Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine

Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine

9-(2-Phosphonylmethoxyethyl)adenine (PMEA; 1) was acylated with chloromethyl pivalate to afford bis(pivaloyloxymethyl) PMEA ( 2). The ester prodrug demonstrated enhanced in vitro potency against HSV-2 greater than 150-fold higher than the parent compound. The antiviral activity of 2 was 50-fold bett...

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Veröffentlicht in:Antiviral research 1992-09, Vol.19 (3), p.267-273
Hauptverfasser: Starrett, John E., Tortolani, David R., Hitchcock, Michael J.M., Martin, John C., Mansuri, Muzammil M.
Format: Artikel
Sprache:eng
Schlagworte:
Adenine - analogs & derivatives
Adenine - chemical synthesis
Adenine - pharmacology
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacology
Cell Line
Cytomegalovirus - drug effects
Drug Evaluation, Preclinical
HCMV
HIV
HIV - drug effects
HSV
Humans
Organophosphonates
Phosphonate transport
PMEA
Prodrug
Prodrugs - chemical synthesis
Prodrugs - pharmacology
Simplexvirus - drug effects
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Zusammenfassung:9-(2-Phosphonylmethoxyethyl)adenine (PMEA; 1) was acylated with chloromethyl pivalate to afford bis(pivaloyloxymethyl) PMEA ( 2). The ester prodrug demonstrated enhanced in vitro potency against HSV-2 greater than 150-fold higher than the parent compound. The antiviral activity of 2 was 50-fold better than PMEA against HSV-1, and equipotent against HIV and HCMV. The toxicity of 2 was studied in both resting and growing cells.
ISSN:0166-3542
1872-9096
DOI:10.1016/0166-3542(92)90084-I