2. Academic Validation
  3. Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach

Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach

  • J Med Chem. 2005 Feb 24;48(4):1211-20. doi: 10.1021/jm040845b.
Lene Petersen 1,  Per T Jørgensen,  Claus Nielsen,  Thomas H Hansen,  John Nielsen,  Erik B Pedersen
Affiliations

Affiliation

  • 1 Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
PMID: 15715487 DOI: 10.1021/jm040845b
Abstract

This paper reports the synthesis and the Antiviral activities of new double-prodrugs against HIV based on the known mixed SATE (S-acyl-2-thioethyl) prodrug approach. The monophosphate of the nucleoside Reverse Transcriptase Inhibitor (NRTI) d4T was masked with one SATE group and one aromatic group through which a nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) was linked. Double-prodrug 1 was a hybrid between d4T monophosphate and the known NNRTI MKC-442, which were linked through a labile p-hydroxybenzoyl protection group in the N-3 position of MKC-442. Double-prodrugs 2 and 3 were conjugates between d4T monophosphate and the new NNRTIs 15 and 19 linked through a stable phenolic linker that was a part of the N-1 substituents of the NNRTIs. The double-prodrugs 1, 2, and 3 all had good activities against wild-type HIV-1, Y181C mutant, and also against a HIV-2 strain that was resistant to NNRTIs.

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