A Continuous-Flow Process for the Synthesis of Artemisinin
Continuous-Flow Synthesis of the Anti-Malaria Drug ..
Over the years, rich efforts have been devoted to the development of better antimalarial drug candidates based on the prototype structure of artemisinin. Notable examples include OZ277 and OZ209 (), two synthetic peroxide trioxolanes in which the critical peroxidic pharmacophore of the artemisinins is present within a 1,2,4-trioxolane rather than a 1,2,4-trioxane heterocycle . As in artemisinins, the intracellular peroxidic bridge is also critical for the malaria inhibitory function of these synthetic peroxide trioxolanes, propelling people thinking they should share some important features in mechanism of action, and also provide an excellent test ground for the validity of working models. OZ277 and OZ209 have higher antimalarial activity than artemisinin, but are two orders of magnitude less active in inhibiting pfATP6, one previously hypothesized target protein of artemisinin . As we proposed artemisinin inhibits malaria by disrupting the normal function of malarial mitochondria, we tested the idea whether the synthetic peroxide trioxolanes may also affect mitochondrial function. In isolated malarial mitochondria, OZ209 also induced dramatic ROS production. In fact, 50 nM OZ209 had similar effect to 100 nM artemisinin in increasing ROS production and depolarizing mitochondrial membrane (). The observation that synthetic peroxide trioxolane was associated with more potent ROS induction ability is consistent with its higher antimalarial activity as observed in cell culture studies . This indicates that artemisinin and its related derivative OZ209 kill malaria by a similar mechanism—all through direct disruption of mitochondrial functions.
A continuous-flow process for the synthesis of artemisinin.
Malaria remains one of the major threats to human health. Nearly two billion people are at risk and likely more than one million die of the disease annually. The past years witnessed the wide emergence of drug-resistant strains in many regions, which has contributed largely to the resurgence of malaria, an ancient disease once deemed under control. Artemisinin, derived from the Chinese herb, Artemisia annua L, is a highly effective drug in our fight against this devastating disease , . Its minimal clinical toxicity and fast action make it the best choice currently available for drug-resistant strains. Derivatives of artemisinin, including dihydroartemisinin, artemether, arteether and artesunate, or so called first generation artemisinin derivatives, were synthesized and have ever since been used in the treatment of malaria . This class of drugs (artemisinins) contains an intramolecular peroxide bridge that is situated in the sesquiterpene lactone backbone structure and is key to the antimalarial function . More recently, semisynthetic and synthetic endoperoxide analogues, some of which deviate distantly in the structural backbone from that of the original artemisinin were also made and in some cases associated with even more potent antimalarial effects. Intriguingly, despite many years of use clinically meaningful resistance to artemisinin has not yet convincingly been shown. What is more, near forty years since its discovery and with large amount of literatures published regarding its mode of action, how artemisinins inhibit the growth of malarial parasites remains an enigma and in a state of confusion , .