Experimental and theoretical charge density study of an antimalarial drug

Malaria, an infection caused by the Plasmodium Falciparum protozoa, is nowadays one of the most lethal parasitic disease. As the Plasmodium protozoon is becoming resistant to quinoline-based molecules, the development of new drugs and the understanding of the key chemical features for their activity and of their mechanism of action is of great importance. In this context, we carried out a thorough analysis on the antimalarial drug dihydroartemisinin (DHA, Figure 1), through the study of its experimental and theoretical charge density (CD) distributions.[1] The experimental CD has been obtained by a single-crystal X-ray diffraction experiment at T = 100 K on a Bruker SMART APEX II diffractometer equipped with a CCD area detector, while the corresponding theoretical CD has been derived through fully periodic single point DFT calculations at the experimental geometry. We have identified nucleophilic as well as electrophilic regions of the molecule by analyzing its electrostatic potential and investigated the crystal packing and the change in the CD distribution moving from the isolated molecule to the crystal. Several CD analysis tools, with special emphasis on the Quantum Theory of Atoms in Molecules (QTAIM) [2], have been adopted, with the aim of fully characterize the chemical nature of specific functional groups, such as the peroxide group and the polyether chain. We have also performed geometry optimizations on deprotonated and radical anion of DHA, the latter being the intermediate species in most of the proposed antimalarial modes of action of the drug. [1] G. Saleh, R. Soave, L. Lo Presti, R. Destro Chem. Eur. J. 2013, 19, 3490. [2] R. F. W. Bader Atoms in Molecules: A Quantum Theory Oxford University Press, Oxford, 1990.