Structure-function relationships in aminoquinolines: Effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity
Tj. Egan et al., Structure-function relationships in aminoquinolines: Effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity, J MED CHEM, 43(2), 2000, pp. 283-291
Comparison of 19 aminoquinolines supports the hypothesis that chloroquine a
nd related antimalarials act by complexing ferriprotoporphyrin IX (Fe(III)P
PM), inhibiting its conversion to beta-hematin (hemozoin) and hence its det
oxification. The study suggests that a basic amino side chain is also essen
tial for antiplasmodial activity. 2- And 4-aminoquinolines are unique in th
eir strong affinity for Fe(III)PPIX, and attachment of side chains to the a
mino group has relatively little influence on the strength of complex forma
tion. Association with Fe(III)PPM is necessary, but not sufficient, for inh
ibiting beta-hematin formation. Presence of a 7-chloro group in the 4-amino
quinoline ring is a requirement for beta-hematin inhibitory activity, and t
his is also unaffected by side chains attached to the amino group. In turn,
beta-hematin inhibitory activity is necessary, but not sufficient, for ant
iplasmodial activity as the presence of an aminoalkyl group attached to the
4-amino-7-chloroquinoline template is essential for strong activity. We th
us propose that the 4-aminoquinoline nucleus of chloroquine and related ant
imalarials is responsible for complexing Fe(III)PPM, the 7-chloro soup is r
equired for inhibition of beta-hematin formation, and the basic amino side
chain is required for drug accumulation in the food vacuole of the parasite
.