A new class of acyclic phosphonate nucleotide analogues: phosphonate isosteres of acyclovir and ganciclovir monophosphates as antiviral agents.
Novel phosphonate isosteres of acyclovir (ACV) and ganciclovir (DHPG) monophosphates were found to be potent and selective antiherpesvirus agents. In the series of phosphonate analogues of ACV monophosphate, only the guanine analogue 20 exhibited activity against herpesviruses, similar to the structure-activity relationship observed for base modification of ACV analogues. The phosphonate isostere of ACV monophosphate (20) was more effective than ACV in the HSV-1 infected mouse model. The 3'-carba analogues of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]purines/pyrimidines (adenine, HPMPA; guanine, HPMPG; cytosine, HPMPC) are devoid of antiherpesvirus activity. This result confirms that the beta-oxygen atom of the phosphonomethyl ether functionality in HPMP-purines/pyrimidines plays a critical role for activity against herpesviruses.
Kim
C U
CU
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
Misco
P F
PF
Luh
B Y
BY
Hitchcock
M J
MJ
Ghazzouli
I
I
Martin
J C
JC
D000212:Acyclovir / Q000031:analogs & derivatives*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D046508:Culture Techniques; D003587:Cytomegalovirus / Q000187:drug effects; D015774:Ganciclovir / Q000031:analogs & derivatives*; D014645:Herpesvirus 3, Human / Q000187:drug effects; D051379:Mice; D009711:Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D009711:Nucleotides; D015774:Ganciclovir; D000212:Acyclovir