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... 

The ease of addition of the Sn-0 bond of a peroxide to a carbonyl group has been exploited in an improved route to the 1,2,4-trioxane antimalarials.152... 

The bicyclic trioxane (248) is important simply by being the first to be described. It is claimed to improve the octane rating of certain diesel fuels and to be effective at promoting the polymerization of diallyl phthalate and dienes such as butadiene and methylpentadienes <58USP2853494>. These claims presage the biological role found for the trioxane antimalarials. 

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

New chemistry of quinghao, a marvelous herb of antiquity, and antimalarial trioxane qinghaosu 97ACR73. 

Trioxane 210 has been used as a model system by Gu and coworkers to study the antimalarial drug artemisinin 211 (Scheme 137) [97CPL234, 99JST103]. It is the boat/twist form rather than the chair conformer of 210 that describes the subunit in 211. Moreover, geometric parameters and vibrational frequencies can only reliably be computed at the DFT level and by post-Hartree-Fock methods. B3-LYP/6-31G calculations on the conformers of 3,3,6,6-tetramethyl-1,2,4,5-tetroxane show that the chair conformer is stabilized with respect to the twisted conformer by about -2.8 kcal/mol [00JST85]. No corresponding boat conformer was found. 

Studies on the mode of activity of the antimalarials related to artemisinin have centred on simpler 1,2,4-trioxanes, 1,2,4,5-tetraoxanes and bicyclic endoperoxides <00H(52)1345 00JCS(P1)1265 00JMC2753 00TL3145>. The chemical and electro-chemical reduction of artemisinin has been reported <00JCS(P1)4279>. 

The large diversity of biological activities including antimalarial, antioxoplasmosis, antileishmaniasis, antishistosomiasis, antitrypanosomiasis, antiviral, antifugal and even anticancer activities displayed by artemisinin and artemisinin derivatives (cf. Ref. 55 for a review) added to the multitude of artemisinin-inspired trioxanes, trioxolanes, tetraoxa-cycloalkanes and peroxide, homodimeric-, trimeric- and even tetrameric artemisinin derivatives recently designed and synthesized is a clear indication that in the future, these compounds will become even more important in the chemotherapy of various diseases, perhaps even above and beyond those mentioned here. 

O Neill PM, Rawe SL, Borsmik K, Miller A, Storr RC, Ward SA, Bray PG Davies J, Ho Oh C, Posner GH. (2005) Enantiomeric 1,2,4-trioxanes display equivalent in vitro antimalarial activity versus Plasmodium falciparum... 

Posner GH, Chang W. (2008) Antimalarial sulfide trioxanes A revision of mechanism. J Phys Org Chem 21 538-540. 

Posner GH, Oh CH, Webster HK, Ager ALJr, Rossan RN. (1994) New antimalarial tricyclic 1,2,4-trioxanes evaluation in mice and monkeys. Am J Prop Med Hyg 50 522-526... 

Posner GH, McRiner AJ, Paik IH, Sur S, Borsmik K, Xie S, Shapiro TA, Alagbala A, Foster B. (2004) Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. J Med Chem 47 1299-1301. 

The triethylsilyl trioxide reacts smoothly with internal disubstituted olefins to give potent antimalarial 1,2,4-trioxanes, especially when there is oxygen functionality in the molecule (equation 84). 

In 1972, Chinese researchers isolated, by extraction at low temperature from a plant, a crystalline compound that they named qinghaosu [the name artemisinin (la) is preferred by Chemical Abstracts, RN 63968-64-9]. The plant source of artemisinin is a herb, Artemisia annua (Sweet wormwood), and the fact that artemisinin is a stable, easily crystallizable compound renders the extraction and purification processes reasonably straightforward. The key pharmacophore of this natural product is the 1,2,4-trioxane unit (2) and, in particular, the endoperoxide bridge. Reduction of the peroxide bridge to an ether provides an analogue, deoxyartemisinin 3, that is devoid of antimalarial activity. ... 

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. 

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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