Malaria parasites invade red blood cells, causing high fever and anemia. By the late 20th century, chloroquine-resistant strains made treatment difficult. Tu Youyou isolated artemisinin from Artemisia annua using low-temperature ether extraction and identified it as a sesquiterpene with an endoperoxide bridge. The drug reacts with iron in infected erythrocytes, generating radicals that kill the parasite. To curb resistance, artemisinin-based combination therapy (ACT) is now standard and has cut malaria deaths in Africa by about half.

Artemisinin (C15H22O5) features a unique 1,2,4-trioxane ring; the peroxide bridge is essential for activity. Contact with ferrous heme in infected erythrocytes cleaves the bridge, producing carbon- and oxygen-centered radicals that damage parasite membranes and DNA. Because of its short half-life, artemisinin is paired with longer-acting drugs such as mefloquine or lumefantrine in ACT regimens. Kelch13 mutations causing delayed parasite clearance have emerged in the Mekong region, demanding intensified surveillance and drug design. Semisynthetic derivatives like dihydroartemisinin and artemether improve bioavailability and are suitable for pediatric use.

The low-temperature ether maceration preserved the peroxide moiety, giving 100 % of the antimalarial activity lost in conventional hot extractions. NMR and X-ray crystallography established a sesquiterpene framework with an 8α-lactone and 10-ketone, leading to a proposed oxidative ring-opening biosynthetic pathway. Early hypotheses of PfATP6 inhibition have given way to a consensus radical damage mechanism. Kelch13 C580Y mutations confer resistance by impairing a ubiquitin-ligase complex and enhancing digestive-vacuole stress responses. The fourth-generation trioxane ozonide OZ439, designed for extended half-life and single-dose cure, has completed phase-II trials.