Efficacy of methylenecyclopropane analogs of nucleosides against herpesvirus replication in vitro.
We have reported previously that purine methylenecyclopropane analogs are potent agents against cytomegaloviruses. In an attempt to extend the activity of these compounds, the 2-amino-6-cyclopropylaminopurine analog, QYL-1064, was selected for further study by modifying the purine 6 substituent. A total of 22 analogs were tested against herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), murine cytomegalovirus (MCMV), Epstein-Barr virus (EBV), human herpesvirus type 6 (HHV-6) and human herpesvirus type 8 (HHV-8). Ten of the analogs had activity against at least one of the viruses tested. One compound had moderate activity against HSV-1 and six had activity against VZV. All but one compound was active against HCMV with a mean EC50 of 2.1 +/- 0.6 microM, compared with a mean EC50 of 3.9 +/- 0.8 microM for ganciclovir. Of special interest was the fact that eight of the ten compounds were active against both HHV-6A and HHV-6B with mean EC50 values of 6.0 +/- 5.2 mciroM and <2.4 +/- 1.5 microM, respectively. Only two compounds had activity against EBV, whereas all but one compound was active against HHV-8 with a mean EC50 of 3.1 +/- 1.7 microM. These results indicate that members of this series of methylenecyclopropane analogs are highly active against HCMV, HHV-6, and HHV-8 but are less active against HSV, VZV, and EBV.
Kushner
Nicole L
NL
The University of Alabama School of Medicine, Birmingham, Alabama, USA.
Williams
Stephanie L
SL
Hartline
Caroll B
CB
Harden
Emma A
EA
Bidanset
Deborah J
DJ
Chen
Xinchao
X
Zemlicka
Jiri
J
Kern
Earl R
ER
D000241:Adenosine / Q000031:analogs & derivatives*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000737:chemistry; D003587:Cytomegalovirus / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D006151:Guanosine / Q000031:analogs & derivatives*; D006564:Herpesviridae / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects; D015654:Herpesvirus 6, Human / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D018146:Muromegalovirus / Q000187:drug effects
D000998:Antiviral Agents; D003521:Cyclopropanes; D006151:Guanosine; D000241:Adenosine