Novel quinolinonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, and biological activities

J Med Chem. 2008 Aug 14;51(15):4744-50. doi: 10.1021/jm8001422. Epub 2008 Jul 23.

Abstract

Novel quinolinonyl diketo acids were designed to obtain integrase (IN) inhibitors selectively active against the strand transfer (ST) step of the HIV integration process. Those new compounds are characterized by a single aryl diketo acid (DKA) chain in comparison to 4, a bifunctional diketo acid reported by our group as an anti-IN agent highly potent against both the 3'-processing and ST steps. Compound 6d was the most potent derivative in IN enzyme assays, while 6i showed the highest potency against HIV-1 in acutely infected cells. The selective inhibition of ST suggested the newly designed monofunctional DKAs bind the IN-DNA acceptor site without affecting the DNA donor site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chemical Phenomena
  • Chemistry, Physical
  • Drug Design*
  • HIV Integrase Inhibitors / chemical synthesis*
  • HIV Integrase Inhibitors / chemistry
  • HIV Integrase Inhibitors / classification
  • HIV Integrase Inhibitors / pharmacology*
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • Humans
  • Keto Acids / chemical synthesis*
  • Keto Acids / chemistry
  • Keto Acids / classification
  • Keto Acids / pharmacology*
  • Molecular Structure
  • Quinolines / chemistry*
  • Structure-Activity Relationship

Substances

  • HIV Integrase Inhibitors
  • Keto Acids
  • Quinolines
  • quinoline

Grants and funding

National Institutes of Health, United States