title: 2,3,4,5-Tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines as inhibitors of the bacterial enoyl ACP reductase, FabI.
abstract: 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.
authors.affiliation: Affinium Pharmaceuticals Inc., 1243 Islington Avenue, Suite 600, Toronto, ON, Canada M8X 1Y9. jramnauth@nrxn.com
authors.forename: Jailall
authors.initials: J
authors.lastname: Ramnauth
authors.forename: Mathew D
authors.initials: MD
authors.lastname: Surman
authors.forename: Peter B
authors.initials: PB
authors.lastname: Sampson
authors.forename: Bryan
authors.initials: B
authors.lastname: Forrest
authors.forename: Jeff
authors.initials: J
authors.lastname: Wilson
authors.forename: Emily
authors.initials: E
authors.lastname: Freeman
authors.forename: David D
authors.initials: DD
authors.lastname: Manning
authors.forename: Fernando
authors.initials: F
authors.lastname: Martin
authors.forename: Andras
authors.initials: A
authors.lastname: Toro
authors.forename: Megan
authors.initials: M
authors.lastname: Domagala
authors.forename: Donald E
authors.initials: DE
authors.lastname: Awrey
authors.forename: Elias
authors.initials: E
authors.lastname: Bardouniotis
authors.forename: Nachum
authors.initials: N
authors.lastname: Kaplan
authors.forename: Judd
authors.initials: J
authors.lastname: Berman
authors.forename: Henry W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D001381:Azepines; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)