The design of 8-hydroxyquinoline tetracyclic lactams as HIV-1 integrase strand transfer inhibitors

Eur J Med Chem. 2016 Jul 19:117:99-112. doi: 10.1016/j.ejmech.2016.03.038. Epub 2016 Mar 22.

Abstract

A novel series of HIV-1 integrase strand transfer inhibitors were designed using the venerable two-metal binding pharmacophore model and incorporating structural elements from two different literature scaffolds. This manuscript describes a number of 8-hydroxyquinoline tetracyclic lactams with exceptional antiviral activity against HIV-1 and little loss of potency against the IN signature resistance mutations Q148K and G140S/Q148H.

Keywords: AIDS; HIV; Integrase; Integrase inhibitor; Quinoline; Strand transfer inhibitor.

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / pharmacology
  • Cell Line
  • Drug Design*
  • Drug Resistance, Viral / drug effects
  • Drug Resistance, Viral / genetics
  • HIV Integrase / drug effects
  • HIV Integrase Inhibitors / chemical synthesis*
  • HIV Integrase Inhibitors / pharmacology
  • HIV-1 / drug effects
  • Humans
  • Lactams / chemical synthesis*
  • Lactams / pharmacology
  • Mutation

Substances

  • Anti-HIV Agents
  • HIV Integrase Inhibitors
  • Lactams
  • HIV Integrase