Sulfonamide-Derived Four-Component Molecular Hybrids as Novel DNA-Targeting Membrane Active Potentiators against Clinical Escherichia coli

Novel sulfonamide-based four-component molecular hybrids as potential DNA-targeting antimicrobial agents were developed from marketed acetanilide through convenient procedures. Biological assays indicated that a few of the target compounds showed significant inhibitory efficiencies toward the tested bacteria and fungi. Noticeably, metronidazole hybrid 6a exhibited a lower minimum inhibitory concentration (MIC) value of 0.019 mM against clinical drug-resistant Escherichia coli (E. coli), which showed to be 84-fold more active than clinical norfloxacin and had no obvious toxicity toward human breast cancer MCF-7 cells. Synergistic combinations of compound 6a with clinical antibacterial or antifungal drugs could improve the antimicrobial efficiency. Further molecular modeling indicated that the active molecule 6a could bind with THR-199, HIS-64, and GLN-92 residues of human carbonic anhydrase isozyme II through hydrogen bonds and was also able to insert into base-pairs of the DNA hexamer duplex by forming hydrogen bonds. The preliminary exploration of the antibacterial mechanism suggested that compound 6a was capable of disturbing the E. coli membrane effectively and intercalating into clinical resistant E. coli bacterial DNA through noncovalent bonds to form a supramolecular complex, thus exerting its powerful antimicrobial activity. This might suggest a great possibility for hybrid 6a to be a DNA-targeting membrane active potentiator against clinical drug-resistant E. coli.