Journal of Medicinal Chemistry p. 5297 - 5310 (2016)
Update date:2022-08-30
Topics:
Wang, Peng-Cheng
Fang, Jim-Min
Tsai, Keng-Chang
Wang, Shi-Yun
Huang, Wen-I
Tseng, Yin-Chen
Cheng, Yih-Shyun E.
Cheng, Ting-Jen Rachel
Wong, Chi-Huey
Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
View MoreContact:+1-416-493-6870
Address:Toronto, Canada
Contact:+86-22-83718541
Address:32th Floor, Rongqiao Center Intersection of Changjiang Road and Nankai Six Road Nankai District Tianjin 300102, China
Contact:+86-633-8332928
Address:No.1,Huanghai Yilu.Rizhao,Shandong
Shanghai agrotree chemical co.,ltd.
Contact:+86-21-50117563
Address:Room 8A,liangfeng building,No.8 dongfang RD.pudong,shanghai,China
Qingdao Kylin Trading Co., Ltd.
Contact:0086-532-68979884/58972912/68972263/65/88171519
Address:Room 2308,A building International Trade Center No.230 Changjiang Middle Road of Qingdao Economic Development Zone,Shandong,China.
Doi:10.1080/00397910902985556
(2010)Doi:10.1039/a704255h
(1998)Doi:10.1002/hlca.193802101123
()Doi:10.1055/s-0037-1610299
(2018)Doi:10.1023/A:1022429322461
(2003)Doi:10.1007/BF02533820
(1974)