Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives

J Med Chem. 2011 Jan 13;54(1):131-42. doi: 10.1021/jm100911f. Epub 2010 Dec 8.


In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / pharmacology
  • Aminoquinolines / toxicity
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology
  • Antimalarials / toxicity
  • Cell Line
  • Chloroquine / pharmacology
  • Drug Resistance
  • Humans
  • In Vitro Techniques
  • Malaria / prevention & control
  • Mice
  • Microsomes, Liver / metabolism
  • Plasmodium berghei
  • Plasmodium falciparum / drug effects
  • Structure-Activity Relationship


  • Aminoquinolines
  • Antimalarials
  • Chloroquine