Comparison of the antiviral activities of alkoxyalkyl and alkyl esters of cidofovir against human and murine cytomegalovirus replication in vitro.
Alkoxyalkyl esters of cidofovir (CDV) have substantially greater antiviral activity and selectivity than unmodified CDV against herpesviruses and orthopoxviruses in vitro. Enhancement of antiviral activity was also noted when cyclic CDV was esterified with alkoxyalkanols. In vitro antiviral activity of the most active analogs against human cytomegalovirus (HCMV) and orthopoxviruses was increased relative to CDV up to 1,000- or 200-fold, respectively. Alkyl chain length and linker structure are important potential modifiers of antiviral activity and selectivity. In this study, we synthesized a series of alkoxyalkyl esters of CDV or cyclic CDV with alkyl chains from 8 to 24 atoms and having linker moieties of glycerol, propanediol, and ethanediol. We also synthesized alkyl esters of CDV which lack the linker to determine if the alkoxyalkyl linker moiety is required for activity. The new compounds were evaluated in vitro against HCMV and murine CMV (MCMV). CDV or cyclic CDV analogs both with and without linker moieties were highly active against HCMV and MCMV, and their activities were strongly dependent on chain length. The most active compounds had 20 atoms esterified to the phosphonate of CDV. Both alkoxypropyl and alkyl esters of CDV provided enhanced antiviral activities against CMV in vitro. Thus, the oxypropyl linker moiety is not required for enhanced activity. CDV analogs having alkyl ethers linked to glycerol or ethanediol linker groups also demonstrated increased activity against CMV.
Wan
William B
WB
Veterans Administration San Diego Healthcare System, Department of Medicine, University of California, San Diego, Mail Code 0676, 9500 Gilman Dr., La Jolla, CA 92093-0676, USA.
Beadle
James R
JR
Hartline
Caroll
C
Kern
Earl R
ER
Ciesla
Stephanie L
SL
Valiaeva
Nadejda
N
Hostetler
Karl Y
KY
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D000077404:Cidofovir; D004396:Coloring Agents; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D005026:Ethylene Glycols / Q000737:chemistry; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009499:Neutral Red; D063065:Organophosphonates / Q000494:pharmacology*; D011409:Propylene Glycols / Q000737:chemistry; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D004396:Coloring Agents; D004952:Esters; D005026:Ethylene Glycols; D007202:Indicators and Reagents; D063065:Organophosphonates; D011409:Propylene Glycols; D009499:Neutral Red; D003596:Cytosine; D000077404:Cidofovir; D005990:Glycerol