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The enthalpies of intramolecular reactions of alkoxy and peroxy radicals formed from polyatomic artemisinin hydroperoxides and of their bimolecular reactions with C-H, S-H, and O-H bonds of biological substrates were calculated. The activation energies and rate constants of these reactions were calculated using the intersecting parabolas method. The decomposition of artemisinin hydroperoxides can initiate the cascade of intramolecular oxida tion reactions involving radicals R • , RO • , HO • , HO 2 • , and RO 2 • . The main sequences of transformation of these radicals were established. The oxidative destruction of the artemisinin peroxy derivatives generates radicals RO 2 • , HO • , and HO 2 • in an amount of 4.5 radicals per peroxide derivative molecule on the average. The kinetic scheme of oxidative transformations of the hydroperoxide with four OOH groups and radicals formed from it was constructed using this radical as an example.Presently, artemisinin is considered the most efficient drug for malaria treatment. 1-6 Artemisinin is sesquiter penic lacton with the peroxide bridge. The peroxide frag ment is key in the medicinal effect of artemisinin. The medicinal effect is based on free radical generation via the reaction of the peroxide group with iron ions Fe II /Fe III , and the radicals formed escape into the bulk and react with enzymes of parasites deactivating them. 3-6 Several kinetic schemes that help to explain the medicinal effect of artemisinin were proposed. Un fortunately, all these schemes are qualitative, including a number of parallel steps, none of which can be preferred.In our previous studies 7,8 the problems of competition of intramolecular and bimolecular reactions of alkoxy and alkyl radicals generated from artemisinin were considered at the quantitative level. It was found 7,8 that the alkoxy radical formed upon the cleavage of the peroxide bridge react very rapidly in intramolecular reactions with hydro gen atom transfer and decyclization, transforming into the C centered radicals. Thus, the free valence is retained on artemisinin as its C centered radicals. Under aerobic con ditions, these radicals rapidly add oxygen and transform into peroxy radicals. The latter are involved in the in tramolecular reaction with hydrogen transfer and rapidly transform into alkyl radicals, which undergo further oxi dation. As a result, artemisinin is oxidized via the intramo lecular chain mechanism to form polyatomic hydroperox ides. This results in the situation where, under aerobic conditions, artemisinin can transform into the polyfunc tional initiator with several hydroperoxy groups. 9,10 Each of the hydroxyperoxide groups formed reacts with the Fe II /Fe III chelates and generates alkoxy radicals via the reactions 11-17 ROOH + Fe 2+ → RO • + FeOH 2+ , ROOH + Fe 3+ → FeO 2+ + H + + RO • ,The alkoxy radicals, in turn, undergo various intramolecu lar transformations. In the present study, we attempted to solve the problem of quantitative kinetic analysis of the further transformations of the radicals ...

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The competition between intramolecular and bimolecular reactions of alkoxyl radicals formed from artemisinin was theoretically analyzed. The enthalpies of these reactions were calculated. The activation energies and rate constants of reactions of intramolecular hydrogen atom transfer, decyclization, and decomposition of alkoxyl radicals of artemisinin and several its derivatives, as well as the activation energies and rate constants of reactions of these radicals with the C-H, S-H, and O-H bonds in biological substrates and their analogs were calcu lated by the intersecting parabolas method The fastest reactions of artemisinin alkoxyl radicals were identified. The full kinetic scheme of transformation of these radicals was proposed. Artemisinin radicals with the free valence on the carbon atom are predominantly formed due to the transformation of the artemisininoxyl radicals.

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