title: Synthesis and anti-HIV activity of some novel diaryl phosphate derivatives of AZT.
abstract: Novel diaryl phosphate triester derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials were designed to act as membrane-soluble pro-drugs of the bio-active free nucleotides. In particular, novel parasubstituted diaryl phosphate derivatives were prepared. In vitro evaluation revealed the compounds to have a pronounced and selective antiviral effect, the magnitude of which varied considerably with the nature of the aryl substituent. In particular, strongly electron-withdrawing aryl substituents correlate with high anti-HIV potency in C8166 cells. Along with AZT, the compounds are poorly effective in JM cells, which appear to lack thymidine kinase, indicating the phosphates to act as pro-drugs of the nucleoside rather than of the free phosphate.
authors.affiliation: Department of Chemistry, University of Southampton, Highfield, UK.
authors.forename: C
authors.initials: C
authors.lastname: McGuigan
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: R
authors.initials: R
authors.lastname: Pathirana
authors.forename: N
authors.initials: N
authors.lastname: Mahmood
authors.forename: A J
authors.initials: AJ
authors.lastname: Hay
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010710:Phosphates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000031:analogs & derivatives*
chemical_list: D000998:Antiviral Agents; D010710:Phosphates; D011355:Prodrugs; D015215:Zidovudine