Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI)

J Med Chem. 2002 Jul 18;45(15):3246-56. doi: 10.1021/jm020050+.


Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acrylamides / chemical synthesis*
  • Acrylamides / chemistry
  • Acrylamides / pharmacology
  • Aminopyridines / chemical synthesis*
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology
  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Crystallography, X-Ray
  • Databases, Factual
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fatty Acid Synthases / antagonists & inhibitors*
  • Fatty Acid Synthases / chemistry
  • Haemophilus influenzae / drug effects
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry
  • Rats
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects
  • Structure-Activity Relationship


  • 3-(6-aminopyridin-3-yl)-N-methyl-N-((1-methyl-1H-indol-2-yl)methyl)acrylamide
  • Acrylamides
  • Aminopyridines
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Oxidoreductases
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
  • Fatty Acid Synthases