound 5p exerted its antibacterial effect by compromising the structural integrity of bacterial cell membranes, resulting in the leakage of intracellular constituents and ultimately causing bacterial demise. Further studies in vivo have demonstrated that 5p exhibited potent antibacterial efficacy against MRSA in murine corneal infection models, particularly at elevated concentrations. The current dataset has also been meticulously analyzed to delineate the structure-activity relationships (SARs) of the synthesized compounds.