Antimalarial artemisinin and its semisynthetic derivatives

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Resistance against Artemisinin (ART) and its semisynthetic derivatives, Artemether and Artesunate, is arising due to the K13 gene mutation in the malarial strain, plasmodium falciparum. ART, obtained from the chinese herb Artemisia annua, is very potent in its natural form. However the mechanism of action is undetermined. Proposed mechanisms involve cleavage of the endoperoxide bridge by heme or a source of iron(II), forming oxyradicals that can alkylate the parasite proteins in vivo, killing the parasite. Modification at C17 of ART alters the properties for each derivative.
Artemisinin-based combination therapy uses ART and semisynthetic derivatives, however the poor pharmacokinetics diminish its effects. Development of new antimalarial drug RKA 182, a 1,2,4,5-tetraoxane, derived from ART is seen to be more stable and potent within the nanomolar range (IC₅₀ = 25 nM) as a new path of treatment for malaria, compared to the 1,2,4-trioxane pharmacophore.

H. M. Ismail, V. Barton, M. Phanchana, S. Charoensutthivarakul, M. H. Wong, J. Hemingway, G. A. Biagini, P. M. O’Neill and S. A. Ward, Proc Natl Acad Sci U S A, 2016, 113, 2080-2085.