Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P. falciparum

J Med Chem. 2006 Jul 27;49(15):4535-43. doi: 10.1021/jm0600951.


Previous data showing that several chloroquine analogues containing an intramolecular hydrogen-bonding motif were potent against multidrug-resistant P. falciparum led to the exploration of the importance of this motif. A series of 116 compounds containing four different alkyl linkers and various aromatic substitutions with hydrogen bond accepting capability was synthesized. The series showed broad potency against the drug-resistant W2 strain of P. falciparum. In particular, a novel series containing variations of the alpha-aminocresol motif gave eight compounds with IC50 values more potent than 5 nM against the W2 strain. Such simple modifications, significantly altering the pKa and sterics of the basic side chain in chloroquine analogues, may prove to be part of a strategy for overcoming the problem of worldwide resistance to affordable antimalarial drugs.

Publication types

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

MeSH terms

  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Combinatorial Chemistry Techniques
  • Drug Resistance
  • Hydrogen Bonding
  • Plasmodium falciparum / drug effects*
  • Structure-Activity Relationship


  • Aminoquinolines
  • Antimalarials