which the 10-position has been functionaiized. The semisynthetic analogue 16 is hydrolytically stable, and retains an IC50 value of 1.4 nM (31). It is also orally available, and is more potent in vivo than artemisinin. Artemisinin-derived trioxane dimers such as 17 are also stable to hydrolysis; 17 has an IC50 of 1.3 nM against cultured P. falciparum (32). In a series of C10-phenoxy analogues of artemisinin, excellent activity was retained, and the analogues were hydrolytically stable (33). Interestingly, the most active analogues were 18, a C10a derivative, and 19, a C10p derivative, with IC50 values of 2.61 and 3.90 nM, respectively. Considerable research has been done aimed at elucidating the potential mechanism of artemisinin and similar compounds, and there are multiple theories as to the fate of the initial adduct produced by iron-mediated opening of the characteristic endoperoxide moiety (34) The promising antimalarial activity of artemisinin and its derivatives prompted the evaluation of dispiro-1,2,4,5-tetraoxanes such as 20, WR148999. Compound 20 possesses antimalarial activity comparable to artemisinin, but also shares the characteristics of being hydrolytically unstable and poorly bioavailable by oral administration (35). Other simpler molecules also possess good activity against Plasmodium, such as the 1,2,5-trioxy- and 1,2,5,6-tetraoxycycloalkanes typified by
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