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
Document Type
Article
Publication Date
12-1-1997
Journal / Book Title
Journal of the American Chemical Society
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 μM) vs 9 (IC50 > 200 μM). 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.
DOI
10.1021/ja963036t
Montclair State University Digital Commons Citation
Rotella, David, "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" (1997). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 554.
https://digitalcommons.montclair.edu/chem-biochem-facpubs/554
