TY - JOUR
T1 - Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors
AU - Feng, Enguang
AU - Shin, Woo Jin
AU - Zhu, Xuelian
AU - Li, Jian
AU - Ye, Deju
AU - Wang, Jiang
AU - Zheng, Mingyue
AU - Zuo, Jian Ping
AU - No, Kyoung Tai
AU - Liu, Xian
AU - Zhu, Weiliang
AU - Tang, Wei
AU - Seong, Baik Lin
AU - Jiang, Hualiang
AU - Liu, Hong
PY - 2013/2/14
Y1 - 2013/2/14
N2 - 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 IC50 value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 μM, H5N1 IC50 = 0.012 μM, H1N1 IC50 = 0.001 μM). Pharmacokinetic studies of compound 9f in rats 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 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.
AB - 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 IC50 value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 μM, H5N1 IC50 = 0.012 μM, H1N1 IC50 = 0.001 μM). Pharmacokinetic studies of compound 9f in rats 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 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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U2 - 10.1021/jm3009713
DO - 10.1021/jm3009713
M3 - Article
C2 - 23330908
AN - SCOPUS:84873916093
SN - 0022-2623
VL - 56
SP - 671
EP - 684
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -