Abstract
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
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Acetamides / chemical synthesis*
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Acetamides / pharmacology
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacology*
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Binding Sites / drug effects
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Carboxylic Acids / chemical synthesis*
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Carboxylic Acids / pharmacology
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Cell Line
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Crystallography, X-Ray
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Cyclohexanes / chemical synthesis*
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Cyclohexanes / pharmacology
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Cyclohexenes
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Disease Models, Animal
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Hydrophobic and Hydrophilic Interactions
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Influenza A virus / drug effects*
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Influenza A virus / enzymology
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Influenza A virus / growth & development
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Neuraminidase / antagonists & inhibitors*
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Quinic Acid / chemistry
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Sialic Acids / chemical synthesis*
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Sialic Acids / pharmacology
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Structure-Activity Relationship
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Viral Plaque Assay
Substances
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(3R,4R,5S,)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid
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Acetamides
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Antiviral Agents
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Carboxylic Acids
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Cyclohexanes
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Cyclohexenes
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Enzyme Inhibitors
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Sialic Acids
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Quinic Acid
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Neuraminidase