Imidazopyrazinones (IPYs): Non-Quinolone Bacterial Topoisomerase Inhibitors Showing Partial Cross-Resistance with Quinolones

In our quest for new antibiotics
able to address the growing threat of multidrug resistant infections
caused by Gram-negative bacteria, we have investigated an unprecedented
series of non-quinolone bacterial topoisomerase inhibitors from the
Sanofi patrimony, named IPYs for imidazopyrazinones, as part of the
Innovative Medicines Initiative (IMI) European Gram Negative Antibacterial
Engine (ENABLE) organization. Hybridization of these historical compounds
with the quinazolinediones, a known series of topoisomerase inhibitors,
led us to a novel series of tricyclic IPYs that demonstrated potential
for broad spectrum activity, in vivo efficacy, and a good developability profile, although later profiling
revealed a genotoxicity risk. Resistance studies revealed partial
cross-resistance with fluoroquinolones (FQs) suggesting that IPYs
bind to the same region of bacterial topoisomerases as FQs and interact
with at least some of the keys residues involved in FQ binding.