Radicals 1,2,4-trioxane antimalarials

Posner and Oh, and later Jefford and coworkers led the earliest investigations by synthetic chemists into the mechanism of action of 1,2,4-trioxane antimalarials. Both proposed that formation of a C-centred radical was essential for activity but the nature of the radical (primary or secondary) and the mechanistic pathways put forward were not identical. The iron degradation studies of Posner and coworkers implicated a role for the... 

Jefford and coworkers have investigated the iron(II) degradation of fenozan BO-7 (4) and have proposed that a primary radical must be implicated in the mechanism of action of 1,2,4-trioxane antimalarials . Fenozan was degraded using iron(II) chloride in aqueous... 

Trioxane antimalarials C3-aryl, 1325-6, 1327, 1332 carbon-centered radicals, 1283-99, 1309 dimers, 283... 

Posner, G. H. Oh, C. H. Wang, D. Gerena, L. Milhous, W. K. Meshnick, S. R. Asawamahasadka, W. Mechanism-based design, synthesis, and in vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin The importance of a carbon-centered radical for antimalarial activity. J. Med Chem., 1994, 37(9) 1256-1258. 

In order to determine the significance of the 1,5-H shift and the secondary radical species for antimalarial activity, the trioxanes 22a-c were synthesized and tested . The diastereomeric trioxanes 22a and 22b possessed very different antimalarial activity against both chloroqnine-resistant and chloroqnine-sensitive strains of the parasite the A-fi isomer was approximately twice as active as artemisinin while the A-a isomer and the disubsti-tnted trioxane were more than sixty times less potent. The anthors proposed that the a-snbstitnent prevented the snprafacial 1,5-H shift and therefore snppressed the activity of these componnds. 

Introduction of a methyl group at the 4-/1 position actually resulted in increased activity, because of the additional stabilization of the secondary C4 radical. A series of trioxanes 25-32 were prepared to determine the effect of C4 substitution on antimalarial activity. The functionalities introduced included radical stabilizing groups (methyl, phenyl, benzyl, CH2TMS) and CH2SnR3 (R = Me, Bn) designed to intercept the C4 radical. As previously observed, for all compounds with measurable antimalarial activity the S-isomers were more antimalarially active than the a-isomers. 

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