Comparative Antimalarial Activities of Six Pairs of 1,2,4,5-Tetraoxanes (Peroxide Dimers) and 1,2,4,5,7,8-Hexaoxonanes (Peroxide Trimers)

Abstract

Six tetraoxanes had 50% inhibitory concentrations in the range of 10 to 100 ng/ml against Plasmodium falciparum, whereas the corresponding hexaoxonanes had minimal antimalarial activity. The lack of ironmediated reactivity of the hexaoxonanes may explain their low activity compared to the tetraoxanes, the latter of which are able to undergo iron(II)-mediated activation.The antimalarial artemisinin (qinghaosu) contains a pharmacophoric peroxide bond within its 1,2,4-trioxane heterocycle. The complex structure of artemisinin is an incentive to identify more synthetically accessible antimalarial peroxides (10,13,15,18). One of the most structurally simple classes of antimalarial synthetic peroxides are 1,2,4,5-tetraoxanes (2,5,6,12,16), as exemplified by WR 148999 (Fig. 1). Tetraoxanes such as WR 148999 (20) differ considerably in structure from artemisinin, are readily prepared in one step from substituted cyclohexanones, and possess good antimalarial activity, although they are significantly less active than the semisynthetic artemisinins.In this study, we disclose the comparative antimalarial activities of six pairs of 1,2,4,5-tetraoxanes (peroxide dimers) 1a-1f and 1,2,4,5,7,8-hexaoxonanes (peroxide trimers) 2a-2f ( Fig. 2) to further elucidate the structure-activity-relationship of 1,2,4,5-tetraoxanes and, to our knowledge, record for the first time the antimalarial activity of 1,2,4,5,7,8-hexaoxonanes. The latter group of synthetic peroxides has been investigated primarily as synthetic precursors to macrocyclic lactones of perfumery interest (17). As previously described (7, 8), tetraoxanes 1a-1f and hexaoxonanes 2a-2f were prepared either by peroxidation of the corresponding ketone derivatives in H 2 SO 4 /CH 3 CN or by ozonolysis of the corresponding ketone O-methyl oximes. 1,3-Dioxolane 3, the nonperoxidic isostere of tetraoxane 1d, was prepared by ketalization of cyclohexanone with 1,1-dimethanolcyclohexane (TsOH, refluxing toluene) in 35% yield after Kugelrohr distillation (melting point 53 to 56°C) and characterized by 1 H and 13 C NMR and elemental analysis.As previously described (6), in vitro and in vivo antimalarial activities were measured using the chloroquine-resistant K1 and chloroquine-sensitive NF54 strains of Plasmodium falciparum-and P. berghei-infected mice, respectively. Groups of three P. berghei-infected MORO mice were treated 1 day postinfection with 100-mg/kg oral and subcutaneous doses of compounds dissolved or suspended in a solubilizing 3% ethanol and 7% Tween 80 vehicle. Antimalarial activity was measured by determining the percent reduction in parasitemia on day 3 postinfection compared to an untreated control group.The data in Table 1 show a clear demarcation in the antimalarial activities of tetraoxanes 1 and hexaoxonanes 2 against P. falciparum. Tetraoxanes 1 had 50% inhibitory concentrations (IC 50 s) in the range of 10 to 100 ng/ml, whereas all hexaoxonanes had minimal antimalarial activity; only three of these (2a, 2d, and 2f) had IC 50 s of Ͻ10,000 ng/ml. The previously rep...

Tetraoxanes: Synthetic and Medicinal Chemistry Perspective

“…It is important to mention here that most common side product of tetraoxane synthesis is 1,2,4,5,7,8-hexaoxonanes; although it contains peroxide bond, this class of compounds shows very poor antimalarial activity. 90 In order to understand the mechanistic insight of the activity difference, reactivity of tetraoxanes and hexaoxonanes with Fe(II) was investigated. 90 Tetraoxane underwent complete degradation in the presence of FeSO 4 , while hexaoxonanes did not show any reactivity with FeSO 4 .…”

“…90 In order to understand the mechanistic insight of the activity difference, reactivity of tetraoxanes and hexaoxonanes with Fe(II) was investigated. 90 Tetraoxane underwent complete degradation in the presence of FeSO 4 , while hexaoxonanes did not show any reactivity with FeSO 4 . Lack of iron-mediated reactivity of hexaoxonanes may be responsible for low antimalarial activity of hexaoxonanes.…”

“…Lack of iron-mediated reactivity of hexaoxonanes may be responsible for low antimalarial activity of hexaoxonanes. 90…”

Quantum chemical study of the intermediate complex required for iron-mediated reactivity and antimalarial activity of dispiro-1,2,4-trioxolanes

“…This study uses a substantially improved level of theory to confirm previous assertions that steric interactions around the peroxide bond influence the interaction with iron, and therefore determine antimalarial activity. The general relationship between peroxide bond exposure, ironmediated reactivity and antimalarial activity has also been shown for other trioxolanes [10], trioxanes [9], trioxepanes [32], tetraoxanes and hexaoxanes [33]. It therefore appears important to limit the steric hindrance around the peroxide bond when designing new synthetic peroxide antimalarials; however it is possible that excessive reactivity with iron may lead to increased drug clearance in vivo [10,13].…”

Cyclic organic peroxides thermal decomposition in the presence of CuFe2O4 magnetic nanoparticles

“…Free radicals or metallic ions in solution can interact with the O O bond, accelerating their decomposition reactions. For example, the antimalarial activities of some 1,2,4,5-tetraoxacyclohexanes and 1,2,4,5,7,8-hexaoxacyclononanes structurally related with I and II have been studied and compared with the antimalarial activity of the artemisinin (qinghaosu) extracted from the Chinese Artemisia plant [20], which contains a pharmacophoric peroxide bond within its 1,2,4-trioxacyclohexane cycle. It was demonstrated that the antimalarial specificity of artemisinin is that its peroxidic bond undergoes reductive activation by heme released by parasite hemoglobin digestion.…”