Kojic acid derived hydroxypyridinone-chloroquine hybrids: synthesis, crystal structure, antiplasmodial activity and β-haematin inhibition

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3263-7. doi: 10.1016/j.bmcl.2014.06.012. Epub 2014 Jun 14.

Abstract

Aminochloroquinoline-kojic acid hybrids were synthesized and evaluated for β-haematin inhibition and antiplasmodial activity against drug resistant (K1) and sensitive (3D7) strains of Plasmodium falciparum. Compound 7j was the most potent compound in both strains (IC50(3D7)=0.004 μM; IC50(K1)=0.03 μM) and had the best β-haematin inhibition activity (0.07 IC50 equiv vs 1.91 IC50 equiv for chloroquine). One compound 8c was found to be equipotent in both strains (IC50=0.04 μM).

Keywords: Antiplasmodial; Haematin inhibition; Hybrids; Hydroxypyridinone; Kojic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemistry*
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Hemeproteins / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Pyridones / chemistry*
  • Pyrones / chemical synthesis
  • Pyrones / chemistry
  • Pyrones / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-(((3-(7-chloroquinolin-4-ylamino)propyl)(methyl)amino)methyl)-5-hydroxy-1-methylpyridin-4(1H)-one
  • 5-(benzyloxy)-2-((6-(7-chloroquinolin-4-ylamino)hexylamino)methyl)-1-cyclopropylpyridin-4(1H)-one
  • Aminoquinolines
  • Antimalarials
  • Hemeproteins
  • Pyridones
  • Pyrones
  • hemozoin
  • kojic acid