Enhancing the aqueous solubility of d4T-based phosphoramidate prodrugs.
A range of polyether para-substituted phosphoramidates were synthesised and found to have substantially elevated aqueous solubilities compared to the underivatised parent prodrug. A 30-fold increase in aqueous solubility could be achieved without a substantial decrease of in vitro activity against HIV-1. Replacement of the aryl (i.e. phenolic) moiety by tyrosine led to a substantial enhancement in aqueous solubility but also to a decrease in antiviral potency. A previously unobserved trend was identified, relating increased aryl substituent steric bulk to decreased antiviral activity.
Siddiqui
A
A
Welsh School of Pharmacy, Cardiff University, UK.
McGuigan
C
C
Ballatore
C
C
Srinivasan
S
S
De Clercq
E
E
Balzarini
J
J
D000577:Amides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004341:Drug Evaluation; D004950:Esterases / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D008099:Liver / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013552:Swine; D013936:Thymidine / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D014867:Water / Q000378:metabolism*
D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; D011355:Prodrugs; D014867:Water; C011067:phosphoramidic acid; D004950:Esterases; D013936:Thymidine