Artemisinin

(3R, 5AS, 6R, 8aS, 9R, 12S, 12aR ) - octahydro- 3,6,9- trimethyl-3 ,12 -epoxy- 12H - pyrano [4,3- j] - 1,2- benzodioxepin -10 (3H )-one

P01BE01

White solid

Antiprotozoals

Very poor in water ( 0.52 g · L- 1 at 20 ° C) ( 0.063 gL -1 at 298 K (25 ° C ), pH = 7.2 )

Attention

5576 mg · kg -1 ( LD50, rat, oral)

Template: Infobox chemical / molecular formula search available

Artemisinin is a secondary plant substance, chemically a sesquiterpene that occurs in the leaves and flowers of annuals wormwood (Artemisia annua). Characteristics of Artemisininstruktur are a Trioxanringsystem and Peroxidbrücke. It is used worldwide for the treatment of infections with multidrug-resistant strains of Plasmodium falciparum, the causative agent of malaria tropica.

Extraction

The Annual mugwort A. synthesized, is grown in China, Vietnam and East African countries. The extraction is carried out by the extraction of dried leaves and flowers with n- hexane, wherein the active ingredient, which is predominantly localized in the essential oil glands shed, is readily soluble. Alternative solvents were also evaluated in order to replace the toxic and harmful to the environment of n-hexane, but have not yet received any practical application. On an area of ​​one hectare up to two tons can be harvested leaf material, which provide two to three kilograms of the extract. The Artemisiningehalt in the wild type plant is between 0.1 and 0.4% based on the dry weight. Engineered with an active ingredient content up to 1.4 % are known. Of the concentrated crude extract, a yellow, viscous oil, artemisinin is recovered by recrystallization, but this process is relatively expensive and, consequently, the price of artemisinin is very high.

Experimentally, more recently, the biosynthesis in genetically modified bacteria (Escherichia coli) and yeast (Saccharomyces cerevisiae) explored. The first successes on the way to artificial substitutes are already available. The work of Jay Keasling it is supported by the Bill and Melinda Gates Foundation with $ 43 million.

Peter Seeberger and François Lévesque introduced in early 2012 before a new and very simple method for extraction of artemisinin from artemisinic. Artemisinic can be obtained in large quantities from the sweet wormwood as artemisinin. In 2013 published Paddon and employees a process for the inexpensive production of artemisinic using genetically engineered yeast, which is not encumbered by patents. With an inexpensive bioreactor could be produce active ingredient for the global need sufficient through an investment of four million euros.

Properties

The compound can exist in two polymorphic forms. The polymorph I melts at 151.4 ° C with a heat of fusion of 78.4 J · g -1, the polymorph II at 153.9 ° C 70.5 J · g -1. Both forms are enantiotropic each other. At 130 ° C can be observed by means of X-ray and DSC, a solid phase transition of polymorph I to polymorph II. Polymorph I crystallizes in orthorhombic crystal lattice with space group P212121, polymorph II in a triclinic lattice with space group P1.

Use as drug

Operation

Artemisinin has a Peroxidstruktur; high concentrations of iron ions of this peroxide is unstable and decomposes into free radicals. Such high concentrations are found in the erythrocytes, but also in Plasmodium, the iron accumulate. Where artemisinin in Plasmodium -infected erythrocytes, the formed radicals may destroy the parasite. However, there is evidence that artemisinin derivatives act specifically, for example by pfATP6, inhibit Ca -ATPase.

Derivatives

From artemisinin semisynthetic derivatives were derived, such as artemether, artesunate and Artemotil. Their activity increases, however, soon after the recording from what is attributed to a rapid metabolism. To solve this problem, in addition lumefantrine is added which inhibits the metabolism and at the same time has an antiplasmodial effects. The half-life of Lumefantrins is three to six days. Other combination therapies are, for example, artesunate - mefloquine, artesunate - amodiaquine and Artesunat-Sulfadoxin/Pyrimethamin. These combination therapies are abbreviated with ACT for artemisinin -based combination therapy.

Development of resistance

In the years 2008 and 2009, evidence of the development of resistance to combination therapy with artesunate (a derivative of artemisinin ) in Pailin ( western Cambodia) have been described. Independent development of resistance against Plasmodium falciparum were described in 2012 in western Thailand.

History

The Chinese scientist Tu Youyou isolated artemisinin in the early 1970s and showed its efficacy against malaria in the following decades. For this she was awarded the Albert Lasker 2011 Award for Clinical Medical Research.