De novo identification and stability of the artemisinin pharmacophore: Studies of the reductive decomposition of deoxyartemisinins and deoxyarteethers and the implications for the mode of antimalarial action

Reactions of seco and carba analogues of artemisinin 1 and arteether 16 have been investigated using DFT (B3LYP/6-31+G∗ level). The data presented here show that O5 is favoured as a protonated site for 1 and its deoxy compounds, whereas protonation at O1 and O2 is unlikely. In contrast, O3 and O4 deoxy compounds of 16 can be protonated at O2, with subsequent scission of the C4-O2 bond, thereby prompting reaction with the antimalarial receptor by a Lewis acid mechanism. In all cases, addition of an electron leads to scission of the O1-O2 bond if present. The O4 deoxy compounds in this study display similar electron affinities to their respective parent compound, while O3 and O5 deoxy compounds show less negative values (about 6-8 kcal mol−1). Formation of the distonic radical anion, with the anion on O1 and the radical on O2, is slightly preferred in all our compounds, but only in the O3 deoxy compounds is this assignment definitive. The energy barrier to subsequent 1,5-intramolecular hydrogen abstraction to produce a carbon-centred radical is similar to that for the parent compounds. Calculations confirm that the generation and subsequent stability of both oxygen and carbon-centred radicals, which contributes to parasitidal action, is influenced most strongly by bioisosteric substitution of O3.