Artemisinin is still one of the most effective drugs against malaria after more than 30 years of use. In our continuous efforts to understand the mechanism of action and structure-activity relationship of artemisinin, we investigated the remote C-H activation of C-7 and C-8, inherently difficulty to activate without affecting the peroxide bridge, indispensable for biological activity. 7-β-hydroxyartemisinin, obtained through the biotransformation of artemisinin by the fungus Cunninghamella elegans, was used as starting material for semi-synthetic derivatives prepared using carbamate, carbonate, and sulfate linkers, some showing better antimalarial activity than the parent drugs. Computational modeling explains this increased activity as a result of additional interactions within the active site of the P. falciparum calcium ATPase PfATP6, which has been hypothesized to be the site of action for the antimalarial activity of artemisinin. Those compounds were also tested against Leishmania donovani, with four derivatives showing increased antileishmanial activity. This approach could open new perspectives for the treatment of malaria and leishmaniasis and potentially overcome the threat presented by strains of Plasmodium falciparum resistant to artemisinin

C-7 functionalization and synthesis of derivatives of the antimalarial agent artemisinin

ACS Spring 2022

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