PMID: 16526129Jan 29, 1997Paper

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

Journal of the American Chemical Society
C U KimR C Stevens

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.

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Citations

Nov 9, 2002·Medicinal Research Reviews·Xiaofang WangXin-Shan Ye
May 3, 2002·Reviews in Medical Virology·Ralf WagnerHans-Dieter Klenk
Dec 14, 2004·Applied Microbiology and Biotechnology·Julia MagdenTero Ahola
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Apr 2, 2013·Bioprocess and Biosystems Engineering·Priyanka TripathiR K Saxena
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