A nuclear magnetic resonance study of the interactions of the antimalarials chloroquine, quinacrine, quinine and mefloquine with dipalmitoylphosphatidylcholine bilayers

Abstract

The interaction of four cationic amphiphilic antimalarials (chloroquine, quinacrine, mefloquine and quinine) with model dipalmitoylphosphatidylcholine (DPPC) bilayer membranes was studied using 2H- and 31P-nuclear magnetic resonance (NMR). The results showed no significant perturbation of lipid bilayer structure by the presence of chloroquine up to a molar ratio of 1:2 of drug to lipid. Addition of quinacrine to DPPC at the same molar ratio resulted in a 2.5°C decrease in the gel to liquid crystalline phase transition temperature ( T c) of the lipids, with only a small perturbation of the order parameters of the lipid side chains. 31P-NMR spectra of quinacrine-DPPC mixtures indicated a quinacrine-induced change of head group conformation of DPPC above the T c. These findings are consistent with quinacrine interacting only with the surface of DPPC bilayers. In contrast, both mefloquine and quinine exhibited stronger interactions with DPPC, decreasing the T c of the lipids by 10°C and 9°C, respectively, and causing significant disordering of the lipid side chains. The basic bilayer structure of DPPC was, however, maintained, even at the highest molar ratio 1:2 of drug to lipid. Such behavior is consistent with penetration of both mefloquine and quinine into the interior of the bilayers. This ability of mefloquine and quinine, but not chloroquine and quinacrine, to intercalate into lipid bilayers correlates with their lower pK a values, which ensures that at physiological pH significant amounts of mefloquine or quinine remain in their uncharged lipophilic form.