Metronidazole containing pyrazole derivatives potently inhibit tyrosyl‐tRNA synthetase: design,synthesis, and biological evaluation

As an important enzyme in bacterial protein biosynthesis, tyrosyl‐tRNA synthetase (TyrRS) has been an absorbing therapeutic target for exploring novel antibacterial agents. A series of metronidazole‐based antibacterial agents has been synthesized and identified as TyrRS inhibitors with low cytotoxicity and significant antibacterial activity, especially against Gram‐negative organisms. Of the compounds obtained, 4f is the most potent agent which inhibited the growth of Pseudomonas aeruginosa ATCC 13525 (MIC = 0.98 μg/mL) and exhibited TryRS inhibitory activity (IC₅₀ = 0.92 μm ). Docking simulation was performed to further understand its potency. Membrane‐mediated apoptosis in P. aeruginosa was verified by flow cytometry.