Lead optimization of 3-carboxyl-4(1H)-quinolones to deliver orally bioavailable antimalarials

J Med Chem. 2012 May 10;55(9):4205-19. doi: 10.1021/jm201642z. Epub 2012 Apr 18.


Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Antimalarials / administration & dosage*
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry*
  • Antimalarials / pharmacokinetics
  • Biological Availability
  • Female
  • Hep G2 Cells
  • Humans
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / parasitology
  • Mice
  • Mice, Inbred ICR
  • Nuclear Magnetic Resonance, Biomolecular
  • Parasitemia / drug therapy
  • Parasitemia / parasitology
  • Plasmodium falciparum / isolation & purification*
  • Quinolines / administration & dosage*
  • Quinolines / chemical synthesis
  • Quinolines / chemistry*
  • Quinolines / pharmacokinetics
  • Spectrometry, Mass, Electrospray Ionization
  • Spectroscopy, Fourier Transform Infrared
  • Structure-Activity Relationship


  • Antimalarials
  • Quinolines