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

• Published in: Journal of medicinal chemistry 2018-04, Vol.61 (8), p.3565-3581
• Main Authors: Jeannot, Frédéric, Taillier, Thomas, Despeyroux, Pierre, Renard, Stéphane, Rey, Astrid, Mourez, Michaël, Poeverlein, Christoph, Khichane, Imène, Perrin, Marc-Antoine, Versluys, Stéphanie, Stavenger, Robert A, Huang, Jianzhong, Germe, Thomas, Maxwell, Anthony, Cao, Sha, Huseby, Douglas L, Hughes, Diarmaid, Bacqué, Eric
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - toxicity; Bacterial Proteins - antagonists & inhibitors; Drug Resistance, Bacterial - drug effects; Gram-Negative Bacteria - drug effects; Hep G2 Cells; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Imidazoles - toxicity; Male; Mice; Microbial Sensitivity Tests; Pyrazines - chemical synthesis; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; Pyrazines - toxicity; Quinazolinones - chemical synthesis; Quinazolinones - pharmacokinetics; Quinazolinones - pharmacology; Quinazolinones - toxicity; Topoisomerase Inhibitors - chemical synthesis; Topoisomerase Inhibitors - pharmacokinetics; Topoisomerase Inhibitors - pharmacology; Topoisomerase Inhibitors - toxicity
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01892

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.