Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N‑Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914)

A novel class of bacterial type-II
topoisomerase inhibitor displaying
a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold
shows potent activity against Gram-positive and fastidious Gram-negative
bacteria. Here, we describe a series of N-linked
oxazolidinone substituents on the benzisoxazole that improve upon
the antibacterial activity of initially described compounds of the
class, show favorable PK properties, and demonstrate efficacy in an
in vivo Staphylococcus aureus infection
model. Inhibition of the topoisomerases DNA gyrase and topoisomerase
IV from both Gram-positive and a Gram-negative organisms was demonstrated.
Compounds showed a clean in vitro toxicity profile, including no genotoxicity
and no bone marrow toxicity at the highest evaluated concentrations
or other issues that have been problematic for some fluoroquinolones.
Compound 1u was identified for advancement into human
clinical trials for treatment of uncomplicated gonorrhea based on
a variety of beneficial attributes including the potent activity and
the favorable safety profile.