Bicyclic nucleoside inhibitors of varicella-zoster virus (VZV): Pd-catalysed synthesis of 5-aryl derivatives and their biological evaluation.
We have recently reported the discovery of an entirely new category of potent antiviral agents based on novel deoxynucleoside analogues with unusual fluorescent bicyclic furano base moieties. In order to probe structure activity relationships we prepared a series of 5-aryl derivatives of the lead structures. We herein report the synthesis, characterization, and antiviral evaluation of these novel compounds. 5-Aryl derivatives of the parent nucleosides were synthesized from the corresponding alkynyl deoxyuridines using a simple, versatile and efficient one-step conversion, based on a palladium-catalysed cyclization. As previously noted for the lead compounds, a long alkyl side-chain on the base moiety is essential for antiviral activity. Even with the optimal (C8-C10) side-chain, most of the present compounds are markedly less active than their parent structures. However, some of the synthesized compounds still retained antiviral activity at non-cytotoxic concentrations, being only two- to fivefold less active than the current clinical agent acyclovir. Possible reasons for this structure activity relationship are discussed.
Carangio
A
A
Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
McGuigan
C
C
Andrei
G
G
Snoeck
R
R
De Clercq
E
E
Balzarini
J
J
D000212:Acyclovir / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D010165:Palladium / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; D010165:Palladium; D000212:Acyclovir