Synthesis and biological activities of potential metabolites of the non-nucleoside reverse transcriptase inhibitor Efavirenz

doi:10.1016/S0960-894X(01)00012-9

Bioorganic & Medicinal Chemistry Letters

Volume 11, Issue 5, 12 March 2001, Pages 619-622

https://doi.org/10.1016/S0960-894X(01)00012-9 Get rights and content

Abstract

Studies on the biotransformation of the clinically important non-nucleoside reverse transcriptase inhibitor efavirenz have shown that oxidation and secondary conjugation are important components of the processing of this molecule in vivo. We have synthesized metabolites of efavirenz to confirm their structure and to evaluate their activity as antivirals.

Efavirenz undergoes species-specific metabolism in vivo. Several primary and secondary metabolites were prepared by total synthesis, and their antiviral activities were determined.

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Acknowledgments

The authors would like to thank Al Mical for his expert assistance on chiral chromatography.

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Therefore, with the ultimate goal of preparing synthetic standards to investigate the oxidative biotransformation of 7-OH-EFV and 8-OH-EFV in vivo, we examined their oxidation in vitro using Frémy's salt. The synthesis of racemic 7-OH-EFV (3) was conducted by adaptation of the multi-step procedure reported by Markwalder et al. [14] (cf. Supporting information); 8-OH-EFV (2) was prepared by direct oxidation of EFV mediated by a bio-inspired nonheme Fe-complex, as described in Wanke et al. [9]. The oxidation of the two phenolic metabolites was subsequently carried out with the radical potassium nitrosodisulfonate (Frémy's salt), which is frequently employed to obtain quinones from phenolic compounds [15–17].
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Synthesis and biological activities of potential metabolites of the non-nucleoside reverse transcriptase inhibitor Efavirenz

Abstract

Section snippets

Acknowledgments

Carbohydr. Res.

Tetrahedron Lett.

Drug Met. Disp.

J. Org. Chem.

J. Am. Chem. Soc.