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Antimicrobial Agents and Chemotherapy, April 2002, p. 991-995, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.991-995.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Enhanced Inhibition of Orthopoxvirus Replication In Vitro by Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir

Earl R. Kern,1* Caroll Hartline,1 Emma Harden,1 Kathy Keith,1 Natalie Rodriguez,2 James R. Beadle,2 and Karl Y. Hostetler2

University of Alabama School of Medicine, Birmingham, Alabama,1 VA Medical Center and University of California, San Diego, La Jolla, California2

Received 5 October 2001/ Returned for modification 10 December 2001/ Accepted 27 December 2001

The nucleotide phosphonates cidofovir (CDV) and cyclic cidofovir (cCDV) are potent antiviral compounds when administered parenterally but are not well absorbed orally. These compounds have been reported to have activity against orthopoxvirus replication in vitro and in animal models when administered parenterally or by aerosol. To obtain better oral activity, we synthesized a novel series of analogs of CDV and cCDV by esterification with two long-chain alkoxyalkanols, 3-hexadecyloxy-1-propanol (HDP-CDV; HDP-cCDV) or 3-octadecyloxy-1-ethanol (ODE-CDV; ODE-cCDV). Their activities were evaluated and compared with those of CDV and cCDV in human foreskin fibroblast (HFF) cells infected with vaccinia virus (VV) or cowpox virus (CV) using a plaque reduction assay. The 50% effective concentrations (EC50s) against VV in HFF cells for CDV and cCDV were 46.2 and 50.6 µM compared with 0.84 and 3.8 µM for HDP-CDV and HDP-cCDV, respectively. The EC50s for ODE-CDV and ODE-cCDV were 0.20 and 1.1 µM, respectively. The HDP analogs were 57- and 13-fold more active than the parent nucleotides, whereas the ODE analogs were 231- and 46-fold more active than the unmodified CDV and cCDV. Similar results were obtained using CV. Cytotoxicity studies indicated that although the analogs were more toxic than the parent nucleotides, the selective index was increased by 4- to 13-fold. These results indicate that the alkoxyalkyl esters of CDV and cCDV have enhanced activity in vitro and need to be evaluated for their oral absorption and efficacy in animal models.

* Corresponding author. Mailing address: Department of Pediatrics, The University of Alabama at Birmingham, BBRB 309, 845 19th St. South, Birmingham, AL 35294-2170. Phone: (205) 934-1990. Fax: (205) 975-1992. E-mail: Kern{at}uab.edu.

Antimicrobial Agents and Chemotherapy, April 2002, p. 991-995, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.991-995.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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