Halogenated Cinnamanilides and Their Activity against Selected Gram-negative Bacteria

Recently published halogenated anilides of chlorinated and trifluorinated cinnamic acids, such as (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-N-(3,5-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enamide or (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide, showed excellent antibacterial activities in vitro against Gram-positive bacteria, especially against reference and quality control strains Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, as well as against representatives of multidrug-resistant bacteria and clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE) with minimum inhibitory concentrations (MICs) against staphylococci <0.2 µg/mL and against enterococci <4 µg/mL. It should be noted that all these compounds are rather lipophilic (software predicted log P values close to 5) and carry electron-withdrawing substituents that allow them to be classified as so-called Michael acceptors. All these facts inspired further investigation of the spectrum of effectiveness against other bacteria, and the most effective agents with various substitutions in both the anilide part and on the phenyl ring of the parent cinnamic acid were chosen and tested against selected pathogenic Gram-negative bacteria, such as reference and quality control strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27859 and clinical isolate of Klebsiella pneumoniae 797. Unfortunately, it was found that none of the selected halogenated anilide derivatives with such high potency against Gram-positive bacteria demonstrated better efficacy against the tested Gram-negative bacteria than MICs 256 µg/mL.