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J Med Chem. 2013 Feb 14;56(3):671-84. doi: 10.1021/jm3009713. Epub 2013 Jan 30.

Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors.

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  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Shanghai 201203, China.

Abstract

In order to exploit the 430-cavity in the active sites of 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 9f exerts the most potency, with IC(50) value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC(50) = 0.0014 μM, H5N1 IC(50) = 0.012 μM, H1N1 IC(50) = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t(1/2)) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.

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