Primaquine (PQ) is a potent therapeutic agent used in the treatment of
malaria and its mechanism of action still lacks a more detailed understanding at a molecular level. In this context, we used differential scanning calorimetry (DSC), pressure perturbation calorimetry (PPC), and electron spin resonance (ESR) to investigate the effects of PQ on the
lipid phase transition, acyl chain dynamics, and on volumetric properties of
lipid model membranes. DSC thermograms revealed that PQ stabilizes the fluid phase of the
lipid model membranes and interacts mainly with the
lipid headgroups. This result was revealed by the great effect on the pretransition of
phosphatidylcholines and the destabilization of the inverted hexagonal phase of a
phosphatidylethanolamine bilayer. Spin probes located at different positions along the
lipid chain were used to monitor different membrane regions. ESR results indicated that PQ is effective in changing the acyl chain ordering and dynamics of the whole chain of
dimyristoylphosphatidylcholine (
DMPC)
phospholipid in the rippled gel phase. The combined ESR and PPC results revealed that the slight
DMPC volume changes at the main phase transition induced by the presence of PQ is probably due to a less dense
lipid gel phase. At physiological pH, the cationic amphiphilic PQ strongly interacts with the
lipid headgroup region of the bilayers, causing considerable disorganization in the hydrophobic core. These results shed light on the molecular mechanism of
primaquine-
lipid interaction, which may be useful in the understanding of the complex mechanism of action and/or the adverse effects of this
antimalarial drug.