Synthesis of esters of phosphonoformic acid and their antiherpes activity

Aliphatic and aromatic mono-, di-, and triesters of phosphonoformic acid (foscarnet) were synthesized. The triesters were prepared by the Michaelis-Arbuzov reaction and were hydrolyzed to di- and monoesters. The compounds were tested for antiviral activity on isolated herpes simplex virus type 1 (HS...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 26; no. 2; pp. 264 - 270
Main Authors:	Noren, Jan O, Helgstrand, Erik, Johansson, Nils G, Misiorny, Alfons, Stening, Goeran
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 01-02-1983
Subjects:	Antiviral Agents - chemical synthesis Esters Foscarnet herpes simplex virus 1 Indicators and Reagents Nucleic Acid Synthesis Inhibitors Organophosphorus Compounds - chemical synthesis Phosphonoacetic Acid - analogs & derivatives Phosphonoacetic Acid - chemical synthesis Phosphonoacetic Acid - pharmacology Simplexvirus - drug effects Simplexvirus - enzymology Structure-Activity Relationship Viral Plaque Assay
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Summary:	Aliphatic and aromatic mono-, di-, and triesters of phosphonoformic acid (foscarnet) were synthesized. The triesters were prepared by the Michaelis-Arbuzov reaction and were hydrolyzed to di- and monoesters. The compounds were tested for antiviral activity on isolated herpes simplex virus type 1 (HSV-1) DNA polymerase, in a HSV-1 plaque reduction assay, and on a cutaneous HSV-1 infection in guinea pigs. None of the esters inhibited the activity of isolated HSV-1 polymerases. Monoesters with a free carboxylic group and diesters with an aromatic carboxylic ester function were active against the cutaneous herpes infection. Mono- and diesters with an aromatic phosphonic ester group also showed activity in the plaque-reduction assay. However, mono- and diesters with an aromatic phosphonic ester group also showed activity in the plaque-reduction assay. However, mono- and diesters with aliphatic carboxylic ester groups were inactive in all test systems. The results show that all three acidic groups of phosphonoformic acid must be free in order to get antiviral activity at the enzyme level. However, certain esters of this acid may be biotransformed to the acid itself to give antiherpes activity.
Bibliography:	istex:98E0E9F53BFF53968D03CACA60120E5A3CF2059D ark:/67375/TPS-FK6B2V8C-N ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00356a028