Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity

J Am Chem Soc. 1997 Jan 29;119(4):681-90. doi: 10.1021/ja963036t.


The design, synthesis, and in vitro evaluation of the novel carbocycles as transition-state-based inhibitors of influenza neuraminidase (NA) are described. The double bond position in the carbocyclic analogues plays an important role in NA inhibition as demonstrated by the antiviral activity of 8 (IC50 = 6.3 microM) vs 9 (IC50 > 200 microM). Structure-activity studies of a series of carbocyclic analogues 6a-i identified the 3-pentyloxy moiety as an apparent optimal group at the C3 position with an IC50 value of 1 nM for NA inhibition. The X-ray crystallographic structure of 6h bound to NA revealed the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid. The high antiviral potency observed for 6h appears to be attributed to a highly favorable hydrophobic interaction in this pocket. The practical synthesis of 6 starting from (-)-quinic acid is also described.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / pharmacology
  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology*
  • Binding Sites / drug effects
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Cyclohexanes / chemical synthesis*
  • Cyclohexanes / pharmacology
  • Cyclohexenes
  • Disease Models, Animal
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Hydrophobic and Hydrophilic Interactions
  • Influenza A virus / drug effects*
  • Influenza A virus / enzymology
  • Influenza A virus / growth & development
  • Neuraminidase / antagonists & inhibitors*
  • Quinic Acid / chemistry
  • Sialic Acids / chemical synthesis*
  • Sialic Acids / pharmacology
  • Structure-Activity Relationship
  • Viral Plaque Assay


  • (3R,4R,5S,)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid
  • Acetamides
  • Antiviral Agents
  • Carboxylic Acids
  • Cyclohexanes
  • Cyclohexenes
  • Enzyme Inhibitors
  • Sialic Acids
  • Quinic Acid
  • Neuraminidase