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.
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.
Kim
C U
CU
Gilead Sciences Inc., Foster City, California 94404, USA.
Lew
W
W
Williams
M A
MA
Liu
H
H
Zhang
L
L
Swaminathan
S
S
Bischofberger
N
N
Chen
M S
MS
Mendel
D B
DB
Tai
C Y
CY
Laver
W G
WG
Stevens
R C
RC
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D053138:Cyclohexenes; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D057927:Hydrophobic and Hydrophilic Interactions; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D011801:Quinic Acid / Q000737:chemistry; D012794:Sialic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
C508640:(3R,4R,5S,)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid; D000081:Acetamides; D000998:Antiviral Agents; D002264:Carboxylic Acids; D003510:Cyclohexanes; D053138:Cyclohexenes; D004791:Enzyme Inhibitors; D012794:Sialic Acids; D011801:Quinic Acid; D009439:Neuraminidase