Halophenyl furanopyrimidines as potent and selective anti-VZV agents.
Bicyclic furano pyrimidines have been previously reported by us to be highly potent and selective inhibitors of varicella zoster virus (VZV). p-Alkyl phenyl analogues are particularly potent with EC50 values below 1 nM. In this article we report the synthesis and anti-VZV activity of a series of halophenyl analogues, with variation in the nature (F, Cl, Br) and location (o, m, p) of the halogen substituent. The compounds show a range of activities from ca. 10 nM to > 50 microM. In most cases, ortho substitution leads to greatest activity, meta substitution is in general poor, and the effect of p-substitution shows a marked dependence on the halogen atom. The p-fluorophenyl compound is unique amongst compounds of this class in being inactive as an antiviral. The possible origins of these marked SARs are discussed.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, Cardiff, UK. mcguigan@cardiff.ac.uk
Jukes
Alison
A
Blewett
Sally
S
Barucki
Hubert
H
Erichsen
Jonathan T
JT
Andrei
Graciella
G
Snoeck
Robert
R
De Clercq
Erik
E
Balzarini
Jan
J
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002478:Cells, Cultured / Q000187:drug effects; D005663:Furans / Q000737:chemistry*; D006219:Halogens / Q000737:chemistry*; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005663:Furans; D006219:Halogens; D011741:Pyrimidine Nucleosides