title: Alkyloxyphenyl furano pyrimidines as potent and selective anti-VZV agents with enhanced water solubility.
abstract: 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.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, UK. mcguigan@cardiff.ac.uk
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.forename: Sally
authors.initials: S
authors.lastname: Blewett
authors.forename: Dario
authors.initials: D
authors.lastname: Siccardi
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Erichsen
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoek
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: 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
chemical_list: D000998:Antiviral Agents; D005663:Furans; D011743:Pyrimidines