Thermodynamic and kinetic investigation of monoketo-aldehyde-peroxyhemiacetal (MKA), a stereolabile degradation product of dihydroartemisinin

Abstract

Monoketo-aldehyde-peroxyhemiacetal (MKA) is a dihydroartemisinin (DHA) derivative, still endowed with significant (on a ng-scale) in vitro antimalarial activity but with lower neurotoxicity than that displayed by its precursor. Through literature, it is known that MKA may be formed under essentially physiological conditions (organic-aqueous environments buffered at pH 7.4) or prepared by the acid decomposition of DHA in water to afford yields that, however, do not reach 50%. We report here a more convenient procedure of preparation at room temperature. Owing to its hemiacetal nature, MKA was expected to occur in solution as a mixture of α and β epimers. In the present study this, in fact, has been demonstrated through dynamic chromatography measurements, which allowed to highlight that for MKA, the β ⇆ α equilibration is about 3 times slower than that for DHA. In consideration of the propensity of MKA to originate from DHA in mild both acid and base conditions, its formation appears possible during the stages of production and storage of its parent drug and also widely expected in physiological environment. Thus, the improvement of knowledge about this product of DHA degradation could have useful impact in the rational development of new methods for the analysis of purity of DHA in its pharmaceutical formulations, as well as in considering the biological activity expressible in vivo by the mixture of α and β epimers of MKA, whose equilibrium composition is a function of the met specific biological environment. In this context, we elucidate the stereo-structure of the epimers of MKA through NMR measurements and performed a comprehensive thermodynamic investigation of the process that governs the related interconversion through linear solvation energy relationships (LSER) approach. A convincing rationalization of the whole findings has then been achieved through support from molecular modeling calculations.