title: New prodrugs of Adefovir and Cidofovir.
abstract: 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.
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 166 10, Czech Republic. tichy78@uochb.cas.cz
authors.forename: Tomáš
authors.initials: T
authors.lastname: Tichý
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Martin
authors.initials: M
authors.lastname: Dračínský
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Marcela
authors.initials: M
authors.lastname: Krečmerová
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry; D006678:HIV / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D063065:Organophosphonates / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018139:Simplexvirus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; C053001:adefovir; D003596:Cytosine; D000225:Adenine; D000077404:Cidofovir