Tetrahydronaphthalene lignan compounds as potent anti-HIV type 1 agents

AIDS Res Hum Retroviruses. 1997 May 20;13(8):695-705. doi: 10.1089/aid.1997.13.695.


Anti-HIV-1 activity of tetrahydronaphthalene (THN) derivatives of lignan compounds was studied. THN derivatives prevented cell death caused by HIV-1 infection in MT-4 cells. They also inhibited giant cell formation by HIV-1 in Sup-T1 cells, and p24 production in HIV-1-infected H9 cells. The 50% effective concentration (ED50) of the most active compound, 1737 [5,6,7-trimethoxy-4-(3,4,5-trimethoxyphenyl)-1,3,3a,4,9,9a-hexahydron aphtho[2,3-c]thiophene], for inhibition of the cytopathic effects of HIV-1 infection ranged from 0.15 to 0.8 microM. The 50% cytotoxic concentration (CC50) of compound 1737 measured by the viability of MT-4 cells was 58 microM, indicating a selective index (CC50/ED50) of 70-400. Substitution of the phenyl ring with other structures markedly decreased cytotoxicity but did not affect the antiviral activity of the compounds. This resulted in compounds with a high selective index. One such compound was 1738 [7-methoxy5,6-methylenedioxy-4-(4-benzyloxy-3-methoxyphenyl)1,3,3a ,4,9,9a-hexahydronaphtho[2,3-c]thiophene], with a selective index higher than 770. The time-of-addition experiment indicated that these compounds acted at or near the reverse transcription step of the HIV-1 life cycle. THN derivatives inhibited HIV-1 reverse transcriptase (RT) in vitro at a concentration of 1 microM. Resistant viruses selected in the presence of THN derivatives showed some degree of cross-resistance to other nonnucleoside RT inhibitors, but not to the nucleoside RT inhibitor, AZT. THN derivatives failed to inhibit replication of pyridinone- and nevirapine-resistant HIV strains. However, compound 1737 inhibited replication of a TIBO-resistant strain more effectively than the wild-type HIV-1. Consistent with this result, compound 1737 also inhibited TIBO-resistant RT more effectively than the wild-type RT in vitro. These results suggested that THN derivatives interact with RT in a manner similar to but slightly different from that of other nonnucleoside HIV-1 RT inhibitors.

MeSH terms

  • Anti-HIV Agents*
  • Cell Line, Transformed / drug effects
  • Cell Line, Transformed / metabolism
  • Cell Line, Transformed / virology
  • Cytopathogenic Effect, Viral / drug effects
  • Drug Resistance
  • Enzyme Inhibitors / pharmacology
  • Genetic Variation / drug effects
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / genetics
  • Humans
  • Kinetics
  • Lignans / pharmacology*
  • Point Mutation
  • Tetrahydronaphthalenes / pharmacology*
  • Time Factors


  • Anti-HIV Agents
  • Enzyme Inhibitors
  • Lignans
  • Tetrahydronaphthalenes
  • HIV Reverse Transcriptase