Antimalarial trioxane analogs

The importance of high-valent Fe=0 in the molecular mechanism of action of antimalarial trioxane analogs of artemisinin has been demonstrated [50]. It is interesting that chloroperoxidase is able to catalyze not only the chlorination of organic compounds, but it is an oxygenase which can also oxidize indoles [51]. 

Since the 1990s, many research studies have demonstrated that 1,2,4-trioxanes and 1,2,4,5-tetraoxanes are important qinghaosu analogs. Some compounds are promising because of their high antimalarial activity and easy preparation. Some reviews about these peroxides have been pubhshed. ... 

Antimalarial activity of 4,5-secoartemisinins (51 1-4) which consisted of 1,2,4-trioxane with a lactone has been reported [53]. (-)-5-Nor-4,5-secoartemisinin (51 2, Rj = CH3> R2= H, R3= CH3) was as effective as artemisinin against the D-6 clone. The same analogs which were prepared by using the prediction in CoMFA analysis showed that the differences of activity were small between the predicted and actual values [41]. 

Artemisinin 17, 1,2,4-trioxane 18 itself, and some ring-fused, artemisinin-analogous 1,2,4-trioxanes have been studied theoretically and reported previously in CHEC-II(1996). While the nonsubstituted 1,2,4-trioxane ring prefers an envelope conformation, stmcturally related analogs favor a twist boat conformation. l,2,4-Trioxane-5-one 19 and a number of derivatives, also investigated theoretically, prefer half-chair conformations (cf Figure 2). Molecular electrostatic potentials (MEPs) obtained by theoretical studies (CHEC-II(1996)) of certain derivatives of 17 and 18 were included in structure/antimalarial activity correlations however, distinct conclusions between MEPs and antimalarial activities were not drawn. 

The definitive assignments of the H and C NMR spectra of artemisinin 17 and other analogs have been reported. The 7c,h coupling constant was employed as a reliable index of the configuration of the substituents on the 1,2,4-trioxane framework and, by dynamic NMR spectroscopy, the barriers to ring interconversion of various 1,2,4-trioxane derivatives were estimated. In addition, a series of strategies has been developed using one-dimensional (TD) and 2-D NMR spectroscopy for identification of the relative stereochemistry in an assembly of substituted antimalarial... 

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