Plasmodium artemisinin

Titanium tetrachloride-catalysed Michael additions of trimethylsilyl enol ethers to artemisitene afforded a neat route to 14-substituted artemisinin derivatives of type 125 (eg. R = allyl) and to 9-epiartemisinin derivatives 126 some of these compounds were more active against Plasmodium falciparum than artemisinin <00BMCL1601>. A series of 11-azaartemisinins also have better activity than artemisinin <00BMC1111>. On the other hand, epiartemisinin, prepared by base-catalysed epimerisation of artemisinin, has been shown to have poor antimalarial activity <00HCA1239>. 

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>. 

The Plasmodium falciparum malaria PD model successfully described the antimalarial effect of artemisinin, mefloquine, and a combination of the two drugs... 

Eckstein-Ludwig U, Webb RJ, van Goethan ID, East JM, Lee AQ Kimura M, O Neill PM, Bray PG Ward SA, Krishna S. (2003) Artemisinins target the SERCA of Plasmodium falciparum. Nature 424 957-961. 

Artemisinin, a tetracyclic 1,2,4-trioxane isolated from Artemisia annua L., is currently recommended as a first-line agent against Plasmodium falciparum malaria. Artemisinin and its synthetic derivatives have also been shown to be promising prototypes for the development of new antiproliferative agents. This chapter presents the recent advances on the analytic methods for extraction and quantification of artemisinin from A. annua plants as well as the biological properties of this natural product. 

The ozonide (176) was prepared as part of a synthetic study towards the antimalarial natural product artemisinin (177) <92JCS(Pl)325l>. It proved stable enough to allow x-ray crystal structure determination (see Section 4.16.3.1). Other, more complex, polycyclic ozonides were prepared in order to investigate possible antimalarial properties. Compounds were evaluated in vitro for antimalarial activity using a multiresistant strain of Plasmodium falciparum. Most were found to be weakly active although a thousand times less active than artemisinin. 

Iron(n) is known to decompose hydrogen and dialkyl peroxides to free radicals by reductive cleavage of the 0—0 bond and early investigations established the parasite s sensitivity to these species. When treated with radiolabelled C-artemisinin, the hemin-hemozoin fraction of the lysed malaria-infected erythrocytes was shown to contain a radiolabel, though the mechanism of incorporation is not clear. Meshnick and coworkers demonstrated that uninfected cells did not contain radiolabelled proteins whereas six radiolabelled proteins were isolated from cells infected with the Plasmodium falciparum (P. falciparum) strain of the parasite. It was suspected that one of the alkylated proteins was the Histidine Rich Protein (HRP) that was known to bind multiple heme monomers and therefore thought to be instrumental to the parasite s detoxification process. Moreover, iron chelators were found to inhibit the lethal effects of peroxides on the parasite. ... 

G3 factor, 199, 201, 202 mechanisms, 1309, 1310 NMR spectroscopy, 710 OZ 277 drug candidate, 1317, 1319, 1331 Plasmodium falciparum resistance, 608 synthetic, 1282, 1317-31 antimalarial activities, 1332 semi-synthetic artemisinin derivatives, 1313-17, 1332... 

Artemisinin is a natural endoperoxide-containing sesquiterpene, isolated from a plant used in traditional Chinese medicine. Acetalic artemisinin derivatives (arte-mether, artesunate) are very active against chemo-resistant forms of Plasmodium falciparum, and are clinically used for the treatment. However, they suffer from an unfavourable pharmacological profile. They are quickly metabolised by fast oxidative metabolism, hydrolytic cleavage and glucuronidation. 

Most studies have concentrated on the synthesis of new active artemisinin analogs. A series of highly lipophilic ether derivatives have been prepared and tested and the two most active compounds 311a,b provided 100% protection to Plasmodium yoelii nigeriensis infected mice <2006JME7227>. 

Artemisia annua L. A. apiacea Hance ex Walpers Qing Guo (Stinking artemisia) (aerial part) Dihydroartemisinin, artesunate, artemisinin, chloroquine, flavonoids, sesquiterpene.33-269-476 This herb is mildly toxic. A schizonticidal agent, antimalarial, treat infections of multidrug-resistant strains of Plasmodium falciparum, the cause of human malignant cerebral malaria. 

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. 

Bhisutthibhan, J., Pan, X.-O., Hossler, P.A., Walker, D.J., Yowell, C.A., Carlton, J., Dame, J.B., and Meshnick, S.R. The plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin,. Biol. Chem., 273,16192,1998. 

Table 2. Relative In Vitro Antimalarial Activity of 3-Substituted Analogues of Artemisinin against Plasmodium falciparum...

As can be seen in Table 5, neither target 240 (-4%) nor 241 (-16%) displayed substantial antimalarial potency relative to artemisinin (100%) in vitro against the W-2 clone of Plasmodium falciparum, yet the isomeric peroxide 258 was found to possess good antimalarial activity (-60%). The fourfold enhancement in activity of 241 relative to 240 is analogous to the ranking of activities between 10-deoxoartemisinin 108 and artemisinin 1. 

O Brien C, Henrich PP, Passi N, Fidock DA (2011) Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum. Curr Opin Infect Dis 24(6) 570-577... 

Artemisinin (Fig. 10.1) is a highly phytotoxic sesquiterpene endoperoxide,12 found only in the glandular trichomes of Artemisia annua,11 Duke et a/.13 first tested it for phytotoxicity because of its high level of activity against malarial parasites (Plasmodium spp).23 Others later verified that it is strongly phytotoxic.3,4,30 These studies showed little more than that the compound is highly phytotoxic. Chen and... 

For many years, the treatment of choice for malaria has been chloroquine. Unfortunately, chloroquine-resistant strains of Plasmodium species have developed, emphasizing the need for new antimalarials. One promising antimalarial is artemisinin. 

---