Artemisinin

Artemisinin and its semi-synthetic derivatives are drugs used to treat malaria caused by Plasmodium falciparum. Discovered in 1972 by Tu Youyou—who received the 2015 Nobel Prize in Physiology or Medicine for this work—artemisinin is extracted from the herb Artemisia annua (sweet wormwood), a plant used in traditional Chinese medicine. It can also be produced more efficiently via a semi-synthetic process using a precursor made by genetically engineered yeast. Artemisinin-based combination therapies (ACTs) are now the global standard for treating malaria from P. falciparum and other Plasmodium species.

These drugs are sesquiterpene lactones with an unusual peroxide bridge—specifically, an endoperoxide 1,2,4-trioxane ring—that gives them their antimalarial properties. Few other natural compounds share this structure. Artemisinin and its derivatives are also used against parasitic worm (helminth) infections. Compared to other anti-parasitics, they clear parasites faster and work across more stages of the parasite life cycle.

Medical use

However, they have low bioavailability, poor pharmacokinetic properties, and high cost. The World Health Organization (WHO) explicitly discourages using artemisinin alone (monotherapy), as malaria parasites show signs of developing resistance. Combination therapy, pairing artemisinin or its derivatives with a longer-lasting partner drug, is the current standard of care.

The WHO recommends artemisinin or one of its derivatives—usually combined with a longer-acting partner—as frontline treatment for all malaria cases. For uncomplicated malaria, the WHO advises three days of oral treatment with any of five ACTs: artemether/lumefantrine, artesunate/amodiaquine (ASAQ), artesunate/mefloquine, dihydroartemisinin/piperaquine, or artesunate/sulfadoxine/pyrimethamine. In these combinations, the artemisinin derivative kills parasites quickly but is itself cleared rapidly from the body, while the longer-lived partner drug eliminates remaining parasites and offers some protection against reinfection. For severe malaria, the WHO recommends intravenous or intramuscular artesunate for at least 24 hours, continuing until the patient can take oral medication, followed by a three-day ACT course for uncomplicated malaria.

If artesunate is unavailable, intramuscular artemether (a less potent derivative) is recommended. For children under six, if injectable artesunate is not available, rectal artesunate is given, followed by referral to a facility with more resources. Artemisinins are not used for malaria prevention because they are active for a very short time (short half-life); effective prevention would require multiple doses each day. The WHO advises avoiding ACTs during the first trimester of pregnancy due to insufficient research on artemisinin’s safety in early pregnancy, recommending instead a seven-day course of clindamycin and quinine.

Contraindications

For pregnant women in the second or third trimesters, normal ACT treatment is recommended. Some ACTs are avoided in certain groups due to side effects from the partner drug: sulfadoxine-pyrimethamine is not used in the first few weeks of life because it interferes with bilirubin and can worsen neonatal jaundice. In HIV-positive people, the combination of trimethoprim/sulfamethoxazole, zidovudine-containing antiretroviral treatments, and ASAQ is linked to neutropenia. The combination of the HIV drug efavirenz and ASAQ is associated with liver toxicity.

Adverse effects

At doses used for malaria, artemisinins are generally well tolerated. Side effects resemble malaria symptoms: nausea, vomiting, loss of appetite, and dizziness. Mild blood abnormalities have been noted. A rare but serious adverse effect is allergic reaction.

One case of significant liver inflammation was reported after prolonged use of a relatively high dose of artemisinin for an unclear reason (the patient did not have malaria). The partner drugs in combination therapies can also contribute to side effects. Adverse effects tend to be higher in patients with acute P. falciparum malaria treated with artemisinin derivatives.

Chemistry

A key feature of artemisinin molecules is the endoperoxide 1,2,4-trioxane ring, which is the main antimalarial component. Modifications at the carbon 10 (C10) position produce derivatives more powerful than the original compound. Because artemisinin itself has poor bioavailability and other physical limitations, semi-synthetic derivatives have been developed. Derivatives of dihydroartemisinin have been made since 1976.

Artesunate, arteether, and artemether were first synthesized in 1986. Many other derivatives exist, including artelinic acid, artemotil, artemisone, SM735, SM905, SM933, SM934, and SM1044—among the most potent. Simplified analogs are in preclinical development. Over 120 other derivatives have been prepared, but clinical testing has not been possible due to lack of funding.