Endoperoxides artesunate

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

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 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. 

Artemisinins (artesunate, artemether,1 dihydroartemisinin1) Sesquiterpene lactone endoperoxides Treatment of P falciparum infections oral combination therapies for uncomplicated disease intravenous artesunate for severe disease... 

The semisynthetic artemisinins are available for oral (dihydroartemisinin, artesunate, and artemether), intramuscular (artesunate and artemether), intravenous (artesunate), and rectal (artesunate) dosing. Absorption after oral dosing typically is <30%. Peak plasma levels occur within minutes with artesunate and at 2-6 hours with artemether. The endoperoxides are not highly bound to plasma proteins. Both artesunate and artemether are converted extensively to dihydroartemisinin, which provides much of their antimalarial activity and has a plasma of 1—2 hours its major uri-... 

The most recent additions to the drug therapy for maiaria are artemisinin and its derivatives, isoiated from Artemisia annua (qinghao, sweetworm wood), this materiai has been used by Chinese herbaiists since 168 BC. Artemisinin and the synthetic and semisynthetic derivatives, artemether, artefiene, and artesunate, are active by virtue of the endoperoxide. 

A series of artemisinin-based semisynthetic antimalarial derivatives, with all of them maintaining the key endoperoxide bridge, such as arteether (18), artemether (19), artesunate (20), and dihydroartemisinin (21), have been designed to improve the water solubility and the metabolic stability of artemisinin [53, 54], Among them, dihydroartemisinin (artenimol), is considered as a common active metaboUte of artemisinin derivatives [53, 54]. Currently, artemisinin-based therapies eombined with standard antimalarials such as amodiaquine, sulfadoxine-pyrimethamine, mefloquine, and lumefantrine are recommended by the World Health Organization (WHO) as first-line therapies for malaria [55, 56]. 

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