New prodrugs of Adefovir and Cidofovir

详细信息    查看全文

• 作者：Tomá ; š ; Tichý ; ^a ; ^{tichy78@uochb.cas.cz"" rel=""nofollow} ; ^{tomastichy78@email.cz"" rel=""nofollow} ; Graciela Andrei^b ; Martin Dra&#x10d ; í ; nský ; ^a ; Antoní ; n Holý ; ^a ; Jan Balzarini^b ; Robert Snoeck^b ; Marcela Kre&#x10d ; merová ; ^a
• 关键词：Adefovir ; Cidofovir ; Antivirals ; Prodrugs ; Acyclic nucleoside phosphonate ; Phosphonate ester ; In vitro evaluation
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：1 June 2011
• 年：2011
• 卷：19
• 期：11
• 页码：3527-3539
• 全文大小：700 K

文摘

New Adefovir (PMEA) prodrugs with a pro-moiety consisting of decyl or decyloxyethyl chain bearing hydroxyl function(s), hexaethyleneglycol or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl unit were prepared starting from the tetrabutylammonium salt of the phosphonate drug and an appropriate alkyl bromide or tosylate. Analogously, two esters of Cidofovir [(S)-HPMPC] bearing a hexaethyleneglycol moiety were prepared. The activity of the prodrugs was evaluated in vitro against different virus families. A loss in the antiviral activities of the hydroxylated decyl or decyloxyethyl esters and hexaethyleneglycol esters of PMEA against human immunodeficiency virus (HIV) and herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (CMV)] occurred in comparison with the parent compound. On the other hand, the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of PMEA showed significant activities against HIV and herpesviruses. (S)-HPMPC prodrugs exhibited anti-cytomegalovirus activities in the same range as the parent drug, whereas the anti-HSV and anti-VZV activities were one- to seven-fold lower than that of Cidofovir.