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

作者：Choung U. Kim, Willard Lew, Matthew A. Williams, Hongtao Liu, Lijun Zhang, Swami Swaminathan, Norbert Bischofberger, Ming S. Chen, Dirk B. Mendel, Chun Y. Tai, William Graeme Laver, Raymond C. Stevens · 发表于：Journal of the American Chemical Society · 年份：1997 · DOI：10.1021/ja963036t · 被引用次数：1101 · 研究领域：Influenza Virus Research Studies、Carbohydrate Chemistry and Synthesis、Glycosylation and Glycoproteins Research

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.