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Synthesis and Anti‐herpetic Activity of Phosphoramidate ProTides
Author(s) -
Maiti Munmun,
Persoons Leentje,
Andrei Graciela,
Snoeck Robert,
Balzarini Jan,
Herdewijn Piet
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300035
Subject(s) - phosphoramidate , prodrug , nucleoside , nucleotide , chemistry , nucleoside analogue , valaciclovir , stereochemistry , potency , biochemistry , combinatorial chemistry , virology , virus , in vitro , biology , herpesviridae , viral disease , gene
Among the many prodrug approaches aimed at delivering nucleoside monophosphates into cells, the phosphoramidate ProTide approach is one that has shown success, which has made it possible for some of the phosphoramidates to enter into clinical trials. Herein, we report the synthesis and antiviral activity of a series of phosphoramidate ProTides designed to bypass the thymidine kinase (TK) dependence of the parent nucleoside analogues. Phosphoramidate derivatives of ( E )‐5‐(2‐bromovinyl)‐2′‐deoxyuridine (BVDU) that contain L ‐alanine or pivaloyloxymethyl iminodiacetate (IDA‐POM) exhibit anti‐HSV‐1 and anti‐VZV activity in cell cultures, but they largely lost antiviral potency against TK‐deficient virus strains. Among deazapurine nucleosides and their phosphoramidate derivatives, the 7‐deazaadenine containing nucleosides and their phosphoramidate triester derivatives showed weak antiviral activity against VZV. Apparently, intracellular nucleotide delivery with these phosphoramidates is partly successful. However, none of the compound prodrugs showed superior activity to their parent drugs.