Potential anti-AIDS Naphthalenesulfonic Acid Derivatives. Synthesis and Inhibition of HIV-1 Induced Cytopathogenesis and HIV-1 and HIV-2 Reverse Transcriptase Activities

J Med Chem. 1992 Dec 25;35(26):4846-53. doi: 10.1021/jm00104a010.

Abstract

Several naphthalenedi- and trisulfonic acids have been synthesized and evaluated for inhibitory potential against cytopathogenesis and purified recombinant human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptase (RT). The most potent derivative that emerged from the anti-RT study was a small molecule 6 (MW = 840), a dipalmitoylated derivative of 2,7-naphthalenedisulfonic acid. Analog 6 demonstrated 50% inhibitory concentration (IC50) values of 2.42 and 0.86 microM for HIV-1 and HIV-2 RT, respectively. The second most active compound was also a derivative of the same naphthalenedisulfonic acid but contained only one palmitoyl moiety. This compound 9 displayed IC50 values of 4.8 and 3.7 microM for HIV-1 and HIV-2 RT, respectively. Both analogs 6 and 9 are active at noncytotoxic doses, exhibit slightly higher potencies for the RT of HIV-2 over HIV-1, and demonstrate activities superior to the hexasulfonic acid derivative suramin (IC50 values of 9.4 and 15.5 microM for HIV-1 and HIV-2 RT, respectively). In the cytopathogenesis assay, the most active compound is a bis naphthalenedisulfonic acid derivative 17, containing a flexible octamethylene spacer and exhibiting an in vitro therapeutic index of 29.7. Most striking, however, is the influence of the palmitoyl functionality in the naphthalenedisulfonic acid series to confer activity against both HIV-1 and HIV-2 RT.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • HIV Reverse Transcriptase
  • Naphthalenesulfonates / chemical synthesis*
  • Naphthalenesulfonates / chemistry
  • Naphthalenesulfonates / pharmacology
  • RNA-Directed DNA Polymerase*
  • Reverse Transcriptase Inhibitors*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Naphthalenesulfonates
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 2
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase