title: Synthesis of ester prodrugs of 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) as anti-poxvirus agents.
abstract: 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and its cyclic form were selected for further evaluation as potential drug candidates against poxvirus infections. To increase bioavailability of these compounds, synthesis of their structurally diverse ester prodrugs was carried out: alkoxyalkyl (hexadecyloxypropyl, octadecyloxyethyl, hexadecyloxyethyl), pivaloyloxymethyl (POM), 2,2,2-trifluoroethyl, butylsalicylyl, and prodrugs based on peptidomimetics. Most HPMPDAP prodrugs were synthesized in the form of monoesters as well as the corresponding cyclic phosphonate esters. The activity was evaluated not only against vaccinia virus but also against different herpes viruses. The most potent and active prodrugs against vaccinia virus were the alkoxyalkyl ester derivatives of HPMPDAP, with 50% effective concentrations 400-600-fold lower than those of the parent compound. Prodrugs based on peptidomimetics, the 2,2,2-trifluoroethyl, the POM, and the butylsalicylyl derivatives, were able to inhibit vaccinia virus replication at 50% effective concentrations that were equivalent or ∼10-fold lower than those observed for the parent compounds.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic. marcela@uochb.cas.cz
authors.forename: Marcela
authors.initials: M
authors.lastname: Krecmerová
authors.forename: Antoín
authors.initials: A
authors.lastname: Holý
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Karel
authors.initials: K
authors.lastname: Pomeisl
authors.forename: Tomás
authors.initials: T
authors.lastname: Tichý
authors.forename: Petra
authors.initials: P
authors.lastname: Brehová
authors.forename: Milena
authors.initials: M
authors.lastname: Masojídková
authors.forename: Martin
authors.initials: M
authors.lastname: Dracínský
authors.forename: Radek
authors.initials: R
authors.lastname: Pohl
authors.forename: Genevieve
authors.initials: G
authors.lastname: Laflamme
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Hon
authors.initials: H
authors.lastname: Hui
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004952:Esters; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011212:Poxviridae / Q000187:drug effects*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012328:RNA Viruses / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014773:Virology / Q000379:methods
chemical_list: D000998:Antiviral Agents; D004952:Esters; D009943:Organophosphorus Compounds; D011355:Prodrugs; C091173:9-(3-hydroxy-2-phosphonomethoxypropyl)-2,6-diaminopurine; D000225:Adenine