Understanding self-recognition in the antimalarial drug chloroquine: an experimental and theoretical charge density study

Malaria is the topmost world parasitic disease, with hundred of thousand deaths for year, most of which drug. In this context, the present work focuses on the experimental and theoretical characterization of chemical bonds and intermolecular interactions in crystalline CQ [1]. Chloroquine diphosphate salt was crystallized by various methods, including sol-gel techniques. Single-crystal X-Ray data collections were performed among room temperature (RT) and 100 K, using a Mo Ka source. CQ is a di-cation with protonated basic functions on quinolone. In the solid-state, complex patterns of hydrogen bonds (HBs) involving both the phosphate groups and co-crystallized water molecules are set up. Phosphate ions form infinite chains parallel to the monoclinic b axis, while CQ molecules keep their fused ring system orthogonal to the chains (see the Figure), setting in the free space among them through allegedly strong N–H···O HBs. The role of the two water molecules is less clear, even though they should help to coordinate phosphate ions. Even at 100 K, the X-ray data were not able to unequivocally determine the exact position of the H atoms. We therefore complemented the X-ray model by solid-state DFT simulations, but at least one water hydrogen has no obvious close acceptors and some kind of disorder cannot be excluded. On the basis of the solid-state DFT model, we applied the Hansen-Coppens multipolar approach [2] to study the experimental charge density in CQ diphosphate. The effect of the crystal field on the molecular conformation and the self-recognition energetics were investigated by both topological and quantum mechanical approaches. The importance of different intermolecular interaction patterns in setting up a stable crystal field is discussed. Acknowledgments: G. Macetti gratefully acknowledges travel support by AIC (Italian Crystallographic Association). This work has been supported by Unimi Development Plan – Line B1 and CINECA – ISCRA C (QUADRUG). [1] Karle et al. Acta Crystallogr . 1988, C44, 1605. [2] Hansen et al. Acta Crystallogr. 1978, A34, 909