Effects of an antimalarial quinazoline derivative on human erythrocytes and on cell membrane molecular models.

ABSTRACT

Plasmodium, the parasite which causes malaria in humans multiplies in the liver and then infects circulating erythrocytes. Thus, the role of the erythrocyte cell membrane in antimalarial drug activity and resistance has key importance. The effects of the antiplasmodial N(6)-(4-methoxybenzyl)quinazoline-2,4,6-triamine (M4), and its inclusion complex (M4/HPßCD) with 2-hydroxypropyl-ß-cyclodextrin (HPßCD) on human erythrocytes and on cell membrane molecular models are herein reported. This work evidences that M4/HPßCD interacts with red cells as follows a) in scanning electron microscopy (SEM) studies on human erythrocytes induced shape changes at a 10µM concentration; b) in isolated unsealed human erythrocyte membranes (IUM) a concentration as low as 1µM induced sharp DPH fluorescence anisotropy decrease whereas increasing concentrations produced a monotonically decrease of DPH fluorescence lifetime at 37°C; c) X-ray diffraction studies showed that 200µM induced a complete structural perturbation of dimyristoylphosphatidylcholine (DMPC) bilayers whereas no significant effects were detected in dimyristoylphosphatidylethanolamine (DMPE) bilayers, classes of lipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively; d) fluorescence spectroscopy data showed that increasing concentrations of the complex interacted with the deep hydrophobic core of DMPC large unilamellar vesicles (LUV) at 18°C. All these experiments are consistent with the insertion of M4/HPßCD in the outer monolayer of the human erythrocyte membrane; thus, it can be considered a promising and novel antimalarial agent.