Design, synthesis and antibacterial activity of novel LpxC inhibitors containing 1,2,3-triazole moieties

Two series of N-aryl-L-threonine derivatives bearing a triazole fragment are described as LpxC inhibitors targeting Gram-negative pathogens. Most compounds demonstrated stronger antibacterial activities against E. coli (MICs: ≤0.03-16 μg/mL). Compounds a5, b1 and b2 exhibited pronounced antibacterial activity against Escherichia coli (MICs: ≤0.03-0.5 μg/mL), Klebsiella pneumoniae (MICs: 1-16 μg/mL), and Pseudomonas aeruginosa (MICs: 1-8 μg/mL). Meanwhile, a5 displayed the lowest cytotoxicity toward A549 (IC₅₀ > 4.032 μg/mL), HepG2 (IC₅₀ > 4.032 μg/mL), and HEK293 (IC₅₀ > 0.9112 ± 0.3461 μg/mL) mammalian cells. Against all tested E. coli strains, a5 displayed a therapeutic index of 3.64-67.20. Molecular docking analyses revealed that a5 simultaneously chelated the catalytic zinc ion and established extensive non-covalent interactions within the LpxC active site. This study provides a basis for further research on 1,2,3-triazole compounds.