Synthesis, Binding and Antiviral Properties of Potent Core-Extended Naphthalene Diimides Targeting the HIV-1 Long Terminal Repeat Promoter G-Quadruplexes

J Med Chem. 2015 Dec 24;58(24):9639-52. doi: 10.1021/acs.jmedchem.5b01283. Epub 2015 Dec 8.


We have previously reported that stabilization of the G-quadruplex structures in the HIV-1 long terminal repeat (LTR) promoter suppresses viral transcription. Here we sought to develop new G-quadruplex ligands to be exploited as antiviral compounds by enhancing binding toward the viral G-quadruplex structures. We synthesized naphthalene diimide derivatives with a lateral expansion of the aromatic core. The new compounds were able to bind/stabilize the G-quadruplex to a high extent, and some of them displayed clear-cut selectivity toward the viral G-quadruplexes with respect to the human telomeric G-quadruplexes. This feature translated into low nanomolar anti-HIV-1 activity toward two viral strains and encouraging selectivity indexes. The selectivity depended on specific recognition of LTR loop residues; the mechanism of action was ascribed to inhibition of LTR promoter activity in cells. This is the first example of G-quadruplex ligands that show increased selectivity toward the viral G-quadruplexes and display remarkable antiviral activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • G-Quadruplexes*
  • HEK293 Cells
  • HIV Long Terminal Repeat*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HeLa Cells
  • Humans
  • Imides / chemical synthesis
  • Imides / chemistry*
  • Imides / pharmacology
  • Ligands
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry*
  • Naphthalenes / pharmacology
  • Promoter Regions, Genetic
  • Protein Binding
  • Structure-Activity Relationship


  • Anti-HIV Agents
  • Imides
  • Ligands
  • Naphthalenes