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Feng, Enguang,Shin, Woo-Jin,Zhu, Xuelian,Li, Jian,Ye, Deju,Wang, Jiang,Zheng, Mingyue,Zuo, Jian-Ping,No, Kyoung Tai,Liu, Xian,Zhu, Weiliang,Tang, Wei,Seong, Baik-Lin,Jiang, Hualiang,Liu, Hong American Chemical Society 2013 Journal of medicinal chemistry Vol.56 No.3
<P>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 <B>9f</B> exerts the most potency, with IC<SUB>50</SUB> value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC<SUB>50</SUB> = 0.0014 μM, H5N1 IC<SUB>50</SUB> = 0.012 μM, H1N1 IC<SUB>50</SUB> = 0.001 μM). Pharmacokinetic studies of compound <B>9f</B> in rats showed a much longer plasma half-life (<I>t</I><SUB>1/2</SUB>) 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.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2013/jmcmar.2013.56.issue-3/jm3009713/production/images/medium/jm-2012-009713_0009.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm3009713'>ACS Electronic Supporting Info</A></P>