Novel antimalarial aminoquinolines: heme binding and effects on normal or Plasmodium falciparum parasitized human erythrocytes. - Related Articles
Novel antimalarial aminoquinolines: heme binding and effects on normal or Plasmodium falciparum parasitized human erythrocytes.
Antimicrob Agents Chemother. 2009 Aug 3;
Authors: Omodeo-Salè F, Cortelezzi L, Basilico N, Casagrande M, Sparatore A, Taramelli D
Two new quinolizidinyl-alkyl derivatives of 7-chloro-4-aminoquinoline named AM-1 and AP4b, which are highly effective in vitro against both D10 (CQ-susceptible) and W2 (CQ-resistant) strains of Plasmodium falciparum and in vivo in the rodent malaria model, have been studied for their ability to bind to and be internalized by normal or parasitized human red blood cells (RBC) and for their effects on RBC membrane stability. In addition, an analysis of the heme binding properties of these compounds and of their ability to inhibit beta-hematin formation in vitro has been performed. Binding of AM1 or AP4b to RBC is rapid, dose-dependent and linearly related to RBC density. Their accumulation into parasitized RBC (pRBC) is increased 2 fold compared to normal RBC. Binding of AM1 or AP4b to both normal and pRBC is higher compared to that of CQ in agreement with the lower pKa and higher lipophilicity of the compounds. AM1 or AP4b are not hemolytic per se and are less hemolytic than CQ when hemolysis is accelerated (induced) by hematin. Moreover, AM-1 and AP4b bind heme with a stoichiometry of interaction similar to that of CQ (about 1:1.7), but with a lower affinity. They both inhibit dose-dependently the formation of beta hematin in vitro with an IC50 comparable to that of CQ. Taken together these results suggest that the antimalarial activity of AM1 or AP4b is likely due to inhibition of hemozoin formation and that their efficacy against the CQ-R strains can be ascribed to their hydrophobicity and capacity to accumulate in the vacuolar lipid (elevated LAR).
PMID: 19651905 [PubMed - as supplied by publisher] [PubMed-Malaria]