The phenolic metabolites of the anti-HIV drug efavirenz: evidence for distinct reactivities upon oxidation with Frémy's salt.

摘要: Abstract Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor administered as first line treatment against HIV-1. The major drawbacks of EFV therapy are neurotoxicity and hepatotoxicity, which may result from bioactivation to reactive metabolites capable reacting with bionucleophiles. We investigated the in vitro oxidation phenolic metabolites, 7-hydroxy-efavirenz (7-OH-EFV) 8-hydroxy-efavirenz (8-OH-EFV), Fremy's salt. A quinoline derivative, 6-chloro-2-cyclopropyl-4-(trifluoromethyl)quinolin-7-ol, presumably stemming radical rearrangement, was selectively obtained 7-OH-EFV in 10% yield. In contrast, when subjected same conditions, 8-OH-EFV considerably more prone oxidative degradation yielded multiple products. Among these, quinone–imine derivative tentatively identified upon LC–ESI–MS/MS analysis reaction mixture. These observations demonstrate remarkable difference reactivities two under conditions. Moreover, taking into consideration toxicological significance derivatives, these findings explain earlier reports that potent toxicant than model test systems.