Synthesis, Antibacterial Activity, and Structure–Activity Relationship of Fusaric Acid Analogs

Forty‐one fusaric acid analogs possessing a pyridine carboxylic acid scaffold have been synthesized. The antibacterial activity results demonstrated that compounds 5b, 7b, 8c, and 8d displayed strong antibacterial activities against Staphylococcus aureus ATCC25923 with minimum inhibitory concentrations (MICs) of 4–16 μg/mL. Molecular docking study indicated that these compounds have strong hydrogen‐bonding interactions with TyrRS. Meanwhile, 8c and 8d showed promising antibacterial activities against Pseudomonas aeruginosa ATCC9027. Compound 4 exhibited pronounced antibacterial activities against a clinically isolated multidrug‐resistant strain of Escherichia coli (MIC: 64 μg/mL as compared 64 μg/mL of levofloxacin and 1024 μg/mL of ceftriaxone sodium). Moreover, compound 17e displayed strong synergistic antibacterial effect with levofloxacin against the multidrug‐resistant strain, decreasing the MIC value of levofloxacin to 1/16 of its original MIC. No obvious cytotoxic activities against LO2 was observed for compounds 4, 5b, 8c, 8d, 17d, and 17e at 50 μM. The preliminary structure–activity relationship of fusaric acid analogs was also discussed. SAR of FA analogs as antibacterial agents