Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.
Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.
Seefeld
Mark A
MA
GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, Pennsylvania 19426, USA. Mark_A_Seefeld@gsk.com
Miller
William H
WH
Newlander
Kenneth A
KA
Burgess
Walter J
WJ
DeWolf
Walter E
WE
Elkins
Patricia A
PA
Head
Martha S
MS
Jakas
Dalia R
DR
Janson
Cheryl A
CA
Keller
Paul M
PM
Manley
Peter J
PJ
Moore
Terrance D
TD
Payne
David J
DJ
Pearson
Stewart
S
Polizzi
Brian J
BJ
Qiu
Xiayang
X
Rittenhouse
Stephen F
SF
Uzinskas
Irene N
IN
Wallis
Nicola G
NG
Huffman
William F
WF
D000038:Abscess / Q000188:drug therapy; D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D013293:Enterococcus faecalis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D006193:Haemophilus influenzae / Q000187:drug effects; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000494:pharmacology
D000178:Acrylamides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007211:Indoles; C474145:N-methyl-N-(2-methyl-1H-indol-3ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide; D009287:Naphthyridines; D014260:Triclosan; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D064429:Fatty Acid Synthases