Molecular Interactions Identified by Two-Dimensional Analysis-Detailed Insight into the Molecular Interactions of the Antimalarial Artesunate with the Target Structure β-Hematin by Means of 2D Raman Correlation Spectroscopy

A thorough understandingof the interaction of endoperoxide antimalarial agents with theirbiological target structures is of utmost importance for the tailoreddesign of future efficient antimalarials. Detailed insights into molecularinteractions between artesunate and & beta;-hematin were derived witha combination of resonance Raman spectroscopy, two-dimensional correlationanalysis, and density functional theory calculations. Resonance Ramanspectroscopy with three distinct laser wavelengths enabled the specificexcitation of different chromophore parts of & beta;-hematin. Theresonance Raman spectra of the artesunate-& beta;-hematin complexeswere thoroughly analyzed with the help of high-resolution and highlysensitive two-dimensional correlation spectroscopy. Spectral changesin the peak properties were found with increasing artesunate concentration.Changes in the low-frequency, morphology-sensitive Raman bands indicateda loss in crystallinity of the drug-target complexes. Differencesin the high-wavenumber region were assigned to increased distortionsof the planarity of the structure of the target molecule due to theappearance of various coexisting alkylation species. Evidence forthe appearance of high-valent ferryl-oxo species could be observedwith the help of differences in the peak properties of oxidation-statesensitive Raman modes. To support those findings, the relaxed ground-statestructures of ten possible covalent mono- and di-meso(C-m)-alkylated hematin-dihydroartemisinyl complexes werecalculated using density functional theory. A very good agreementwith the experimental peak properties was achieved, and the out-of-planedisplacements along the lowest-frequency normal coordinates were investigatedby normal coordinate structural decomposition analysis. The strongestchanges in all data were observed in vibrations with a high participationof C-m-parts of & beta;-hematin.