Benzo-α-pyrone-derived multitargeting actions to enhance the antibacterial performance of sulfanilamides against Escherichia coli.

A novel class of benzopyrone-sulfanilamide hybrids was synthesized from phenols via multi-step reactions. Some prepared compounds effectively suppressed bacterial growth at low concentrations, and especially, sulfanilamide-hybridized 2-methyl-5-nitroimidazolyl benzopyrone 11c exhibited significant inhibitory potency against Escherichia coli (MIC = 0.0022 mM), which was 11-fold more active than clinical norfloxacin. Furthermore, compound 11c showed negligible hemolytic activity, low cytotoxicity and no drug resistance. Mechanistic studies indicated that the highly active 11c disrupted bacterial membrane integrity, reduced metabolic activity, bound DNA grooves to inhibit replication without the ability to cleave DNA, and induced reactive oxygen species (ROS) accumulation, collectively leading to bacterial death. These results highlight the potential of sulfanilamide-hybridized benzopyrones as multitarget antibacterial agents, warranting further development to combat bacterial infections.