Compound b1(Chinese Academy of Medical Sciences & Peking Union Medical College)

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, HepG2, and HEK293 mammalian cells. 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.