ArticleJournal of medicinal chemistry2026
Discovery and Optimization of Novel Nonhydroxamate LpxC Inhibitors for the Treatment of Multidrug-Resistant Gram-Negative Infections.
Article in Journal of medicinal chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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13 authors.
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Abstract
This report summarizes the discovery and optimization of a novel series of nonhydroxamate inhibitors targeting LpxC, a Zn2+-dependent hydrolase that is essential for the survival of Gram-negative bacteria. Beginning with a 5-hydroxypyrimidin-4-one metal-binding pharmacophore, structure-based approaches were utilized to generate a series of potent inhibitors that exhibited activity against a wide variety of Enterobacterales, including both susceptible and multidrug-resistant pathogens, and efficacy in murine thigh infection models. These novel compounds were evaluated in a rat model of cardiovascular toxicity to demonstrate the safety of the scaffold relative to another LpxC inhibitor that proved unsuccessful in Phase I clinical trials. A variety of inhibitors with potent in vivo efficacy and no hemodynamic effects were identified, which constituted an initial suite of potential development candidates.
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