Synthesis and antimicrobial activity of salicylamide azaisosteres

Salicylic acid (SAL) derivatives are organic compounds derived from 2-hydroxybenzoic acid, where the ortho position of the phenolic and carboxyl groups is important for biological activity and facilitates chemical modifications of the molecule with optimized physicochemical properties and biological activity. Halogenated SAL derivatives are among the important multi-target anti-invasive agents. These effects of SAL derivatives are significantly influenced by their chemical structure. Simple compounds, such as halogenated SAL anilides, have been gradually prepared, up to complex molecules mimicking peptidomimetics with several different amino acids between the salicylic and anilide parts. One of the most promising compounds was 5-chloro-2-hydroxy-N-[(2S)-4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide, which demonstrated the broadest spectrum of activity against various pathogens, comparable to clinically used antibiotics. To further understand the structure-activity relationships, nitrogen isosteres were prepared by replacing the benzene ring of salicylic acid with pyridine and pyrazine rings. A series of ten azaisosteres were synthesized and evaluated against the reference strains Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Mycobacterium smegmatis ATCC 700084, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27859 and against three clinical isolates of methicillin-resistant S. aureus (MRSA), three isolates of vancomycin-resistant E. faecalis (VRE) and a clinical isolate of Klebsiella pneumoniae 797. Unfortunately, it was found that none of the prepared SAL azaisosteres showed activity against any of the tested bacteria higher than MIC 256 µg/mL.