2,3,4,5-Tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines as inhibitors of the bacterial enoyl ACP reductase, FabI.
In the search for new antibacterial agents, the enzyme FabI has been identified as an attractive target. Employing a structure guided approach, the previously reported ene-amide series of FabI inhibitors were expanded to include 2,3,4,5-tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines. These novel series incorporate additional H-bonding functions and can be more water soluble than their naphthyridinone progenitors; diazepine 16c is shown to be efficacious in a mouse infection model.
Ramnauth
Jailall
J
Affinium Pharmaceuticals Inc., 1243 Islington Avenue, Suite 600, Toronto, ON, Canada M8X 1Y9. jramnauth@nrxn.com
Surman
Mathew D
MD
Sampson
Peter B
PB
Forrest
Bryan
B
Wilson
Jeff
J
Freeman
Emily
E
Manning
David D
DD
Martin
Fernando
F
Toro
Andras
A
Domagala
Megan
M
Awrey
Donald E
DE
Bardouniotis
Elias
E
Kaplan
Nachum
N
Berman
Judd
J
Pauls
Henry W
HW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001381:Azepines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology
D000900:Anti-Bacterial Agents; D001381:Azepines; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)