Chemical Properties
Crystalline Solid
Usage
Active antimalarial constituent of the tradional Chinese medicinal herb Artemisia annua L., Compositae, which has been known for almost 2000 years as Qinghao. Antimalarial
Biological Activity
Antimalarial agent; interacts with heme to produce carbon-centred free radicals, causes protein alkylation and damages parasite microorganelles and membranes. Also selectively inhibits the P-type ATPase (PfATP6) of Plasmodium falciparum (K i~ 150 nM). Displays antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies.
Description
Artemisinin, a sesquiterpene isolated from a traditional Chinese remedy (quinghao), is
useful in the treatment of Fafciparum malaria, including infections caused by chloroquine
resistant strains. It is reported to clear parasitemia quicker than i.v. quinine, and is
effective in cerebral malaria.
Physical properties
Appearance: colorless needles or white crystalline powder. Solubility: practically
insoluble in water, very soluble in dichloromethane, freely soluble in acetone and
ethyl acetate, and soluble in glacial acetic acid, methanol, and ethanol. Melting
point: 150–153?°C. Specific optical rotation: +75 to +78°.
Originator
Ping Hau Sau Res. Group (China)
History
The discovery of artemisinin dramatically changes the landscape to combat malaria
and leads to a paradigm shift in antimalarial drug development.
However, the discovery of artemisinin is the first stage; the development of artemisinin derivatives and their compound preparations is another important stage.
Based on artemisinin, scientists obtained artemisinin ether derivatives by semisynthetic method. After screening of antimalarial activity, artemether was found. To
further improve the solubility of artemisinin derivatives, artesunate was also found.
The discovery of artesunate makes artemisinin and its derivatives much easier to
promote, and more convenient dosage forms to treat malaria enriched the clinic
application of artemisinin and its derivatives .
Definition
ChEBI: A sesquiterpene lactone obtained from sweet wormwood, Artemisia annua, which is used as an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria.
Antimicrobial activity
Artemisinins are active against the erythrocytic and gametocyte
stages of chloroquine-sensitive and chloroquine-resistant
strains of P. falciparum and other malaria parasites. Two anomers
of artemether are produced on synthesis, α-artemether
and β-artemether, of which the latter has higher antimalarial
activity. Activity against the protozoa Tox. gondii and
Leishmania major and the helminth Schistosoma mansoni has
been demonstrated in experimental models.
Acquired resistance
Resistance caused, for example, by changes in the plasmodial
endoplasmic reticulum ATPase has been shown in experimental
models. There have been clinical reports of reduced
susceptibility to treatment with artesunate in Cambodia.
General Description
The artemisinin series are the newest of the antimalarialdrugs and are structurally unique when comparedwith the compounds previously and currently used. Theparent compound, artemisinin, is a natural product extractedfrom the dry leaves of Artemisia Annua (sweetwormwood). The plant has to be grown each year fromseed because mature plants may lack the active drug. The growing conditions are critical to maximize artemisininyield. Thus far, the best yields have been obtained fromplants grown in North Vietnam, Chongqing province inChina, and Tanzania.
Biochem/physiol Actions
Artemisinin (Qinghaosu), a sesquiterpene lactone, is a highly active anti-malarial (falciparum malaria) drug. Artemisinin is also an anthelmintic (parasitic worm) effective against the blood fluke, schistosomiasis.
Pharmacokinetics
Oral absorption: Incomplete
Cmax 500 mg oral: 0.4 mg/L after 1.8 h
Plasma half-life (dihydroartemisinin): 40–60 min
Volume of distribution: c. 0.25 L/kg
Plasma protein binding (artemether): 77%
Artemisinins are concentrated by erythrocytes and are rapidly
hydrolyzed to dihydroartemisinin. They are hydroxylated by cytochromes
2B6, 2C19 and 3A4; the derivatives induce this metabolism.
After injection, peak plasma concentrations are reached
within 1–3 h, when levels of dihydroartemisinin are included.
The elimination half-life of intravenous artesunate is <30 min;
artemether appears to have a much longer half-life (4–11 h).
Pharmacology
The mechanism of artemisinins is not known, but the most widely accepted theory
is that they are first activated through cleavage after reacting with haem and iron(II)
oxide, which results in the generation of free radicals that in turn damage susceptible proteins, resulting in the death of the parasite .
Artemisinin and its derivatives also show a good antitumor effect , which is
mainly via (1) apoptosis, ferroptosis, or necrosis; (2) anti-angiogenesis; (3) oxidative stress; (4) tumor suppressor genes; and (5) protein targeting. In addition, artemisinin can exhibit antiarrhythmic, anti-fibrotic, and immunomodulating effects.
Clinical Use
Malaria (including cerebral malaria), in combination with other antimalarials.
Safety Profile
Moderately toxic by ingestion,intramuscular, and intraperitoneal routes. When heated todecomposition it emits acrid smoke and fumes.
Synthesis
Quinghaosu, octahydro-3,6,9-trimethyl-3,12-epoxy-12Hpyrano-(4,3-di)-1,2-benzodioxepin-10-(3H)-one (37.1.1.57), is isolated from the plant
Artemisia annua. It also has been made synthetically.
