期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 6, 页码 2950-2973出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01750
关键词
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资金
- Chinese Academy of Sciences [CASIMM0120162010]
- National Science and Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
Spiropyrimidinetriones are a novel class of antibacterial agents that target the bacterial type II topoisomerase via a new mode of action. Compound ETX0914 is thus far the only drug from this class that is being evaluated in clinical trials. To improve the antibacterial activity and pharmacokinetic properties of ETX0914, we carried out systematic structural modification of this compound, and a number of compounds with increased potency were obtained. The most promising compound 33e, with incorporation of a spirocyclopropane at the oxazolidinone 5 position reduced metabolism, exhibited excellent antibacterial activity against Gram-positive pathogens and a good pharmacokinetic profile combined with high aqueous solubility. In addition, compound 33e exhibited good selectivity for Staphylococcus aureus gyrase over human Topo II alpha. In a murine model of systemic methicillin-resistant S. aureus infection, 33e exhibited superior in vivo efficacy (ED50 = 3.87 mg/kg) compared to ETX0914 (ED50 = 11.51 mg/kg).
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