Bicyclic nucleoside inhibitors of varicella-zoster virus: effect of terminal aryl substitution in the side-chain.
We have previously reported the discovery and preliminary structure-activity relationships of a new class of inhibitors of varicella-zoster virus (VZV). These novel furanopyrimidine nucleosides bear unusual bicyclic base moieties and exhibit complete specificity for VZV. Limited in vitro cytotoxicity has been detected and the bicyclic nucleosides are now well established as a new family of potent antivirals. Our initial studies revealed an absolute requirement of a long alkyl side-chain, with an optimal chain length of C8-C10, for antiviral activity. Following further studies, we recently reported a significant enhancement of both antiviral potency and selectivity by the inclusion of a phenyl group within the alkyl side-chain of these compounds. The new lead p-alkylphenyl analogues displayed EC50 values below 1 nM versus VZV and selectivity index values >1000000. We herein report the synthesis and characterization of a further series of alkylaryl analogues bearing terminal phenyl groups with varying n-alkyl side-chain lengths. Synthesis of the target bicyclic systems involved the Pd-catalysed coupling of terminal acetylenes with 5-iodo-2'-deoxyuridine to give intermediate 5-alkynyl nucleosides which were then cyclized in the presence of copper (I) iodide. The current compounds display excellent selectivity for VZV with no detectable in vitro cytotoxicity but despite being chemically isomeric with the previous lead p-alkylphenyl analogues, the compounds reported herein exhibit only moderate antiviral activities. A possible correlation between antiviral activity and conformational freedom of the side-chain is discussed.
Carangio
A
A
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, UK.
Srinivasan
S
S
McGuigan
C
C
Andrei
G
G
Snoeck
R
R
De Clercq
E
E
Balzarini
J
J
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides