An important role of intramolecular free radical reactions in antimalarial activity of artemisinin and its analogs

Abstract

The kinetic schemes of intramolecular reactions of five analogs of artemisinin were built. The method of intersecting parabolas was used for the calculation of activation energies and rate constants of each elementary step of these schemes. The competition between monomolecular and bimolecular free radicals was taken into account. It was evidenced that the intramolecular oxidation of these compounds proceeds as a cascade of consecutive free radical reactions with the formation of hydroperoxide groups. The latter decompose via reactions with the Fe(II) complexes generating free radicals. Among the radicals formed, the hydroxyl radical was proved to play the key role. A correlation between the yield of hydroxyl radicals n(OH) and antimalarial activity of compounds (IC(50)) was observed. The dependence of index IC(50) on n(OH) is linear in the logarithmic coordinates: ln[IC(50)(Artemisinin)/IC(50)(Compound)] = -14.10 + 3.85 ×n(OH). The proposed scheme explains and demonstrates a strong dependence of the antimalarial effectiveness of a drug on the chemical structure.

Mechanisms of the pH- and Oxygen-Dependent Oxidation Activities of Artesunate

“…Iron(II) is known to generate oxidizing substances, such as ferryl species or hydroxyl radical then is oxidized to the iron(III) form. 34) The results in Figs. 3 and 4 show that when iron was incubated with an excess amount of artesunate, iron(III) was reduced to iron(II), and thereafter oxidizing species were continuously generated by autoxidation.…”

Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

“…Artemisinin is believed to increase the oxidative stress in parasitized erythrocytes by production of hydroxyl radical 16) and the drug potency is reduced by antioxidants such as Nacetylcysteine. 17) Antioxidants such as vitamin E promote the growth of malaria parasites, 18) and vitamin E deficiency increases the antimalarial activity of artemisinin in vivo.…”

Hydroxyl Radical as Key Intermediate in Curing Action of Artemisinin and its Analogs

“…The latter generates a line of free radicals via the reaction with Fe(II), which results in the death of the parasite. It was evidenced in our latest kinetic studies that namely hydroxyl radical, produced in some reactions of 1 oxidation plays the key role in curing action of 1 and its peroxide analogs [28][29][30][31]. This paper summarizes the results received during the latest four years on kinetic analysis of reactions induced by 1 and its derivatives.…”

“…One can suppose that the more free radicals are produced by one molecule of drug curing by free radical generation, the more will be activity of antimalarial drug. A kinetic scheme of oxidation was built up for a line of 1 derivatives with the following structures [28][29][30] The total yield of free radicals n ΣR was compared with values of relative indexes IC 50 ( Figure 2) [28][29][30][31].…”

“…Comparison of the antimalarial activity of compound 1 and its analogs (2−13)[35][36][37] with the number of hydroxyl radicals n OH , which are formed due to their intramolecular oxidation[28][29][30][31]. (i)IC 50 (1)/M(1)IC 50 (i) = 1 + 0.27(n OH (i) − 3.17)…”