What are molecular effects of co-administering vitamin C with artemisinin-type antimalarials? A model mass spectrometry and quantum chemical study

In this study the electrospray ionization mass spectrometry (ESI MS) and quantum chemical modeling methods are employed to examine the interactions of molecules of artemisinin-type drugs and of ascorbic acid (ASC). These biologically significant interactions are relevant to antimalarial therapy, in particular, when artemisinin agents are co-administrated with supporting vitamin/antioxidant preparations or could be affiliated with the patient's food. The formation of stable noncovalent complexes of the artemisinin-type drugs (artemisinin, dihydroartemisinin, α-artemether, and β-arteether) with ascorbic acid molecules in a polar solvent, such as methanol, is revealed by the ESI MS probing of binary systems containing an antimalarial drug and ASC in the 1:1 molar ratio. Also, a peak corresponding to noncovalent [ASC•DPPC•Na]⁺ cationized complexes is identified in the spectrum of the mixture of ASC and dipalmitoylphosphatidylcholine (DPPC, membrane phospholipid) with the 1:5 molar ratio. Next, the ternary system containing dihydroartemisinin (DHAn; the assumed active metabolite of the artemisinin-type drugs in the human organism), ASC, and DPPC in the 1:1:5 molar ratio is examined. The study reveals a competition between the antimalarial agent and ASC for binding with the DPPC molecules. The existence of the competition is supported by the observation of peaks with similar intensities corresponding to the noncovalent DHAn•DPPC and ASC•DPPC complexes in the mass spectra. An evidence for the complexation between the antimalarial drug and ASC is also found in the spectra of triple model systems studied. To elucidate the structural and energetic characteristics of the noncovalent complexes observed in the ESI MS experiments, model ab initio calculations of DHAn and ASC complexes and clusters of the drug molecules with the polar phosphatidylcholine head of DPPC are performed using the DFT/B3LYP/aug-cc-pVDZ approach. The results of the model study show the possibility of the noncovalent complexation and of the modulation of the biological activity of artemisin-type agents and of the ascorbic acid when they are co-administered in the therapy.