Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria

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 IIα.
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).