Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity

J Med Chem. 2011 Oct 27;54(20):7084-93. doi: 10.1021/jm200636z. Epub 2011 Sep 26.


We previously reported that substituted 4-aminoquinolines with a phenyl ether substituent at the 7-position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine's alkyl substituents exhibited potent antimalarial activity against the multidrug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogues in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain as well as for cytotoxicity against mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1 strain and good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study.

Publication types

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

MeSH terms

  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Cell Line
  • Drug Resistance
  • Humans
  • Membranes, Artificial
  • Permeability
  • Plasmodium falciparum / drug effects
  • Solubility
  • Structure-Activity Relationship


  • Aminoquinolines
  • Antimalarials
  • Membranes, Artificial