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Antimicrobial Agents and Chemotherapy, February 2005, p. 656-662, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.656-662.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Comparison of the Antiviral Activities of Alkoxyalkyl and Alkyl Esters of Cidofovir against Human and Murine Cytomegalovirus Replication In Vitro

William B. Wan,1 James R. Beadle,1 Caroll Hartline,2 Earl R. Kern,2 Stephanie L. Ciesla,1 Nadejda Valiaeva,1 and Karl Y. Hostetler1*

Veterans Administration San Diego Healthcare System and the Department of Medicine, University of California, San Diego, La Jolla, California,1 Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama2

Received 11 June 2004/ Returned for modification 26 August 2004/ Accepted 6 October 2004

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.

* Corresponding author. Mailing address: Department of Medicine, University of California, San Diego, Mail Code 0676, 9500 Gilman Dr., La Jolla, CA 92093-0676. Phone: (858) 552-8585, ext. 2616. Fax: (858) 534-6133. E-mail: khostetl{at}ucsd.edu.

Antimicrobial Agents and Chemotherapy, February 2005, p. 656-662, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.656-662.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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