Artemisinin: Tentative Mechanism of Action and Resistance

The sesquiterpene lactones constitute a large class of secondary plant metabolites, which carry a‑methylene‑g‑lactone groups as common structural element and display a number of bioactivities. Every year, 1–2 million people living in the tropics and subtropics die of malaria. Lactone artemisinin is the most effective treatment vs. malaria, the most infectious disease in the world today. Artemisinins are derived from extracts of sweet wormwood (Artemisia annua) and are well established for the treatment of malaria, e.g., highly drug-resistant strains. They resulted in one of the most significant advances in the treatment of malaria since the discovery and first use of quinine over 300 years ago. Their efficacy also extends to phylogenetically unrelated parasitic infections, e.g., schistosomiasis. They showed potent and broad anticancer properties in cell lines and animal models. What hope does this drug offer for the future? The pharmacophoric peroxide –O₁–O₂– linkage in the endoperoxide ring triggers artemisinin to explode. Artemisinin and its derivatives present structures different from the classical quinoline. It is poorly soluble in water (and oil). When creating the first generation of artemisinin derivative drugs in 1970s, the overriding goal was to improve its solubility characteristics, so that artemisinin derivatives be more easily formulated and efficiently delivered. What did it make lactones reach cancer clinical trials? Despite much research, artemisinin remains the only known natural product to contain a 1,2,4‑trioxane ring and A. annua continues to be the only known natural source. Phytochemical investigation of the species revealed an abnormally wide range of other endoperoxides and hydroperoxides, many of which were not tested for their antimalarial activity. It was reported the design, synthesis and cytotoxicity of novel dihydroartemisinin-coumarin hybrids via click chemistry.