Artemisinin

from Wikipedia, the free encyclopedia
Structural formula
Structure of artemisinin
General
Non-proprietary name Artemisinin
other names

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

Molecular formula C 15 H 22 O 5
Brief description

white solid

External identifiers / databases
CAS number 63968-64-9
EC number 700-290-5
ECHA InfoCard 100.110.458
PubChem 68827
ChemSpider 62060
DrugBank DB13132
Wikidata Q426921
Drug information
ATC code

P01 BE01

Drug class

Antiprotozoal drugs

properties
Molar mass 282.34 g · mol -1
Melting point
  • 151.4 ° C (polymorph I)
  • 153.9 ° C (polymorph II)
solubility

very poor in water (0.052 g l −1 at 20 ° C) (0.063 g l −1 at 25 ° C, pH = 7.2)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
02 - Highly / extremely flammable 09 - Dangerous for the environment

Caution

H and P phrases H: 242-410
P: 210-280-273-391-410-420
Toxicological data

5576 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Artemisinin is a secondary plant substance , chemically a sesquiterpene , that occurs in the leaves and flowers of the annual mugwort ( Artemisia annua ). The artemisinin structure is characterized by a trioxane ring system and a peroxide bridge . It is used worldwide to treat infections with multi-resistant strains of Plasmodium falciparum , the causative agent of tropica malaria .

Extraction

Annual mugwort ( Artemisia annua ) contains artemisinin.

The annual mugwort , from which artemisinin is extracted, is grown in China, Vietnam and in East African countries. It is obtained by extracting dried leaves and flowers with n- hexane , in which the active ingredient, which is mainly localized in the essential oil gland scales , is readily soluble. Alternative solvents have also been evaluated to replace the n -hexane, but have not yet found practical application. On an acreage of one hectare , up to two tons of leaf material can be harvested, which provide two to three kilograms of the extract. The artemisinin content in the wild-type plant is between 0.1 and 0.4% based on the dry weight. Cultivars with an active ingredient content of up to 1.4% are known. Artemisinin is obtained from the evaporated crude extract, a yellow, viscous oil, by recrystallization , but this process is relatively expensive and consequently the price of artemisinin is very high.

Large-scale production

A Sanofi plant has been in operation in Garessio, northern Italy, since April 2013 and is expected to produce up to 40 tons of artemisinin per year. The facility is the result of a project by the Bill and Melinda Gates Foundation , the One World Health organization (now Path ) and other partners that has been running since 2004. Artemisinin is produced semi-synthetically by photochemical oxidation from artemisinic acid produced by fermentation . The plant works in a semi-continuous process. The tonnage of the plant is to be increased to 60 tons per year. 10 to 15 percent of the amount of artemisinin produced is sold directly, the rest is converted into the active ingredient artesunate, which is used in a fixed combination with amodiaquine (another active ingredient) in the anti-malarial agent ASAQ . However, no artemisinin was produced in the plant, which is based on genetically modified yeast, in 2015. In addition, Sanofi wanted to sell the plant, Nature reported in February 2016. The reasons are the low price for natural artemisinin and the lack of demand from manufacturers of malaria drugs.

properties

The compound can appear in two polymorphic forms. Polymorph I melts at 151.4 ° C with a heat of fusion of 78.4 J g −1 , polymorph II at 153.9 ° C with 70.5 J g −1 . Both forms are enantiotropic to one another. At 130 ° C., a solid phase transition from polymorph I to polymorph II can be observed by means of X-ray powder diffractometry and DSC . Polymorph I crystallizes in an orthorhombic crystal lattice with space group P 2 1 2 1 2 1 (space group no. 19) , polymorph II in a triclinic crystal lattice with space group P 1 (space group no. 1) . Template: room group / 19 Template: room group / 1

Analytics

For the reliable qualitative and quantitative determination of artemisinin, the coupling of HPLC with mass spectrometry is used after appropriate sample preparation .

Use as a drug

Mode of action

Artemisinin has a peroxide structure ; if the concentration of iron ions is high , this peroxide becomes unstable and breaks down into free radicals . Such high concentrations are found in erythrocytes , but also in plasmodia, which accumulate iron. If artemisinin gets into erythrocytes infected with plasmodia, the radicals formed may destroy the parasite. However, there is evidence that artemisinin derivatives act more specifically, for example by inhibiting pfATP6, a Ca-ATPase.

Derivatives

Partially synthetic derivatives were derived from artemisinin, such as artemether , artesunate and artemotil . However, their activity decreases quickly after ingestion, which is attributed to rapid metabolism. To solve this problem, lumefantrine is also given, which inhibits metabolism and at the same time has an antiplasmodial effect. The half-life of lumefantrin is three to six days. Other combination therapies are e.g. B. artesunate mefloquine , artesunate amodiaquine and artesunate sulfadoxine / pyrimethamine . This combination therapies with ACT for A rtemisinin-based c ombination t herapy abbreviated.

Development of resistance

In 2008 and 2009, signs of the development of resistance to combination therapies with artesunate (a derivative of artemisinin) were described in Pailin, Western Cambodia. Independent developments in resistance to Plasmodium falciparum were described in western Thailand in 2012.

In the meantime, resistance is spreading in Southeast Asia and China, and no resistance outside this area was found until 2016. The mutations are concentrated around two geographical foci, one in the border area between Myanmar , southern China and the western border regions of Thailand , the other in Cambodia , Laos and Vietnam . This shows mutations in the Plasmodium gene of the β-propeller domain of the K13 calyx protein . So far, 13 mutations have been identified that are associated with reduced parasite clearance . The most common mutation, a single nucleotide polymorphism (C580Y), results in reduced binding of phosphoinositide-3-kinases , but the further metabolic pathway is still unknown, as is whether the resistance mechanism is identical in the other mutations.

history

Chinese scientist Tu Youyou isolated artemisinin in the early 1970s and demonstrated its effectiveness against malaria in the decades that followed. For this she was awarded the Albert Lasker Award for Clinical Medical Research in 2011 and the Nobel Prize for Physiology or Medicine in 2015.

literature

Web links

Commons : Antiprotozoic drugs  - collection of images, videos and audio files

Individual evidence

  1. ↑ a b c d e data sheet Artemisinin (PDF) from Carl Roth , accessed on February 8, 2013.
  2. ^ A b c d E. Horosanskaia, A. Seidel-Morgenstern, H. Lorenz: Investigation of drug polymorphism: Case of artemisinin. In: Thermochim. Acta . 578, 2014, pp. 74-81, doi: 10.1016 / j.tca.2013.12.019 .
  3. ↑ Yan Liu Huisheng Lu, Fei Pang: Solubility of artemisinin in Seven Different Pure Solvents from (283.15 to 323.15) K . In: Journal of Chemical & Engineering Data . tape 54 , no. 3 , 2009, p. 762–764 , doi : 10.1021 / je800515w .
  4. ↑ a b Guidelines for the Treatment of Malaria (Nonseral Publication) . 2nd Edition. World Health Organization, Geneva 2010, ISBN 978-92-4154792-5 (English, who.int [PDF; accessed September 23, 2010]).
  5. ↑ Alexei A. Lapkin, Martina Peters, Lasse Greiner, Smain Chemat, Kai Leonhard, Marcel A. Liauw, Walter Leitner: Screening of new solvents for artemisinin extraction process using ab initio methodology . In: Green Chemistry . tape 12 , no. 2 , January 1, 2010, p. 241 , doi : 10.1039 / b922001a . and literature cited therein.
  6. ↑ Brigitte Osterath: On a ton scale against malaria. In: News from chemistry. February 2014, pp. 125–127.
  7. ↑ Synthetic biology's first malaria drug meets market resistance. In: Nature News & Comment. Retrieved April 5, 2016 .
  8. ↑ KI Chan: Polymorphism of artemisinin from Artemisia annua. In: Phytochem. 46, 1997, pp. 1209-1214, doi: 10.1016 / S0031-9422 (97) 80013-1 .
  9. ^ Q. Min, W. Lu, MY Wang, D. Zhang, TY Zhou, L. Li: Simultaneous quantitation of artemisinin, arteannuin B, artemisic acid, and scopoletin in mice plasma by HPLC-MS. In: Zhongguo Zhong Yao Za Zhi. 39 (17), Sep 2014, pp. 3306-3310, PMID 25522617 , (Chinese).
  10. ↑ P. Byakika-Kibwika, M. Lamorde et al .: Update on the efficacy, effectiveness and safety of artemether-lumefantrine combination therapy for treatment of uncomplicated malaria . In: Therapeutics and Clinical Risk Management . tape 6 , 2010, p. 11-20 , PMID 20169032 , PMC 2817784 (free full text).
  11. ↑ H. Noedl, Y. Se, K. Schaecher include: Evidence of artemisinin-resistant malaria in western Cambodia. In: The New England Journal of Medicine . Volume 359, Number 24, December 2008, pp. 2619-2620, doi: 10.1056 / NEJMc0805011 . PMID 19064625 .
  12. ↑ AM Dondorp, F. Nosten, P. Yi et al .: Artemisinin resistance in Plasmodium falciparum malaria. In: The New England Journal of Medicine . Volume 361, Number 5, July 2009, pp. 455-467, doi: 10.1056 / NEJMoa0808859 . PMID 19641202 .
  13. ^ VI Carrara, J. Zwang et al: Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. In: PloS one. Volume 4, number 2, 2009, p. E4551, doi: 10.1371 / journal.pone.0004551 . PMID 19234601 . PMC 2641001 (free full text).
  14. ^ Johanna P. Daily: K13-Propeller Mutations and Malaria Resistance . In: New England Journal of Medicine . tape 374 , no. 25 , 23 June 2016, p. 2492-2493 , doi : 10.1056 / NEJMe1604520 .
  15. ^ W. Burns: East meets West: How China almost cured malaria. In: Endeavor. 32, 2008, pp. 101-106, doi: 10.1016 / j.endeavor.2008.07.001 .
  16. ↑ Nature News Blog: Protein folding and malaria meds take Laskers .
  17. ^ Lasker Foundation: Lasker Clinical Medical Research Award - Tu Youyou .
  18. ^ Nobelprize.org: The Nobel Prize in Physiology or Medicine 2015 .