title: Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors.
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.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Shanghai 201203, China.
authors: Enguang
authors: E
authors: Feng
authors: Woo-Jin
authors: WJ
authors: Shin
authors: Xuelian
authors: X
authors: Zhu
authors: Jian
authors: J
authors: Li
authors: Deju
authors: D
authors: Ye
authors: Jiang
authors: J
authors: Wang
authors: Mingyue
authors: M
authors: Zheng
authors: Jian-Ping
authors: JP
authors: Zuo
authors: Kyoung Tai
authors: KT
authors: No
authors: Xian
authors: X
authors: Liu
authors: Weiliang
authors: W
authors: Zhu
authors: Wei
authors: W
authors: Tang
authors: Baik-Lin
authors: BL
authors: Seong
authors: Hualiang
authors: H
authors: Jiang
authors: Hong
authors: H
authors: Liu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053243:Zanamivir / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009439:Neuraminidase; D053243:Zanamivir