Artemisinin or qinghaosu has now largely given way to the more potent dihydroartemisinin (DHA, 1) and its derivatives in the treatment of drug-resistant malaria, in combination with other classical antimalarial drugs. DHA is obtained by NaBH4 reduction of artemisinin and contains a stereochemically labile center at C-10, which provided two lactol hemiacetal interconverting epimers, namely 1 alpha and 1 beta. In the solid state, the drug consists exclusively of the beta-epimer; however, upon dissolution, the two epimers equilibrate, reaching different solvent-dependent ratios with different rates. Such equilibration also occurs in vivo, irrespective of the isomeric purity at which the drug would have been administered. The aim of this study was then to achieve an in-depth understanding of the kinetic features of the alpha/beta equilibration. To this purpose, free energy activation barriers (Delta G(double dagger)) of the interconversion were determined as a function of both general and specific acid and base catalysts, ionic strength, and temperature in different solvents by dynamic HPLC (DHPLC). In hydro-organic media, the dependence of Delta G(double dagger) on temperature led to the evaluation of the related enthalpic and entropic contributions. Theoretical calculations suggested that the rate-determining step of the interconversion is not the ring-opening of the cyclic hemiacetal but the previous reversible deprotonation of the individual epimers (base-catalyzed mechanism). The whole findings may contribute to shed some light on the mechanism of action and/or bioavailability of the drug at the molecular level.

Stereolability of Dihydroartemisinin, an Antimalarial Drug: A Comprehensive Kinetic Investigation. Part 2 / Walter, Cabri; D'Acquarica, Ilaria; Simone, Patrizia; M., Di Iorio; M., Di Mattia; Gasparrini, Francesco; Fabrizio, Giorgi; Andrea, Mazzanti; Pierini, Marco; Marco, Quaglia; Villani, Claudio. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 0022-3263. - STAMPA. - 76:12(2011), pp. 4831-4840. [10.1021/jo102392p]

Stereolability of Dihydroartemisinin, an Antimalarial Drug: A Comprehensive Kinetic Investigation. Part 2

D'ACQUARICA, Ilaria;SIMONE, PATRIZIA;GASPARRINI, Francesco;PIERINI, MARCO;VILLANI, Claudio
2011

Abstract

Artemisinin or qinghaosu has now largely given way to the more potent dihydroartemisinin (DHA, 1) and its derivatives in the treatment of drug-resistant malaria, in combination with other classical antimalarial drugs. DHA is obtained by NaBH4 reduction of artemisinin and contains a stereochemically labile center at C-10, which provided two lactol hemiacetal interconverting epimers, namely 1 alpha and 1 beta. In the solid state, the drug consists exclusively of the beta-epimer; however, upon dissolution, the two epimers equilibrate, reaching different solvent-dependent ratios with different rates. Such equilibration also occurs in vivo, irrespective of the isomeric purity at which the drug would have been administered. The aim of this study was then to achieve an in-depth understanding of the kinetic features of the alpha/beta equilibration. To this purpose, free energy activation barriers (Delta G(double dagger)) of the interconversion were determined as a function of both general and specific acid and base catalysts, ionic strength, and temperature in different solvents by dynamic HPLC (DHPLC). In hydro-organic media, the dependence of Delta G(double dagger) on temperature led to the evaluation of the related enthalpic and entropic contributions. Theoretical calculations suggested that the rate-determining step of the interconversion is not the ring-opening of the cyclic hemiacetal but the previous reversible deprotonation of the individual epimers (base-catalyzed mechanism). The whole findings may contribute to shed some light on the mechanism of action and/or bioavailability of the drug at the molecular level.
2011
artesunic acid; complexation gas-chromatography; dynamic hplc; electrochemical detection; human plasma; ionizable compounds; mass-spectrometry; metabolite dihydroartemisinin; performance liquid-chromatography; water mobile phases
01 Pubblicazione su rivista::01a Articolo in rivista
Stereolability of Dihydroartemisinin, an Antimalarial Drug: A Comprehensive Kinetic Investigation. Part 2 / Walter, Cabri; D'Acquarica, Ilaria; Simone, Patrizia; M., Di Iorio; M., Di Mattia; Gasparrini, Francesco; Fabrizio, Giorgi; Andrea, Mazzanti; Pierini, Marco; Marco, Quaglia; Villani, Claudio. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 0022-3263. - STAMPA. - 76:12(2011), pp. 4831-4840. [10.1021/jo102392p]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/404916
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