Journal Article
Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram Positive Activity and Improved Safety Profile
Surivet, JP; Ertel, EA; Hess, P; Gauvin, JC; Mirre, A; Kaegi, V; Dos Santos, M; Kraemer, S; Gaertner, M; Delers, J; Enderlin-Paput, M; Zumbrunn, C; Weiss, M; Sube, R; Hadana, H; Keck, W; Hubschwerlen, C; Rueedi, G; Bur, D; Bruyere, T; Locher, H; Ritz, D; Seiler, P; Kohl, C; ,
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804
AMER CHEMICAL SOC
Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K+ channels and hNa(V)1.5 Na+ channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.
1 (5 amino tetrahydro pyran 2 yl) 2 (6 methoxy[1,5]naphthyridin 4 yl)ethanol; 1 (5 aminotetrahydro 2h pyran 2 yl) 2 (6 methoxy 1,5 naphthyridin 4 yl)ethan 1 ol; 1 [5 [[(2,3 dihydro[1,4]dioxino[2,3 c]pyridin 7 yl)methyl]amino]tetrahydro 2h pyran 2 yl] 2 (6 methoxy 1,5 naphthyridin 4 yl)ethan 1 ol; 1 [5 [[(2,3 dihydro[1,4]oxathiino[2,3 c]pyridin 7 yl)methyl]amino]tetrahydro 2h pyran 2 yl] 2 (6 methoxy 1,5 naphthyridin 4 yl)ethan 1 ol; 1 [5 [[(6,7 dihydro[1,4]dioxino[2,3 c]pyridazin 3 yl)methyl]amino]tetrahydro 2h pyran 2 yl] 2 (6 methoxy 1,5 naphthyridin 4 yl)ethan 1 ol; 1 [5 [[(6,7 dihydro[1,4]oxathiino[2,3 c]pyridazin 3 yl)methyl]amino]tetrahydro 2h pyran 2 yl] 2 (3 fluoro 6 methoxy 1,5 naphthyridin 4 yl)ethan 1 ol; 1 [5 [[(6,7 dihydro[1,4]oxathiino[2,3 c]pyridazin 3 yl)methyl]amino]tetrahydro 2h pyran 2 yl] 2 (6 methoxy 1,5 naphthyridin 4 yl)ethan 1 ol; 6 [[[6 [1 hydroxy 2 (6 methoxy 1,5 naphthyridin 4 yl)ethyl]tetrahydro 2h pyran 3 yl]amino]methyl] 2h pyrido[ 3,2 b][1,4]oxazin 3(4h)one; 6 [[[6 [1 hydroxy 2 (6 methoxy 1,5 naphthyridin 4 yl)ethyl]tetrahydro 2h pyran 3 yl]amino]methyl] 2h pyrido[3,2 b][1,4]thiazin 3(4h)one; antibiotic agent; ciprofloxacin; DNA topoisomerase (ATP hydrolysing); DNA topoisomerase inhibitor; gyrase inhibitor; linezolid; potassium channel HERG; tert butyl [6 [(6 methoxy 1,5 naphthyridin 4 yl)ethynyl]tetrahydro 2h pyran 3 yl]carbamate; tert butyl [6 [1 hydroxy 2 (6 methoxy 1,5 naphthyridin 4 yl)ethyl]tetrahydro 2h pyran 3 yl]carbamate; tert butyl [6 [2 (3 fluoro 6 methoxy 1,5 naphthyridin 4 yl) 1 hydroxyethyl]tetrahydro 2h pyran 3 yl]carbamate; tert butyl [6 [2 (6 fluoro 3 methoxyquinoxalin 5 yl) 1 hydroxyethyl]tetrahydro 2h pyran 3 yl]carbamate; tert butyl [6 [2 (7 fluoro 2 methoxyquinolin 8 yl) 1 hydroxyethyl]tetrahydro 2h pyran 3 yl]carbamate; tert butyl [6 [5 (3 fluoro 6 methoxy 1,5 naphthyridin 4 yl) 2 oxo 1,3 dioxolan 4 yl]tetrahydro 2h pyran 3 yl]carbamate; tert butyl [6 [5 (6 fluoro 3 methoxyquinoxalin 5 yl) 2 oxo 1,3 dioxolan 4 yl]tetrahydro 2h pyran 3 yl] carbamate; tert butyl [6 [5 (6 methoxy 1,5 naphthyridin 4 yl) 2 oxo 1,3 dioxolan 4 yl]tetrahydro 2h pyran 3 yl]carbamate; tert butyl [6 [5 (7 fluoro 2 methoxyquinolin 8 yl) 2 oxo 1,3 dioxolan 4 yl]tetrahydro 2h pyran 3 yl]carbamate; tetrahydropyran derivative; unclassified drug; unindexed drug; [6 (6 methoxy[1,5]naphthyridin 4 ylethynyl)tetrahydro pyran 3 yl]carbamic acid benzyl ester; [6 [1 hydroxy 2 (6 methoxy[1,5]naphthyridin 4 yl)ethyl]tetrahydro pyran 3 yl]carbamic acid benzyl ester; [6 [2 (6 methoxy[1,5]naphthyridin 4 yl)acetyl]tetrahydro pyran 3 yl]carbamic acid benzyl ester; antiinfective agent; gyrase inhibitor; pyran derivative; Acinetobacter baumannii; animal experiment; animal model; antibacterial activity; antibiotic resistance; area under the curve; Article; cardiovascular function; controlled study; drug bioavailability; drug clearance; drug half life; drug potency; drug safety; drug synthesis; Enterococcus faecalis; Enterococcus faecium; enzyme activity; enzyme inhibition; Escherichia coli; experimental dog; female; Gram positive bacterium; guinea pig; Haemophilus influenzae; heart rate; IC50; in vitro study; in vivo study; male; mean arterial pressure; minimum bactericidal concentration; minimum inhibitory concentration; Moraxella catarrhalis; mouse; nonhuman; QT interval; rat; Staphylococcus aureus; Staphylococcus epidermidis; Streptococcus agalactiae; Streptococcus pneumoniae; Streptococcus pyogenes; structure activity relation; animal; drug effects; Gram positive bacterium; hemodynamics; human; microbial sensitivity test; synthesis; Wistar rat; Animals; Anti-Bacterial Agents; Gram-Positive Bacteria; Guinea Pigs; Hemodynamics; Humans; Male; Mice; Microbial Sensitivity Tests; Pyrans; Rats; Rats, Wistar; Structure-Activity Relationship; Topoisomerase II Inhibitors