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

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 of reacting with bionucleophiles. We investigated the in vitro oxidation of the phenolic EFV metabolites, 7-hydroxy-efavirenz (7-OH-EFV) and 8-hydroxy-efavirenz (8-OH-EFV), with Frémy's salt. A quinoline derivative, 6-chloro-2-cyclopropyl-4-(trifluoromethyl)quinolin-7-ol, presumably stemming from a radical rearrangement, was selectively obtained from 7-OH-EFV in 10% yield. In contrast, when subjected to the same oxidation conditions, 8-OH-EFV was considerably more prone to oxidative degradation and yielded multiple products. Among these, a quinone-imine derivative was tentatively identified upon LC-ESI-MS/MS analysis of the reaction mixture. These observations demonstrate a remarkable difference in the reactivities of the two phenolic EFV metabolites under oxidative conditions. Moreover, taking into consideration the toxicological significance of quinone-imine derivatives, these findings may explain earlier reports that 8-OH-EFV is a more potent toxicant than 7-OH-EFV in model test systems.

Keywords: Anti-HIV drug; Efavirenz; Oxidation; Phenolic metabolites; Quinoline; Quinone–imine.