Dispiro-1,2,4,5-tetraoxanes: a new class of antimalarial peroxides

Abstract

Dispiro-1,2,4,5-tetraoxanes 2-4 were synthesized as potential peroxide antimalarial drugs. They had curative activity against Plasmodium berghei in vivo at single doses of 320 and 640 mg/kg which confirms earlier unpublished data. Moreover, artemisinin (1) and 4 had equivalent ED50's against P. berghei in vivo in the multiple-dose Thompson test; neither showed any evidence of acute toxicity at total doses of more than 12 g/kg. Dispiro-1,2,4,5-tetraoxane 4 had IC50's comparable to those of 1 against Plasmodium falciparum clones in vitro. These results confirm the potential of dispiro-1,2,4,5-tetraoxanes as a new class of inexpensive peroxide antimalarial drugs.

Assessment of the antimalarial potential of tetraoxane WR 148999.

“…2,3 Numerous antimalarial synthetic 1,2,4-trioxanes have been prepared. [3][4][5] We reported 6 that three dispiro-1,2,4,5-tetraoxanes, another class of antimalarial peroxides, were also active antimalarial agents, a confirmation of earlier unpublished data (Doorenbos HE and Decker DL). The most active of these was the tetraoxane WR 148999.…”

“…6 In the present study, we extend the pharmacodynamic comparison between WR 148999 and artemisinin with respect to duration of action in a mouse malaria model. In addition, we compare the antimalarial efficacy of WR 148999 in mice infected with chloroquine-sensitive or chloroquine-resistant Plasmodium berghei.…”

“…WR 148999 was synthesized as previously reported. 6 Tritiated hypoxanthine (1.0 mCi/ml, specific activity 24.2 Ci/mmol), was obtained from NEN Life Science Products, Inc. (Boston, MA). Scintillation counting supplies were obtained from Wallac, Inc. (Gaithersburg, MD).…”

Synthesis, antimalarial activity evaluation and molecular docking studies of some novel dispiro-1,2,4,5-tetraoxanes

“…Tetraoxanes are believed to have a similar mode of activity as the naturally occurring endoperoxides such as artemisinin Vennerstrom et al, 1992Vennerstrom et al, , 2000.…”

A new oxidation process. Transformation of gem-bishydroperoxides into esters

“…In recent years, interest in organic gem-bishydroperoxides has increased sharply with respect to the cyclic peroxides possessing high antimalarial activity [1][2][3][4][5][6][7][8][9]. Previously we reported a new effective method for the synthesis of gem-bishydroperoxides based on a reaction of ketals with hydrogen peroxide catalyzed by boron trifluoride complexes [10].…”