Synthesis of ester prodrugs of 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) as anti-poxvirus agents
Language English Country United States Media print
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
1UC1 AI062540-01
NIAID NIH HHS - United States
PubMed
20809641
DOI
10.1021/jm901828c
Knihovny.cz E-resources
- MeSH
- Adenine analogs & derivatives chemical synthesis chemistry pharmacology MeSH
- Antiviral Agents chemical synthesis chemistry pharmacology MeSH
- Esters MeSH
- Herpesviridae drug effects MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Organophosphorus Compounds chemical synthesis chemistry pharmacology MeSH
- Poxviridae drug effects MeSH
- Prodrugs chemical synthesis chemistry pharmacology MeSH
- Cell Proliferation drug effects MeSH
- RNA Viruses drug effects MeSH
- Stereoisomerism MeSH
- Virology methods MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- 9-(3-hydroxy-2-phosphonomethoxypropyl)-2,6-diaminopurine MeSH Browser
- Adenine MeSH
- Antiviral Agents MeSH
- Esters MeSH
- Organophosphorus Compounds MeSH
- Prodrugs MeSH
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.
References provided by Crossref.org
Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects
New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity
