Structural analysis of the anti-malaria active agent chloroquine under physiological conditions.
UV resonance Raman spectroscopy was applied for a selective enhancement of molecular vibrations of the important antimalarial chloroquine under physiological conditions. The resonance Raman spectra of chloroquine at pH values resembling the pH value of blood and the pH value of the acid food vacuole of plasmodium can unambiguously be distinguished via Raman resonantly enhanced mode at 721 cm(-1). These vibrations are assigned to -(CH2)n- rocking mode of the chloroquine side chain and are expected to be influenced by protonation of chloroquine. Furthermore, vibrations belonging to the quinoline ring (important for pi-pi-interactions to hemozoin) are resonantly enhanced and can be studied selectively. A convincing mode assignment was performed by means of DFT calculations. These calculations proved that the different protonation states of chloroquine remarkably influence various vibrational modes, the molecular geometry, and molecular orbitals. The presented results are of significant relevance for a Raman spectroscopical localization of chloroquine inside the acid food vacuole of plasmodium, the study of pi-pi-interactions of chloroquine to the biological target molecules hematin and hemozoin and the protonation state of chloroquine during this docking process. The protonation of the weak base chloroquine is considered to be crucial for an accumulation inside the acid food vacuole of plasmodium and an object for resistances against this drug.
Frosch
Torsten
T
Institut für Physikalische Chemie, Friedrich-Schiller-Universität Jena, Helmholtzweg 4, D-07743 Jena, Germany.
Schmitt
Michael
M
Bringmann
Gerhard
G
Kiefer
Wolfgang
W
Popp
Jürgen
J
D000465:Algorithms; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D002738:Chloroquine / Q000737:chemistry* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D010961:Plasmodium / Q000502:physiology*; D011522:Protons; D013059:Spectrum Analysis, Raman; D014617:Vacuoles / Q000737:chemistry / Q000378:metabolism
D000962:Antimalarials; D011522:Protons; D002738:Chloroquine