Ring opening of artemisinin (qinghaosu) and dihydroartemisinin and interception of the open hydroperoxides with Formation of N-oxides — a chemical model for antimalarial mode of action

Interaction of Artemisinins with Oxyhemoglobin Hb–FeII, Hb–FeII, CarboxyHb–FeII, Heme–FeII, and Carboxyheme FeII: Significance for Mode of Action and Implications for Therapy of Cerebral Malaria

“…[38] In the cases of artemisinin or DHA at least, this process may also be engendered by the formation of free hydroperoxide. [34,39,40] In contrast, it was reported by Robert, Meunier, and co-workers that under aqueous conditions in the presence of oxygen or CO, either oxyHb-Fe II or CO-Hb-Fe II are formed, but both systems in 9:1 H 2 O/DMSO are apparently destroyed by artemisinin to generate adducts otherwise obtained from free ferrous heme. [41] The artemisinin-Hb mixtures were diluted with water, and then treated with trifluoroacetic acid for submission to specific HPLC conditions which were stated to 'denature' the hemoglobin.…”

Highly Antimalaria‐Active Artemisinin Derivatives: Biological Activity Does Not Correlate with Chemical Reactivity

“…[14,18,40] Whilst many peroxides are susceptible to reductive cleavage by ferrous iron, [41] a large number also display at best feeble antimalarial activity, [36,42] and further, the Fe III formed by oxidation of Fe II by the peroxide (cf. Scheme 1) is capable of oxidizing the Ccentered radicals to carbocations.…”

“…Scheme 1) is capable of oxidizing the Ccentered radicals to carbocations. [40,43,44] Artemisinin derivatives do not inhibit but rather are potent inducers of Phase Imetabolizing P450 (CYP) enzymes, in which the heme hydroxylates the periphery of the molecule syn to the peroxide without interfering with it. [2] Further, the seco-C4 radical (Scheme 1) held to be produced in the reaction with ferrous heme clearly cannot be trapped by the l-cysteine (present work), or other thiols, [13] used to generate ferrous heme; clearly, if the C-centered seco-C4 is formed at all, it reacts exclusively with the proximate heme.…”

Revisão de literatura sobre o mecanismo de ação da artemisinina e dos endoperóxidos antimaláricos - parte II

“…Posner et al (1994) propuseram um mecanismo via espécies radicalares e por carbocátions, que explicariam a formação dos produtos encontrados. Estes compostos seriam fontes de hidroperóxidos, os quais fornecem espécies eletrofílicas, radicais hidróxidos ou radicais alcóxidos, que seriam capazes de hidroxilar biomoléculas ou abstrair átomos de hidrogênio delas, levando consequentemente à morte do parasita (Figura 12) (HAYNES et al, 1999;OLLIARO et al, 2001). Algumas observações podem ser feitas a respeito dessa hipótese.…”