artemisinin artemisinin artemisinin (/ˌɑːtɪˈmiːsɪnɪn/) and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to plasmodium falciparum. it was discovered in 1972 by tu youyou, who shared the 2015 nobel prize in physiology or medicine for her discovery. artemisinin-based combination therapies (acts) are now standard treatment worldwide for p. falciparum malaria as well as malaria due to other species of plasmodium. artemisinin is extracted from the plant artemisia annua, sweet wormwood, a herb employed in chinese traditional medicine. a precursor compound can be produced using a genetically engineered yeast, which is much more efficient than using the plant. artemisininclinical datapronunciation/ɑːrtɪˈmɪsɪnɪn/ other namesartemisinine, qinghaosuroutes ofadministrationoralatc codep01be01 (who) identifiers iupac name (3r,5as,6r,8as,9r,12s,12ar)-octahydro-3,6,9-trimethyl-3,12-epoxy-12h-pyrano-1,2-benzodioxepin-10(3h)-one cas number63968-64-9 ypubchem cid68827chemspider62060 yunii9rmu91n5k2keggd02481 ychebichebi:223316 ychemblchembl567597 ncomptox dashboard (epa)dtxsid2040652 echa infocard100.110.458 chemical and physical dataformulac15h22o5molar mass282.336 g·mol−13d model (jsmol)interactive imagedensity1.24 ± 0.1 g/cm3melting point152 to 157 °c (306 to 315 °f)boiling pointdecomposes smiles o=c3o4o1(oo42(cc1)(c)cc23c)c inchi inchi=1s/c15h22o5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-11,13h,4-7h2,1-3h3/t8-,9-,10+,11+,13-,14-,15-/m1/s1 ykey:bluafehzuwynde-nnwcwbajsa-n y ny (what is this?) (verify) artemisinin and its derivatives are all sesquiterpene lactones containing an unusual peroxide bridge. this endoperoxide 1,2,4-trioxane ring is responsible for their antimalarial properties. few other natural compounds with such a peroxide bridge are known. artemisinin and its derivatives have been used for the treatment of malarial and parasitic worm (helminth) infections. advantages of such treatments over other anti-parasitics include faster parasite elimination and broader efficacy across the parasite life-cycle; disadvantages include their low bioavailability, poor pharmacokinetic properties, and high cost. moreover, use of the drug by itself as a monotherapy is explicitly discouraged by the world health organization, as there have been signs that malarial parasites are developing resistance to the drug. combination therapies, featuring artemisinin or its derivatives alongside some other antimalarial drug, constitute the contemporary standard-of-care treatment regimen for malaria. medical use the world health organization (who) recommends artemisinin or one of its derivatives ― typically in combination with a longer-lasting partner drug ― as frontline therapy for all cases of malaria. for uncomplicated malaria, the who recommends three days of oral treatment with any of five artemisinin-based combination therapies (acts): artemether/lumefantrine, artesunate/amodiaquine (asaq), artesunate/mefloquine, dihydroartemisinin/piperaquine, or artesunate/sulfadoxine/pyrimethamine. in each of these combinations, the artemisinin derivative rapidly kills the parasites, but is itself rapidly cleared from the body. the longer-lived partner drug kills the remaining parasites and provides some lingering protection from reinfection. for severe malaria, the who recommends intravenous or intramuscular treatment with the artemisinin derivative artesunate for at least 24 hours. artesunate treatment is continued until the treated person is well enough to take oral medication. they are then given a three-day course of an act, as for uncomplicated malaria. where artesunate is not available, the who recommends intramuscular injection of the less potent artemisinin derivative artemether. for children less than six years old, if injected artesunate is not available the who recommends rectal administration of artesunate, followed by referral to a facility with the resources for further care. artemisinins are not used for malaria prevention because of the extremely short activity (half-life) of the drug. to be effective, it would have to be administered multiple times each day. contraindications the who recommends avoiding act for women in their first trimester of pregnancy due to a lack of research on artemisinin's safety in early pregnancy. instead the who recommends a seven-day course of clindamycin and quinine. for pregnant women in their second or third trimesters, the who recommends a normal treatment course with an act. for some other groups, certain acts are avoided due to side effects of the partner drug: sulfadoxine-pyrimethamine is avoided during the first few weeks of life as it interferes with the action of bilirubin and can worsen neonatal jaundice. in hiv-positive people, the combination of trimethoprim/sulfamethoxazole, zidovudine-containing antiretroviral treatments, and asaq is associated with neutropenia. the combination of the hiv drug efavirenz and asaq is associated with liver toxicity. adverse effects artemisinins are generally well tolerated at the doses used to treat malaria. the side effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, loss of appetite, and dizziness. mild blood abnormalities have also been noted. a rare but serious adverse effect is allergic reaction. one case of significant liver inflammation has been reported in association with prolonged use of a relatively high-dose of artemisinin for an unclear reason (the patient did not have malaria). the drugs used in combination therapies can contribute to the adverse effects experienced by those undergoing treatment. adverse effects in patients with acute p. falciparum malaria treated with artemisinin derivatives tend to be higher. chemistry an unusual component of the artemisinin molecules is an endoperoxide 1,2,4-trioxane ring. this is the main antimalarial centre of the molecule. modifications at carbon 10 (c10) position give rise to a variety of derivatives which are more powerful than the original compound. because the physical properties of artemisinin itself, such as poor bioavailability, limit its effectiveness, semisynthetic derivatives of artemisinin have been developed. derivatives of dihydroartemisinin were made since 1976. artesunate, arteether and artemether were first synthesized in 1986. many derivatives have been produced of which artelinic acid, artemotil, artemisone, sm735, sm905, sm933, sm934, and sm1044 are among the most powerful compounds. there are also simplified analogs in preclinical development. over 120 other derivatives have been prepared, but clinical testing has not been possible due to lack of financial support. artemisinin is poorly soluble in oils and water. therefore, it is typically administered via the digestive tract, either by oral or rectal administration. artesunate however can be administered via the intravenous and intramuscular, as well as the oral and rectal routes. a synthetic compound with a similar trioxolane structure (a ring containing three oxygen atoms) named rbx-11160 showed promise in in vitro testing. phase ii testing in patients with malaria was not as successful as hoped, but the manufacturer decided to start phase iii testing anyway. mechanism of action as of 2018, the exact mechanism of action of artemisinins has not been fully elucidated. artemisinin itself is a prodrug of the biologically active dihydroartemisinin. this metabolite undergoes cleavage of its endoperoxide ring inside the erythrocytes. as the drug molecules come in contact with the haem (associated with the hemoglobin of the red blood cells), the iron(ii) oxide breaks the endoperoxide ring. this process produces free radicals that in turn damage susceptible proteins, resulting in the death of the parasite. in 2016 artemisinin was shown to bind to a large number of targets suggesting that it acts in a promiscuous manner. artemisinin's endoperoxide moiety is however less sensitive to free iron(ii) oxide, and therefore more active in the intraerythrocytic stages of p. falciparum. in contrast, clinical practice shows that unlike other antimalarials, artemisinin is active during all life cycle stages of the parasite. resistance clinical evidence for artemisinin drug resistance in southeast asia was first reported in 2008, and was subsequently confirmed by a detailed study from western cambodia. resistance in neighbouring thailand was reported in 2012, and in northern cambodia, vietnam and eastern myanmar in 2014. emerging resistance was reported in southern laos, central myanmar and northeastern cambodia in 2014. the parasite's kelch gene on chromosome 13 appears to be a reliable molecular marker for clinical resistance in southeast asia. in 2011, the who stated that resistance to the most effective antimalarial drug, artemisinin, could unravel national indian malaria control programs, which have achieved significant progress in the last decade. who advocates the rational use of antimalarial drugs and acknowledges the crucial role of community health workers in reducing malaria in the region. artemisinins can be used alone, but this leads to a high rate of return of parasites and other drugs are required to clear the body of all parasites and prevent a recurrence. the who is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large, aware of the catastrophe that would result if the malaria parasite developed resistance to artemisinins. two main mechanisms of resistance drive plasmodium resistance to antimalarial drugs. the first one is an efflux of the drug away from its action site due to mutations in different transporter genes (like pfcrt in chloroquine resistance) or an increased number of the gene copies (like pfmdr1 copy number in mefloquine resistance). the second is a change in the parasite target due to mutations in corresponding genes (like, at the cytosol level, dhfr and dhps in sulfadoxine-pyrimethamine resistance or, at the mitochondrion level, cytochrome b in atovaquone resistance). resistance of p. falciparum to the new artemisinin compounds involves a novel mechanism corresponding to a quiescence phenomenon. as of 2020 future resistance research will make use of transgenic mice to discover relevant molecular markers. synthesis biosynthesis in artemisia annua the biosynthesis of artemisinin is believed to involve the mevalonate pathway (mva) and the cyclization of farnesyl diphosphate (fdp). it is not clear whether the non-mevalonate pathway can also contribute 5-carbon precursors (ipp or dmapp), as occurs in other sesquiterpene biosynthetic systems. the routes from artemisinic alcohol to artemisinin remain controversial, and they differ mainly in when the reduction step takes place. both routes suggested dihydroartemisinic acid as the final precursor to artemisinin. dihydroartemisinic acid then undergoes photo-oxidation to produce dihydroartemisinic acid hydroperoxide. ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation finish the biosynthesis of artemisinin. figure 1. biosynthesis of artemisinin chemical synthesis the total synthesis of artemisinin has been performed from available organic starting materials, using basic organic reagents, many times. the first two total syntheses were a stereoselective synthesis by schmid and hofheinz at hoffmann-la roche in basel starting from (−)-isopulegol (13 steps, ~5% overall yield), and a concurrent synthesis by zhou and coworkers at the shanghai institute of organic chemistry from (r)-(+)-citronellal (20 steps, ~0.3% overall yield). key steps of the schmid–hofheinz approach included an initial ohrloff stereoselective hydroboration/oxidation to establish the "off-ring" methyl stereocenter on the propene side chain; two sequential lithium-reagent mediated alkylations that introduced all needed carbon atoms and that were, together highly diastereoselective; and further reduction, oxidation, and desilylation steps performed on this mono-carbocyclic intermediate, including a final singlet oxygen-utilizing photooxygenation and ene reaction, which, after acidic workup closed the three remaining oxacyclic rings of the desired product, artemisinin, in a single step.(in essence, the final oxidative ring-closing operation in these syntheses accomplishes the closing three biosynthetic steps shown above.) a wide variety of further routes continue to be explored, from early days until today, including total synthesis routes from (r)-(+)-pulegone, isomenthene, and even 2-cyclohexen-1-one, as well as routes better described as partial or semisyntheses from a more plentiful biosynthetic precursor, artemisinic acid—in the latter case, including some very short and very high yielding biomimetic synthesis examples (of roth and acton, and haynes et al., 3 steps, 30% yield), which again feature the singlet oxygen ene chemistry. synthesis in engineered organisms the partnership to develop semisynthetic artemisinin was led by path's drug development program (through an affiliation with oneworld health), with funding from the bill & melinda gates foundation. the project began in 2004, and initial project partners included the university of california, berkeley (which provided the technology on which the project was based – a process that genetically altered yeast to produce artemisinic acid) and amyris (a biotechnology firm in california, which refined the process to enable large-scale production and developed scalable processes for transfer to an industrial partner). in 2006, a team from uc berkeley reported they had engineered saccharomyces cerevisiae yeast to produce a small amount of the precursor artemisinic acid. the synthesized artemisinic acid can then be transported out, purified and chemically converted into artemisinin that they claim will cost roughly us$0.25 per dose. in this effort of synthetic biology, a modified mevalonate pathway was used, and the yeast cells were engineered to express the enzyme amorphadiene synthase and a cytochrome p450 monooxygenase (cyp71av1), both from artemisia annua. a three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid. the uc berkeley method was augmented using technology from various other organizations. the final successful technology is based on inventions licensed from uc berkeley and the national research council (nrc) plant biotechnology institute of canada. commercial production of semisynthetic artemisinin is now underway at sanofi's site in garessio, italy. this second source of artemisinin is poised to enable a more stable flow of key antimalarial treatments to those who need them most. the