title: Stereolability of dihydroartemisinin, an antimalarial drug: a comprehensive kinetic investigation. Part 2.
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 NaBH(4) reduction of artemisinin and contains a stereochemically labile center at C-10, which provided two lactol hemiacetal interconverting epimers, namely 1α and 1β. In the solid state, the drug consists exclusively of the β-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 α/β equilibration. To this purpose, free energy activation barriers (ΔG(‡)) 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 ΔG(‡) 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.
authors.affiliation: Analytical Development, R&D Department, Sigma-Tau S.p.A., Via Pontina km 30.400, 00040 Pomezia, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.forename: Ilaria
authors.initials: I
authors.lastname: D'Acquarica
authors.forename: Patrizia
authors.initials: P
authors.lastname: Simone
authors.forename: Marta
authors.initials: M
authors.lastname: Di Iorio
authors.forename: Michela
authors.initials: M
authors.lastname: Di Mattia
authors.forename: Francesco
authors.initials: F
authors.lastname: Gasparrini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giorgi
authors.forename: Andrea
authors.initials: A
authors.lastname: Mazzanti
authors.forename: Marco
authors.initials: M
authors.lastname: Pierini
authors.forename: Marco
authors.initials: M
authors.lastname: Quaglia
authors.forename: Claudio
authors.initials: C
authors.lastname: Villani
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry*; D002384:Catalysis; D006865:Hydrogenation; D007700:Kinetics; D015394:Molecular Structure; D009994:Osmolar Concentration; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D037621:Artemisinins