Optimisation of the allylsilane approach to C-10 deoxo carba analogues of dihydroartemisinin: synthesis and in vitro antimalarial activity of new, metabolically stable C-10 analogues

An optimised protocol has been developed for the coupling of dihydroartemisinin benzoate with a range of aromatic allylsilanes to provide a number of new C-10 deoxo derivatives (11a-11g) in yields ranging from 70 to 94%. These compounds were up to ten times more potent than artemisinin in in vitro tests against the chloroquine resistant K1 strain of Plasmodium falciparum. Ferrous mediated degradation of these analogues produces as the main product, a dicarbonyl formate 12, which is not seen when the same reaction is carried out with artemisinin or artemether. This finding may indicate that analogues in this class have a subtly different "antimalarial" mechanism of action.