Investigations on the Novel Antimalarial Ferroquine in Biomimetic Solutions Using Deep UV Resonance Raman Spectroscopy and Density Functional Theory

Deep ultraviolet (DUV) resonance Raman experiments are performed, investigating the novel, promising antimalarial ferroquine (FQ). Two buffered aqueous solutions with pH values of 5.13 and 7.00 are used, simulating the acidic and neutral conditions inside a parasite's digestive vacuole and cytosol, respectively. To imitate the different polarities of the membranes and interior, the buffer's 1,4-dioxane content was increased. These experimental conditions should mimic the transport of the drug inside malaria-infected erythrocytes through parasitophorous membranes. Supporting density functional theory (DFT) calculations on the drug's microspeciation were performed, which could be nicely assigned to shifts in the peak positions of resonantly enhanced high-wavenumber Raman signals at lambda exc = 257 nm. FQ is fully protonated in polar mixtures like the host interior and the parasite's cytoplasm or digestive vacuole (DV) and is only present as a free base in nonpolar ones, such as the host's and parasitophorous membranes. Additionally, the limit of detection (LoD) of FQ at vacuolic pH values was determined using DUV excitation wavelengths at 244 and 257 nm. By applying the resonant laser line at lambda exc = 257 nm, a minimal FQ concentration of 3.1 mu M was detected, whereas the pre-resonant excitation wavelength 244 nm provides an LoD of 6.9 mu M. These values were all up to one order of magnitude lower than the concentration found for the food vacuole of a parasitized erythrocyte.

Automated summary

Deep ultraviolet resonance Raman experiments were conducted to investigate the antimalarial drug FQ. The drug's behavior in different pH environments and membrane polarities was simulated using buffered aqueous solutions. Density functional theory calculations were performed to analyze the drug's microspeciation and shifts in Raman signals. The study found that FQ exists in different forms in polar and nonpolar environments and determined the limit of detection at different pH values.