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Antimicrobial Agents and Chemotherapy, June 2000, p. 1506-1511, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vitro Activities of Methylenecyclopropane Analogues of Nucleosides and Their Phosphoralaninate Prodrugs against Cytomegalovirus and Other Herpesvirus Infections

Rachel J. Rybak,1 Caroll B. Hartline,1 Yao-Ling Qiu,2 Jiri Zemlicka,2 Emma Harden,1 Gwen Marshall,1 Jean-Pierre Sommadossi,1 and Earl R. Kern1,*

University of Alabama School of Medicine, Birmingham, Alabama,1 and Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan2

Received 16 September 1999/Returned for modification 18 January 2000/Accepted 22 February 2000

Human cytomegalovirus (HCMV) infection does not generally cause problems in the immunocompetent adult but can result in severe clinical disease in the fetus, neonate, and immunocompromised host. Ganciclovir (GCV), the agent currently used to treat most HCMV infections, has resulted in much therapeutic success; however, efficacy remains suboptimal. Therefore, there is still a need to develop new compounds for use against HCMV infections. In the present study, several Z- and E-series methylenecyclopropane analogues and their phosphoroalaninate prodrugs were tested initially for activity against HCMV, strain AD169, and murine cytomegalovirus (MCMV) in vitro. Many were found to exhibit efficacy comparable to that of GCV against HCMV in plaque assays and were active against MCMV as well. The compounds were also tested for efficacy against herpes simplex virus types 1 and 2, varicella-zoster virus, and Epstein-Barr virus, and some had levels of activity that were comparable to that of acyclovir. In addition, the compounds synguanol (QYL-438) and 2-amino-6-cyclopropylamino analogue (QYL-769) were chosen for further evaluation and were found to be effective against additional laboratory and clinical isolates of HCMV and GCV-resistant isolates. QYL-438 and QYL-769 were found to be nontoxic in human and mouse fibroblasts and were considerably less toxic than GCV in granulocyte macrophage CFUs and erythroid burst-forming units. These results provide evidence for the high activity of some of these methylenecyclopropane analogues against various herpesviruses, particularly HCMV, in tissue culture and suggest that further evaluation is warranted to determine their potential for use in future clinical studies.

* Corresponding author. Mailing address: UAB-Dept. of Pediatrics, BBRB 309, 1530 3rd Ave. S., Birmingham, AL 35294-2170. Phone: (205) 934-1990. Fax: (205) 975-1992. E-mail: Kern{at}uab.edu.

Antimicrobial Agents and Chemotherapy, June 2000, p. 1506-1511, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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