Synthesis and anti-HIV activity of [AZT]-[TSAO-T] and [AZT]-[HEPT] dimers as potential multifunctional inhibitors of HIV-1 reverse transcriptase

J Med Chem. 1995 May 12;38(10):1641-9. doi: 10.1021/jm00010a008.


In an attempt to combine the HIV-inhibitory capacity of 2',3'-dideoxynucleoside (ddN) analogues and non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI), we have designed, synthesized, and evaluated for their anti-HIV activity several dimers of the general formula [ddN]-(CH2)n-[NNRTI]. These dimers combine in their structure a ddN such as AZT and a NNRTI such as TSAO-T and HEPT linked through an appropriate spacer between the N-3 of the thymine base of both compounds. The [TSAO-T]-(CH2)n-[AZT] dimers proved markedly inhibitory to HIV-1. Also, if AZT was replaced by thymidine in the dimer molecules, potent anti-HIV-1 activity was observed. However, although the compounds proved inhibitory to HIV-1, they were less potent inhibitors than the parent compounds from which they were derived. None of the dimers were endowed with anti-HIV-2 activity. In contrast with the TSAO-T monomers, none of the TSAO-T-containing dimers proved markedly cytotoxic to the cells. There was a clear trend toward decreased antiviral potency with lengthening the methylene spacer in the [TSAO-T]-(CH2)n-[AZT] dimers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cell Line
  • HIV Reverse Transcriptase
  • HIV-1 / enzymology*
  • Humans
  • Polymers
  • Reverse Transcriptase Inhibitors*
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Thymidine / analogs & derivatives*
  • Thymidine / chemical synthesis
  • Thymidine / chemistry
  • Thymidine / pharmacology
  • Thymine / analogs & derivatives*
  • Thymine / chemical synthesis
  • Thymine / chemistry
  • Thymine / pharmacology
  • Uridine / analogs & derivatives
  • Zidovudine / chemical synthesis*
  • Zidovudine / chemistry
  • Zidovudine / pharmacology


  • Antiviral Agents
  • Polymers
  • Reverse Transcriptase Inhibitors
  • Spiro Compounds
  • 1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine
  • Zidovudine
  • HIV Reverse Transcriptase
  • Thymine
  • Thymidine
  • TSAO-T
  • Uridine