Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: synthesis, characterization and in vitro antimalarial activity

Dalton Trans. 2012 Mar 7;41(9):2764-73. doi: 10.1039/c2dt12083f. Epub 2012 Jan 17.

Abstract

Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η(6)-cym)(L(1))Cl]Cl (1, cym = p-cymene, L(1) = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η(6)-cym)(L(2))Cl]Cl (2, L(2) = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η(6)-cym)(L(3))Cl] (3, L(3) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1-3 and ligands L(1), L(2) and L(3), as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L(4)), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L(2) also shows good activity against both the chloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR(50)) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR(50) properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L(3) to ruthenium, to give a metal complex (3) with promising antimalarial activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Octanol / chemistry
  • Animals
  • Antimalarials / chemistry*
  • Antimalarials / pharmacology
  • CHO Cells
  • Cell Survival / drug effects
  • Chloroquine / analogs & derivatives*
  • Chloroquine / chemistry*
  • Chloroquine / pharmacology
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Electric Conductivity
  • Heme / chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Inhibitory Concentration 50
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacology
  • Plasmodium falciparum / drug effects
  • Ruthenium / chemistry*
  • Ruthenium / pharmacology
  • Water / chemistry

Substances

  • Antimalarials
  • Ligands
  • Organometallic Compounds
  • Water
  • Heme
  • Ruthenium
  • Chloroquine
  • 1-Octanol