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Antimalarial chemotherapy: orally curative artemisinin-derived trioxane dimer esters.

ABSTRACT: Eight new artemisinin-derived trioxane dimer esters 5 have been prepared and tested for antimalarial efficacy in malaria-infected mice. At a single oral dose of only 6mg/kg combined with 18mg/kg of mefloquine, each of the dimer esters 5 outperformed the antimalarial drug artemether (2). The most efficacious dimer, dichlorobenzoate ester 5h, prolonged mouse survival past day 30 of infection with three of the four mice in this group having no detectable parasitemia and appearing and acting healthy on day 30.

SUBMITTER: Conyers RC

PROVIDER: S-EPMC4277730 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Antimalarial chemotherapy: orally curative artemisinin-derived trioxane dimer esters.

Conyers Ryan C RC Mazzone Jennifer R JR Tripathi Abhai K AK Sullivan David J DJ Posner Gary H GH

Bioorganic & medicinal chemistry letters 20141127 2

Eight new artemisinin-derived trioxane dimer esters 5 have been prepared and tested for antimalarial efficacy in malaria-infected mice. At a single oral dose of only 6mg/kg combined with 18mg/kg of mefloquine, each of the dimer esters 5 outperformed the antimalarial drug artemether (2). The most efficacious dimer, dichlorobenzoate ester 5h, prolonged mouse survival past day 30 of infection with three of the four mice in this group having no detectable parasitemia and appearing and acting healthy ...[more]

PMID: 25481079

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Antimalarial chemotherapy: artemisinin-derived dimer carbonates and thiocarbonates.

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| S-EPMC4074917 | biostudies-literature

Synthesis and antimalarial efficacy of two-carbon-linked, artemisinin-derived trioxane dimers in combination with known antimalarial drugs.

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| S-EPMC3630999 | biostudies-literature

The survival times of malaria-infected mice are prolonged more by several new two-carbon-linked artemisinin-derived dimer carbamates than by the trioxane antimalarial drug artemether.

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Novel series of 1,2,4-trioxane derivatives as antimalarial agents.

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| S-EPMC8741894 | biostudies-literature

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An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV) and anti-cancer activities.

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Project description:Elucidation of the principal targets of the action of the antimalarial drug artemisinin is an ongoing pursuit that is important for understanding the action of this drug and for the development of more potent analogues. We have examined the chemical reaction of Hb with artemisinin. The protein-bound haem in Hb has been found to react with artemisinin much faster than is the case with free haem. It appears that the uptake of Hb and the accumulation of artemisinin into the food vacuole, together with the preferred reactivity of artemisinin with haem in Hb, may make Hb the primary target of artemisinin's antimalarial action. Both monoalkylated (HA) and dialkylated (HAA) haem derivatives of artemisinin have been isolated. These 'haemarts' bind to PfHRP II (Plasmodium falciparum histidine-rich protein II), inhibiting haemozoin formation, and possess a significantly decreased ability to oxidize ascorbic acid. The accelerated formation of HAA from Hb is expected to decrease the ratio of haem to its alkylated derivatives. The haemarts that are generated from 'haemartoglobins' may bring about the death of malaria parasite by a two-pronged effect of stalling the formation of haemozoin by the competitive inhibition of haem binding to its templates and creating a more reducing environment that is not conducive to the formation of haemozoin.

| S-EPMC1134711 | biostudies-other

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