Discovery and Optimization of Indolyl-Containing 4‑Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

There exists an urgent medical need
to identify new chemical entities
(NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly
those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent
a novel class of nonfluoroquinolone inhibitors of bacterial type II
topoisomerases active against MDR Gram-negative bacteria. Herein,
we report on the discovery and structure–activity relationships
of a series of fused indolyl-containing 4-hydroxy-2-pyridones with
improved in vitro antibacterial activity against
fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial
DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility
screen, compounds 6o and 6v showed improved
MIC90 values against Escherichia coli (0.5–1
μg/mL) and Acinetobacter baumannii (8–16
μg/mL) compared to the precursor compounds. In a murine septicemia
model, both compounds showed complete protection in mice infected
with a lethal dose of E. coli.