Malaria is caused by the Plasmodium protozoa, which infect human through the bite of Anopheles mosquitoes. After entering the erythrocytes, Plasmodium digests the hemoglobin, releasing free toxic heme (Fe(III)-protoporphyrin-IX) into its digestive vacuole (DV). The dimerization of the free heme and its subsequent sequestration into triclinic hemozoin crystals is an effective way for the parasite to attain its detoxification. 4-Aminoquinoline (4-AQ) type drugs are believed to interfere with this process, either by hampering the dimerization of the heme in solution or by inhibiting the growth of the hemozoin crystals.[1] Piperaquine (PQ) is a 4-AQ drug, nowadays used as a phosphate salt in expensive ACTs (Artemisinin Combined Therapies) for the treatment of malaria in areas where drug-resistant parasites are present.[2] The understanding of the intermolecular interactions that are involved in the molecular action of these drugs is essential for the design of novel, effective and cheap alternatives. Purposes of the present work are (i) to study the self-recognition of PQ in the solid state, to identify the leading non-covalent interactions that determine how the charged drug recognizes its environment, and (ii) to correlate structural and energetic aspects of the crystal packing with the measured solubility of PQ crystals. To these ends, we report for the first time the structures, together with the corresponding crystallization methods from aqueous solvents, of various PQ4+ salts with H2PO4-, NO3–, HSO4–, Br– and SO3CF3- anions. The crystals were prepared starting from neutral PQ, that was dissolved in concentrated solutions of the corresponding inorganic acid. Crystals were then grown by slow evaporation of solvent. The structures were solved by single-crystal X-ray diffraction in the 120 K – RT T range. The electrostatic nature of the dominant interactions was confirmed with the use of A. Gavezzotti’s AA-CLP method,[3] while the main stabilizing contacts were highlighted using Hirshfeld surface fingerprint plots.[4] It turns out that the structure-determining interactions are (i) charge-assisted hydrogen bonds (CAHBs) among the charged N-H donors and the negatively charged counterions and, possibly, (ii) π-π interactions between PQ quinoline rings. Similar interactions were also found to be relevant in the molecular recognition pattern of Chloroquine phosphate,[5,6] another important 4-AQ class drug, and can therefore play an important role in the heme-drug recognition process. Structure-solubility relations in the PQ salts were explored in the 293–323 K T range by means of UV-Vis Spectroscopy in water. Correlations with DFT estimates of the lattice energies by solid-state quantum mechanical calculations were rationalized in terms of relevant packing features and discussed in the context of investigating the possible utility of the newly synthesized crystal structures in practical pharmaceutical formulations. Acknowledgments: This research was funded by the Development Plan of Athenaeum (Università degli Studi di Milano) – Line 2, Action B, project NOVAQ (Understanding structure-function relationships in 4-aminoquinoline drugs: an experimental and theoreti-cal route toward novel antimalarials), nº PSR2015-1716FDEMA_08 1 Olafson et al., Proc. Natl. Acad. Sci. 2017, 114(29), 7531 2 Davis et al., Drugs 2005, 65(1), 75 3 Gavezzotti, A. New J. Chem. 2011, 35(7), 1360 4 McKinnon et al., Acta Crystallographica Section B: Structural Science. 2004, 60, 627 5 Macetti et al., Cryst. Growth Des. 2016, 16 (10), 6043 6 Macetti et al., Phys. Scr. 2016, 91 (2), 23001

Correlations among solubility and crystal structure: a crystallographic and spectroscopic study of the antimalarial drug piperaquine / P. Sacchi, G. Macetti, S. Rizzato, L. Loconte, F. Beghi, L. LO PRESTI. ((Intervento presentato al convegno Italian Crystal Growth tenutosi a Milano nel 2017.

Correlations among solubility and crystal structure: a crystallographic and spectroscopic study of the antimalarial drug piperaquine

G. Macetti;S. Rizzato;L. Loconte;F. Beghi;L. LO PRESTI
2017-11-20

Abstract

Malaria is caused by the Plasmodium protozoa, which infect human through the bite of Anopheles mosquitoes. After entering the erythrocytes, Plasmodium digests the hemoglobin, releasing free toxic heme (Fe(III)-protoporphyrin-IX) into its digestive vacuole (DV). The dimerization of the free heme and its subsequent sequestration into triclinic hemozoin crystals is an effective way for the parasite to attain its detoxification. 4-Aminoquinoline (4-AQ) type drugs are believed to interfere with this process, either by hampering the dimerization of the heme in solution or by inhibiting the growth of the hemozoin crystals.[1] Piperaquine (PQ) is a 4-AQ drug, nowadays used as a phosphate salt in expensive ACTs (Artemisinin Combined Therapies) for the treatment of malaria in areas where drug-resistant parasites are present.[2] The understanding of the intermolecular interactions that are involved in the molecular action of these drugs is essential for the design of novel, effective and cheap alternatives. Purposes of the present work are (i) to study the self-recognition of PQ in the solid state, to identify the leading non-covalent interactions that determine how the charged drug recognizes its environment, and (ii) to correlate structural and energetic aspects of the crystal packing with the measured solubility of PQ crystals. To these ends, we report for the first time the structures, together with the corresponding crystallization methods from aqueous solvents, of various PQ4+ salts with H2PO4-, NO3–, HSO4–, Br– and SO3CF3- anions. The crystals were prepared starting from neutral PQ, that was dissolved in concentrated solutions of the corresponding inorganic acid. Crystals were then grown by slow evaporation of solvent. The structures were solved by single-crystal X-ray diffraction in the 120 K – RT T range. The electrostatic nature of the dominant interactions was confirmed with the use of A. Gavezzotti’s AA-CLP method,[3] while the main stabilizing contacts were highlighted using Hirshfeld surface fingerprint plots.[4] It turns out that the structure-determining interactions are (i) charge-assisted hydrogen bonds (CAHBs) among the charged N-H donors and the negatively charged counterions and, possibly, (ii) π-π interactions between PQ quinoline rings. Similar interactions were also found to be relevant in the molecular recognition pattern of Chloroquine phosphate,[5,6] another important 4-AQ class drug, and can therefore play an important role in the heme-drug recognition process. Structure-solubility relations in the PQ salts were explored in the 293–323 K T range by means of UV-Vis Spectroscopy in water. Correlations with DFT estimates of the lattice energies by solid-state quantum mechanical calculations were rationalized in terms of relevant packing features and discussed in the context of investigating the possible utility of the newly synthesized crystal structures in practical pharmaceutical formulations. Acknowledgments: This research was funded by the Development Plan of Athenaeum (Università degli Studi di Milano) – Line 2, Action B, project NOVAQ (Understanding structure-function relationships in 4-aminoquinoline drugs: an experimental and theoreti-cal route toward novel antimalarials), nº PSR2015-1716FDEMA_08 1 Olafson et al., Proc. Natl. Acad. Sci. 2017, 114(29), 7531 2 Davis et al., Drugs 2005, 65(1), 75 3 Gavezzotti, A. New J. Chem. 2011, 35(7), 1360 4 McKinnon et al., Acta Crystallographica Section B: Structural Science. 2004, 60, 627 5 Macetti et al., Cryst. Growth Des. 2016, 16 (10), 6043 6 Macetti et al., Phys. Scr. 2016, 91 (2), 23001
Malaria; 4-Aminoquinoline drugs; solubility; UV-visible spectroscopy; X-ray diffraction; crystal structure
Settore CHIM/02 - Chimica Fisica
Settore CHIM/03 - Chimica Generale e Inorganica
Correlations among solubility and crystal structure: a crystallographic and spectroscopic study of the antimalarial drug piperaquine / P. Sacchi, G. Macetti, S. Rizzato, L. Loconte, F. Beghi, L. LO PRESTI. ((Intervento presentato al convegno Italian Crystal Growth tenutosi a Milano nel 2017.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/532830
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