STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF NOVEL CARBOCYCLIC INFLUENZA NEURAMINIDASE INHIBITORS

A series of influenza neuraminidase inhibitors with the cyclohexene sc affold containing lipophilic side chains have been synthesized anti ev aluated for influenza A and B neuraminidase inhibitory activity. The s ize and geometry of side chains have been modified systematically in o rder to investigate structure-activity relationships of this class of compounds. The X-ray crystal structures of several analogues complexed with neuraminidase revealed that the lipophilic side chains bound to the hydrophobic pocket consisted of Glu276, Ala246, Arg224, and Ile222 of the enzyme active site. The structure-activity relationship studie s of this series have also demonstrated remarkably different inhibitor y potency between influenza A and B neuraminidase. This indicated that the lipophilic side chains had quite different hydrophobic interactio ns with influenza A and B neuraminidase despite their complete homolog y in the active site. Influenza B neuraminidase appeared to be much mo re sensitive toward the increased steric bulkiness of inhibitors compa red to influenza A neuraminidase. From the extensive structure-activit y relationship investigation reported in this article, GS 4071 emerged as one of the most potent influenza neuraminidase inhibitors against both influenza A and B strains.