Sodium artesunate water-soluble

Deoxoartemisinin and carboxypropyldeoxoartimisinin have also been shown to have anti-tumour activity and, NMR studies on solution conformations have been reported <00BBR359>. One of the problems with artemisinin use is its poor water solubility characteristics. An attempt to rectify this, and to overcome stability problems associated with sodium artesunate in solution, has involved the introduction of amino group functionality as in 127 (eg. R = 0(CH2)3NR r2 where NR r2 = morpholine). The maleate salt of this compound has reasonable water solubility and aqueous solutions are stable at room temperature for an extended time. However activity against Plasmodium knowlesi in rhesus monkeys after oral administration was poorer compared with artesunic acid <00JMC1635>. 

Artemisinin (18) is a natural product for which many semisynthetic derivatives have been generated. The major rationale to produce these derivatives was to deal with the low aqueous solubility of artemisinin and its short half-life in plasma. The lipid-soluble arteether (22) and artemether (23), and the water-soluble sodium artesunate (24), were designed for... 

The pharmaceutical properties of artemisinin are far from optimal it is insoluble in water and only marginally soluble in oil. It has poor oral bioavailability and has been administered for the treatment of Plasmodium falciparum malaria in humans at total doses of about 1 g (over 3 days). Early studies by Chinese scientists in 1979 led to the discovery of dihydroartemisinin 3, artemether 4 (Artenam), and sodium artesunate 5, oil and water soluble derivatives, respectively (Figure 9.1 ).6-7 These drugs are currently in clinical use in Asia in a number of preparations such as suppositories, i.v. injectables, oil depos, to name only a few.8 Capsules containing 0.5 g of artemisinin for oral administration are available in Vietnam. 

Oil-soluble artemether and water-soluble sodium artesunate were developed and approved as new antimalarial drugs by the Chinese authorities in 1987. After 1992, dihydroartemisinin, Coartem (a combination of artemether and benflumetol), and Artekin (a combination of dihydroartemisinin and piperaquine) were also marketed as new antimalarial dmgs. Since then, over 10 million malaria patients on a global scale have been cured after administration of these drugs. As a result, artemether, artesunate, and Coartem were added by the World Health Organization to the ninth, eleventh, and twelfth Essential Medicine List respectively. 

Sodium artesunate is the first water-soluble qinghaosu derivative and used for treatment of the severe malaria patients by intravenous or intramuscular administration. However, the aqueous solution is unstable, and its hydrolysis product,... 

Water solubility can be greatly improved by the standard ploy of esterification with succinic acid and conversion to the sodium salt. Applied to compound (155), this technique gives sodium artesunate (158), a water-soluble prodrug that may be given intravenously (196). It may be assumed that hydrolysis occurs in vivo to give back (155) as the active antimalarial because (156) has been shown to be unstable in aqueous solution and because analogous carboxylic acids with a nonhydro-lyzable ether link are relatively inactive. 

B. Because artemisinin is lipophilic it must be formulated as an oily preparation. Various derivatives have been produced which are more water soluble, including an ether called artemether and an ester, sodium artesunate. Quinghao is now extensively cultivated in many areas where malaria is endemic. 

Esters (32 4, R = C(=0)-alkyl or -aryl), of which a-epimers were mainly obtained, were more active than the ethers. Sodium artesunate (32 5, R = C(=0)-CH2CH2C00Na), the half succinic acid half-ester of dihydroartemisinin is water-soluble and shows potent antimalarial activity. Therefore, this can be administered intravenously. However it is uncertain whether this derivative is pharmacologically effective because of its sensitivity to hydrolysis. In considering this result new ether derivatives of dihydroartemisinin, which are stable and water soluble derivatives have been prepared [46]. Dihydroartemisinin was condensed with esters of aliphatic or aromatic carboxylic acids with hydroxy groups to produce mainly ethers with the P-configuration. Ethyl 2-( 10-dihydroartemisininoxy) acetate (31 4, R = CH2COOCH2CH3) and methyl... 

Dihydroartemisinin ethers. A water-soluble derivative of artemisinin, the sodium salt of artesunic acid (the succinic half-ester derivative of dihydroartemisinin Fig. 35.2), can be administered by intravenous injection, a property that makes it especially useful in the treatment of advanced and potentially lethal cases of Plasmodium falciparum. Sodium artesunate is capable of rapidly reversing parasitaemia and causing the restoration to consciousness of the comatose cerebral malaria patient. The utility of sodium artesunate, however, is impaired by its poor stability due to the facile hydrolysis of the ester linkage. To overcome the ease of hydrolysis of the ester function in sodium artesunate, Lin et aO prepared a series of analogues in which the solubilizing moiety is joined to dihydroartemisinin by an... 

Since poor bioavailability and a short half-life limit the pharmacological activity of artemisinin, several derivatives have been developed to address such disadvantages. A key compound among them is dihydroartemisinin, which serves not only as an intermediate, but is used as a drug by itself Reduction of the lactone is achieved under very mild conditions with sodium boranate in methanol at 0 °C. Esterification with succinic acid anhydride leads to artesunate, a water soluble compound, which is suitable for different routes of application (oral, rectal, intramuscular, and intravenous). Acetalisation of dihydroartemisinin with methanol produces artemether, which is soluble in lipids and can therefore be formulated for oral, rectal and intramuscular dosing. 

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