Artemisinin: An Ancient Text and a Modern Malaria Drug

A desperate search

By the 1960s the malaria parasite Plasmodium falciparum had become resistant to chloroquine, the main antimalarial drug. In 1967 China set up a secret national programme, Project 523, to find new treatments. In 1969 a young pharmaceutical chemist, Tu Youyou, was put in charge of a research group and told to search traditional Chinese medicine for leads.

Her team collected more than 2000 traditional recipes and tested hundreds of plant extracts against malaria in mice. An extract of qinghao (sweet wormwood, Artemisia annua) looked promising at first, but the results were inconsistent.

The clue in a fourth-century book

Tu went back to the ancient literature. In a handbook of emergency prescriptions written by Ge Hong around 340 CE, she read that qinghao should be soaked in cold water, wrung out, and the juice drunk. The usual method was to boil herbs. Perhaps, she reasoned, heat destroyed the active compound.

She changed the extraction: instead of hot ethanol, her team used diethyl ether, which boils at only 35 °C. In October 1971, extract number 191 cleared the parasites completely from infected mice and monkeys. In 1972 the team isolated the pure compound, qinghaosu, now called artemisinin.

A molecule with a weak link

Artemisinin, $\ce{C15H22O5}$, is a sesquiterpene lactone (a cyclic ester), but its most unusual feature is an endoperoxide bridge: two oxygen atoms bonded to each other, O–O, inside a ring. In a peroxide, each of these oxygens has an oxidation number of −1, and the O–O bond is weak.

Inside red blood cells, the parasite digests haemoglobin and releases haem containing iron(II). The accepted model is that $\ce{Fe^2+}$ breaks the O–O bond (a redox reaction), producing highly reactive radicals that damage the parasite’s proteins. That explains why molecules without the peroxide bridge are inactive, and why the extraction had to avoid heat.

From plant to medicine

Artemisinin acts fast but is cleared from the body within hours, and it dissolves poorly in water. Chemists therefore made derivatives: reducing the lactone gives dihydroartemisinin (1973), and from it come artemether (an ether) and water-soluble artesunate (an ester), which can be injected in severe malaria. To prevent resistance, these are given with a longer-acting partner drug, as artemisinin-based combination therapies (ACTs), the standard treatment recommended by the World Health Organization.

Supply was a problem: the plant contains only a small percentage of artemisinin by dry mass. Since 2013, part of the world’s supply has been made semi-synthetically from artemisinic acid produced by genetically engineered yeast.