Artesunic acid

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 DihydroartemIsinIn Artemether Arteether Artelinic acid Artesunic acid... 

Artesunate is a water-soluble hemisuccinate derivative, available in parenteral and oral formulations. The parenteral drug is dispensed as powdered artesunic acid. Neutral aqueous solutions are unstable. Artesunate is effective by the intravenous, intramuscular, and oral routes in a dose of 10 mg/kg given for 5-7 days. The combination with mefloquine is very effective even against highly multi-resistant strains of Plasmodium falciparum, the combination must be given for at least 3 days. 

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... 

Artesunic acid DHA Artemisinin (IS) Dichloromethane-MTBE Octa-decyl Acetonitrile-aq. sodium acetate (100 mmol ir pH 4.8) (45+55) 10 (16.7%) 10 (7.8%) 163... 

Z.M. Zhou, J.C. Anders, H. Chung and A.D. Theoharides, Analysis of artesunic acid and dihydroqinghaosu in blood by high-performance liquid chromatography with reductive electrochemical detection, /. Chromatogr., mi, 414, 77-90. 

V. Navaratnam, M.N. Mordi and S.M. Mansor, Simultaneous determination of artesunic acid and dihydroartemisinin in blood plasma by high-performance liquid chromatography for application in clinical pharmacological studies, J. Chromatogr. B, 1997, 692, 157-62. 

Woerdenbag and coworkers reported on the cytotoxicity of artemisinin endoperoxides to Ehrlich ascites tumour cells . Artemisinin had an IC50 of 29.8 p.M, whereas arteether, artemether, artelininc acid and sodium artesunate all had more potent activities, ranging from 12.2 to 19.9 p.M. It was found that opening of the lactone ring of artemisinin dramatically reduced the cytotoxicity. An ether dimer of dihydroartemisinin 106, prepared by... 

Artemisinin is very poorly soluble in water or oil and can thus only be administered orally. Active derivatives have been synthesized such as artemether, arteether and beta-arteether (Artemotil), artelinic acid and artesunate, which are used for oral, intramuscular, rectal and intravenous administration. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself (see Fig. 2). 

Based on these results, lO-CFs-analogues of dihydroartemisinin (DMA), arte-mether, arteetherand artesunate have been prepared. They also exhibit very interesting in vivo anti-malarial properties, a better stability under stomach acidic conditions. A prolonged plasma half-life was demonstrated for some of them [171,173], This approach has led to the pre-clinical development of the orally active 10-trifluoromethyl DMA and a 10-trifluoromethyl deoxoartemisinin (Fig. 73) [170-172],... 

In conclusion, the vast literature and its derivatives, particularly artesunate, artemether, and arteether, point out to the need to make these derivatives in quantities that would reduce their current production cost to make these drugs accessible to the economically underprivileged societies that are often the victims of malaria. A recent promising method in which artemisinic acid, a precursor to artemisinin, has been produced in engineered yeast. Therefore, microbially produced artemisinic acid holds promise to the syntheses of antimalarial drugs at affordable prices <2006N940>. Furthermore, anticancer activities of artemisinin 1 and its derivatives have been reviewed <2005MI995>. 

Further support for a hydrophobic binding domain in the southeast quadrant of the artemisinin pharmacophore comes from the carboxylic acid 58 (originally designed as a chemically stable replacement for sodium artesunate), which was found to be nearly devoid of antimalarial activity. Of course, bioavailability of the acid 58 could be poor in contrast to hydrophobic analogues. 

To search for stable, water-soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunate and artelinic acid, deoxoarteli-nic acid 134 was prepared (Scheme 5-18) and tested in vitro and in vivo. It was reported that 134 showed superior antimalarial activity and was more stable in simulated stomach acid than arteether. In 1992, Haynes et al. already reported on the synthesis of 5-carba-4-deoxoartesunic acid (135) from artemisinic acid (20) in a similar way, but they did not mention its activity at that time. ... 

Jung et al. prepared 11-substituted deoxoartemisinin 136 from artemisinic acid (20) using photooxidation as the key step (Scheme 5-21). Compound 136 (R = CH2OH) was more active than qinghaosu and artesunate in vitro. 

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. 

Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoper-oxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisjmthetic derivatives have been developed from dihydroartemisinin (1). 

Sodium AmitaR amylobarbitone. sodium artesunate artesunate. sodium ascorbate ascorbic acid, sodium aurothiomalate gold sodium thiomalate. sodium aurotiosulfate [inn] (aurothlosulphate) is a thiogold derivative, and can be used as an ANTIINFLAMMATORY in antiarthritic and antirheumatic treatment. Also a reported ANTIHYPEKTENSIVE, acting as a CYCLOOXYGENASE INHIBITOR. 

Dihydroqinghaosu (32) (Scheme 1) is a key intermediate in the synthesis of artemisinin analogues / derivatives, which have shown antimalarial activity. Following the Chinese scientists s work, Lin et al. [95] synthesized a series of water soluble derivatives of artemisinin of which artenilic acid (36d) was found to exhibit activity and better stability than artemisinin or artesunate. Brossi et al. [96] reported the synthesis of arteether (36b), which after preclinical studies is now in clinical evaluation in India [96a], Deoxyqinghaosu described in scheme 11 has been reported to have high antimalarial activity. Synthesis of (+)-12-butyldeoxoartemisinin (99) and some tricyclic analogues (100) of artemisinin has recently been achieved [97,98]. 

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