Alkyloxyphenyl furano pyrimidines as potent and selective anti-VZV agents with enhanced water solubility.
We have previously reported bicyclic furanopyrimidines as potent and selective inhibitors of varicella zoster virus (VZV) with subnanomolar activity for p-alkylphenyl substituted analogues. These compounds are highly lipophilic and of limited water solubility. In an effort to address this issue, and with a view to oral dosing, we have sought to enhance water solubility whilst retaining high antiviral potency and we herein report a novel series of p-alkyloxyphenyl compounds which contain a phenolic ether atom intended to boost hydrophilicity. We report the synthesis, characterisation and antiviral evaluation of this series and note the retention of extremely high antiviral potency, with EC50 values as low as 1 nanomolar.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, UK. mcguigan@cardiff.ac.uk
Blewett
Sally
S
Siccardi
Dario
D
Erichsen
Jonathan T
JT
Andrei
Graciela
G
Snoek
Robert
R
De Clercq
Erik
E
Balzarini
Jan
J
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D005663:Furans; D011743:Pyrimidines