Malaria is due to protozoa of the genus Plasmodium, which infect human red blood cells and digest the host hemoglobin. Degradation of the latter in the acidic food vacuole (pH ~ 5) releases free hematin (hydroxylated Fe protoporphyrin-IX, FePPIX(OH)), which is toxic to the parasite [1]. Therefore, Plasmodium deactivates hematin by promoting its crystallization into harmless pale yellow P1bar crystals of beta-hematin. 4-aminoquinoline drugs (AQ), such as chloroquine (CQ) and piperaquine (PQ), interfere with this detoxification process, either by coordinating free heme in solution [2], or by poisoning fastest-growing crystal faces of beta-hematin [3]. However, there is no general consensus on the structure of the AQ/heme complex [4], which depends on various chemical variables (aqueous/lipidic environment, pH). We here aim at quantitatively disclosing the chemical physics underlying the pharmacophoric features of CQ and PQ in the context of predicting which chemical modifications should be applied on the AQ scaffold to enhance the drug functionality against the biochemical resistance mechanism evolved by Plasmodium [5,6]. EXAFS spectroscopy in solution across the Fe Kalpha absorption edge (~ 7.1 keV) explored the first shell coordination geometry of iron in hematin, both in the presence and in the absence of AQ systems. Differences in the signal were related to the possible occurrence of a direct Fe–N coordinative bond involving the quinoline nitrogen atom, which might coexist with other possible (e.g. pi···pi stacked) adduct geometries [5] (Fig. 1). Quantum mechanical DFT calculations showed that an aliphatic tertiary NH+ amino group might also be a crucial part of the pharmacophore (Fig. 1), as it is able to set up strong charge-assisted hydrogen bonds with proprionate groups of hematin. This complies well with single-crystal X-ray diffraction outcomes on the CQ dihydrogen phosphate salt at 103 K[6], where H2PO4– ions form hydrogen-bonded pillars which strongly interact with positively charged chloroquine molecules. Comparison of the CQ crystal structure with those of various hydrated salts of PQ (NO3–, SO42–, H2PO4–), grown by advanced sol-gel methods, disclosed subtle analogies and differences in the non-covalent interaction networks of the two drugs, which are also related to their solubilities. [1] L. Kořený, M. Oborník, J. Lukeš, PLoS Pathog. 2013, 9(1), e1003088. [2] D.C. Warhurst J.C. Craig, K.S. Raheem, Biochem. Pharmacol. 2007, 73, 1910. [3] M.S.Walczak, K. Lawniczak-Jablonska, A. Wolska, A. Sienkiewicz, L. Suarez, A.J. Kosar, D.S. Bohle J. Phys. Chem. B 2011, 115, 1145. [4] J. Gildenhuys, T. Roex, T.J. Egan, K.A. De Villiers, J. Am. Chem. Soc. 2013, 135, 1037. [5] G. Macetti, S. Rizzato, F. Beghi, L. Silvestrini, L. Lo Presti, Physica Scripta 2016, 91, 023001. [6] G. Macetti, L. Loconte, S. Rizzato, C. Gatti, L. Lo Presti, Crystal Growth Des. 2016. 16, 6043.

On the interplay among non-covalent interactions and activity of 4-aminoquinoline antimalarials: a crystallographic and spectroscopic study / L. Lo Presti, S. Rizzato, P. Sacchi, G. Macetti, L. Loconte, F. Beghi, L. Silvestrini. ((Intervento presentato al 46. convegno Annual Meeting of the AIC tenutosi a Perugia nel 2017.

On the interplay among non-covalent interactions and activity of 4-aminoquinoline antimalarials: a crystallographic and spectroscopic study

L. Lo Presti
;
S. Rizzato
Secondo
;
G. Macetti;L. Loconte;F. Beghi
Penultimo
;
2017

Abstract

Malaria is due to protozoa of the genus Plasmodium, which infect human red blood cells and digest the host hemoglobin. Degradation of the latter in the acidic food vacuole (pH ~ 5) releases free hematin (hydroxylated Fe protoporphyrin-IX, FePPIX(OH)), which is toxic to the parasite [1]. Therefore, Plasmodium deactivates hematin by promoting its crystallization into harmless pale yellow P1bar crystals of beta-hematin. 4-aminoquinoline drugs (AQ), such as chloroquine (CQ) and piperaquine (PQ), interfere with this detoxification process, either by coordinating free heme in solution [2], or by poisoning fastest-growing crystal faces of beta-hematin [3]. However, there is no general consensus on the structure of the AQ/heme complex [4], which depends on various chemical variables (aqueous/lipidic environment, pH). We here aim at quantitatively disclosing the chemical physics underlying the pharmacophoric features of CQ and PQ in the context of predicting which chemical modifications should be applied on the AQ scaffold to enhance the drug functionality against the biochemical resistance mechanism evolved by Plasmodium [5,6]. EXAFS spectroscopy in solution across the Fe Kalpha absorption edge (~ 7.1 keV) explored the first shell coordination geometry of iron in hematin, both in the presence and in the absence of AQ systems. Differences in the signal were related to the possible occurrence of a direct Fe–N coordinative bond involving the quinoline nitrogen atom, which might coexist with other possible (e.g. pi···pi stacked) adduct geometries [5] (Fig. 1). Quantum mechanical DFT calculations showed that an aliphatic tertiary NH+ amino group might also be a crucial part of the pharmacophore (Fig. 1), as it is able to set up strong charge-assisted hydrogen bonds with proprionate groups of hematin. This complies well with single-crystal X-ray diffraction outcomes on the CQ dihydrogen phosphate salt at 103 K[6], where H2PO4– ions form hydrogen-bonded pillars which strongly interact with positively charged chloroquine molecules. Comparison of the CQ crystal structure with those of various hydrated salts of PQ (NO3–, SO42–, H2PO4–), grown by advanced sol-gel methods, disclosed subtle analogies and differences in the non-covalent interaction networks of the two drugs, which are also related to their solubilities. [1] L. Kořený, M. Oborník, J. Lukeš, PLoS Pathog. 2013, 9(1), e1003088. [2] D.C. Warhurst J.C. Craig, K.S. Raheem, Biochem. Pharmacol. 2007, 73, 1910. [3] M.S.Walczak, K. Lawniczak-Jablonska, A. Wolska, A. Sienkiewicz, L. Suarez, A.J. Kosar, D.S. Bohle J. Phys. Chem. B 2011, 115, 1145. [4] J. Gildenhuys, T. Roex, T.J. Egan, K.A. De Villiers, J. Am. Chem. Soc. 2013, 135, 1037. [5] G. Macetti, S. Rizzato, F. Beghi, L. Silvestrini, L. Lo Presti, Physica Scripta 2016, 91, 023001. [6] G. Macetti, L. Loconte, S. Rizzato, C. Gatti, L. Lo Presti, Crystal Growth Des. 2016. 16, 6043.
28-giu-2017
chloroquine; piperaquine; antimalarials; X-ray diffraction; EXAFS; DFT calculations
Settore CHIM/02 - Chimica Fisica
On the interplay among non-covalent interactions and activity of 4-aminoquinoline antimalarials: a crystallographic and spectroscopic study / L. Lo Presti, S. Rizzato, P. Sacchi, G. Macetti, L. Loconte, F. Beghi, L. Silvestrini. ((Intervento presentato al 46. convegno Annual Meeting of the AIC tenutosi a Perugia nel 2017.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/516539
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