In vitro antimalarial activity of a series of cationic 2,2'-bipyridyl- and 1,10-phenanthrolineplatinum(II) benzoylthiourea complexes

J Med Chem. 2004 May 20;47(11):2926-34. doi: 10.1021/jm031132g.

Abstract

We have synthesized a series of novel 2,2'-bipyridyl and 1,10-phenanthroline benzoylthiourea complexes of platinum(II) with various substituents on the bipyridyl and phenanthroline ligands. All of these square-planar mixed-ligand cationic complexes were found to form moderately strong complexes with ferriprotoporphyrin IX in 40% aqueous DMSO (log K ranging from 4.81 to 6.24). The complexes also all inhibit beta-hematin (synthetic hemozoin or malaria pigment) formation in acetate solution. Four of the compounds were found to exhibit in vitro antimalarial activity, with (N-benzoyl-N',N'-di(2-hydroxyethyl)thioureato)(4,4'-di-tert-butyl-2,2'-bipyridyl)platinum(II) chloride being particularly active. These active complexes exhibited equally strong activity against both the D10 chloroquine sensitive and K1 chloroquine resistant strains of malaria parasite. Cytotoxicity testing of the four most active compounds shows that they exhibit selective activity against malaria parasites with selectivity indices greater than 85. These compounds represent a new family of potential antimalarials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,2'-Dipyridyl / chemical synthesis*
  • 2,2'-Dipyridyl / chemistry
  • 2,2'-Dipyridyl / pharmacology
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • CHO Cells
  • Cricetinae
  • Hemin / chemistry
  • Organoplatinum Compounds / chemical synthesis*
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology
  • Phenanthrolines / chemical synthesis*
  • Phenanthrolines / chemistry
  • Phenanthrolines / pharmacology
  • Plasmodium falciparum / drug effects
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives*
  • Thiourea / chemical synthesis*
  • Thiourea / chemistry
  • Thiourea / pharmacology

Substances

  • (N-benzoyl-N',N'-di(2-hydroxyethyl)thioureato-S,O)(4,4'-di-tert-butyl-2,2'-bipyridyl)platinum(II)
  • Antimalarials
  • Organoplatinum Compounds
  • Phenanthrolines
  • 2,2'-Dipyridyl
  • Hemin
  • Thiourea
  • 1,10-phenanthroline