Structural and theoretical studies of [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid as HIV-1 integrase inhibitor

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4806-9. doi: 10.1016/j.bmcl.2009.06.044. Epub 2009 Jun 14.

Abstract

Ethyl [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl]-4-hydroxy-2-oxo-3-butenoate 1 and [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid 2 were synthesized as potential HIV-1 integrase inhibitors and evaluated for their enzymatic and antiviral activity, acidic compound 2 being more potent than ester compound 1. X-ray diffraction analyses and theoretical calculations show that the diketoacid chain of compound 2 is preferentially coplanar with the quinolinone ring (dihedral angle of 0-30 degrees ). Docking studies suggest binding modes in agreement with structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Quinolones / chemical synthesis
  • 4-Quinolones / chemistry*
  • 4-Quinolones / pharmacology
  • Butyrates / chemical synthesis
  • Butyrates / chemistry*
  • Butyrates / pharmacology
  • Catalytic Domain
  • Computer Simulation
  • Crystallography, X-Ray
  • HIV Integrase / chemistry*
  • HIV Integrase / metabolism
  • HIV Integrase Inhibitors / chemical synthesis
  • HIV Integrase Inhibitors / chemistry*
  • HIV Integrase Inhibitors / pharmacology
  • Humans
  • Molecular Conformation
  • Protein Binding
  • Quantum Theory
  • Structure-Activity Relationship

Substances

  • (6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)-4-hydroxy-2-oxo-3-butenoic acid
  • 4-Quinolones
  • Butyrates
  • HIV Integrase Inhibitors
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 1