Metronidazole Containing Pyrazole Derivatives Potently Inhibit Tyrosyl-tRNA Synthetase: Design, Synthesis and Biological Evaluation

Abstract

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. Out 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.

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A series of metronidazole-pyrazole derivatives were designed and synthesized as anti-bacterial agent to target the tyrosyl-tRNA synthetase (TyrRS). All of the synthesized compounds were examined by bioactivity assays, and the structure-activity relationship was also discussed. Membrane-mediated apoptosis in P. aeruginosa induced by compound 4f was verified by flow cytometry.

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