Oxidation of 2-Hydroxynevirapine, a Phenolic Metabolite of the Anti-HIV Drug Nevirapine: Evidence for an Unusual Pyridine Ring Contraction

Molecules

Alexandra M. M. Antunes¹  Muna Sidarus¹  David A. Novais¹  Shrika G. Harjivan¹  Pedro P. Santos¹  João L. Ferreira da Silva¹  Frederick A. Beland¹ 

[1]¹Centro de Química Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, Lisboa 1049-001, Portugal[2] height:6px

[3]"> ²National Center for Toxicological Research, Jefferson, AR 72079, USA

关键词: anti-HIV drug;    nevirapine;    oxidation;    pyridine ring contraction;   

DOI  :  10.3390/molecules17032616

来源: mdpi

【 摘 要 】

Nevirapine (NVP) is an anti-HIV drug associated with severe hepatotoxicity and skin rashes, which raises concerns about its chronic administration. There is increasing evidence that metabolic activation to reactive electrophiles capable of reacting with bionucleophiles is likely to be involved in the initiation of these toxic responses. Phase I NVP metabolism involves oxidation of the 4-methyl substituent and the formation of phenolic derivatives that are conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species prone to react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As part of a program aimed at evaluating the possible contribution of quinoid derivatives of Phase I phenolic NVP metabolites to the toxic responses elicited by the parent drug, we have investigated the oxidation of 2-hydroxy-NVP with dipotassium nitroso-disulfonate (Frémy’s salt), mimicking the one-electron oxidation involved in enzyme-mediated metabolic oxidations. We report herein the isolation and full structural characterization of a 1H-pyrrole-2,5-dione derivative as a major product, stemming from an unusual pyridine ring contraction.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.