Structure-Based Designand Synthesis of C-1-and C-4-Modified Analogs of Zanamivir as Neuraminidase Inhibitors.

In order to exploit the 430-cavity in the active sitesof neuraminidases,22 zanamivir analogs with C-1 and C-4 modification were synthesized,and their inhibitory activities against both group-1 (H5N1, H1N1)and group-2 neuraminidases (H3N2) were determined. Compound 9fexerts the most potency, with IC50value of0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, whichis similar to that of zanamivir (H3N2 IC50= 0.0014 μM,H5N1 IC50= 0.012 μM, H1N1 IC50= 0.001μM). Pharmacokinetic studies of compound 9finrats showed a much longer plasma half-life (t1/2) than that of zanamivir following administration (po dose).Molecular modeling provided information about the binding model betweenthe new inhibitors and neuraminidase, with the elongated groups atthe C-1-position being projected toward the 430-loop region. Thisstudy may represent a novel starting point for the future developmentof improved antiflu agents. [ABSTRACT FROM AUTHOR]