Structure-function relationships in aminoquinolines: effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity.
Comparison of 19 aminoquinolines supports the hypothesis that chloroquine and related antimalarials act by complexing ferriprotoporphyrin IX (Fe(III)PPIX), inhibiting its conversion to beta-hematin (hemozoin) and hence its detoxification. The study suggests that a basic amino side chain is also essential for antiplasmodial activity. 2- And 4-aminoquinolines are unique in their strong affinity for Fe(III)PPIX, and attachment of side chains to the amino group has relatively little influence on the strength of complex formation. Association with Fe(III)PPIX is necessary, but not sufficient, for inhibiting beta-hematin formation. Presence of a 7-chloro group in the 4-aminoquinoline ring is a requirement for beta-hematin inhibitory activity, and this is also unaffected by side chains attached to the amino group. In turn, beta-hematin inhibitory activity is necessary, but not sufficient, for antiplasmodial activity as the presence of an aminoalkyl group attached to the 4-amino-7-chloroquinoline template is essential for strong activity. We thus propose that the 4-aminoquinoline nucleus of chloroquine and related antimalarials is responsible for complexing Fe(III)PPIX, the 7-chloro group is required for inhibition of beta-hematin formation, and the basic amino side chain is required for drug accumulation in the food vacuole of the parasite.
Egan
T J
TJ
Department of Chemistry, University of Cape Town, South Africa. tegan@psipsy.uct.ac.za
Hunter
R
R
Kaschula
C H
CH
Marques
H M
HM
Misplon
A
A
Walden
J
J
D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D006427:Hemin / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D000962:Antimalarials; D006427:Hemin