Antibacterial Spiropyrimidinetriones with N‑Linked Azole Substituents on a Benzisoxazole Scaffold Targeting DNA Gyrase

Herein,
we report spiropyrimidinetriones (SPTs) incorporating N-linked
azole substituents on a benzisoxazole scaffold with improved Gram-positive
antibacterial activity relative to previously described analogues.
SPTs have an unusual spirocyclic architecture and represent a new
antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors.
They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase
IV inhibitors used clinically. The activity of the SPTs was assessed
for DNA gyrase inhibition, and the antibacterial activity across Gram-positive
and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted
on the 5-position provides the most worthwhile profile. Directed nucleophilic
and electrophilic chemistry was developed to vary this 5-position
with carbon, nitrogen, or oxygen substituents and explore structure–activity
relationships including those around a target binding model. Compounds
with favorable pharmacokinetic parameters were identified, and two
compounds demonstrated cidality in a mouse model of Staphylococcus aureus infection.