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J Med Chem. 2018 Apr 26;61(8):3565-3581. doi: 10.1021/acs.jmedchem.7b01892. Epub 2018 Apr 10.

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

Author information

1
Therapeutic Area Infectious Diseases , Sanofi R&D , 1541 Avenue Marcel Mérieux , 69280 Marcy L'Etoile , France.
2
R&D, Integrated Drug Discovery , Sanofi-Aventis Deutschland GmbH , Industriepark Hoechst , 65926 Frankfurt am Main , Germany.
3
LGCR, Analytical Sciences , Sanofi R&D , 13 Quai Jules Guesde , 94400 Vitry sur Seine , France.
4
Evotec France , 195 Route d'Espagne , BP 13669, 31036 Toulouse Cedex 1, France.
5
Antibacterial DPU , GlaxoSmithKline , 1250 Collegeville Road , Collegeville , Pennsylvania 19426 , United States.
6
Department of Biological Chemistry , John Innes Centre , Norwich Research Park , Norwich NR4 7UH , U.K.
7
Department of Medical Biochemistry and Microbiology, Biomedical Center , Uppsala University , Box 582, Uppsala S-751 23 , Sweden.

Abstract

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.

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