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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.

Project description:Malaria continues to be a difficult disease to eradicate largely because of the widespread populations it affects and the resistance that malaria parasites have developed against once very potent therapies. The natural product artemisinin has been a boon for antimalarial chemotherapy, as artemisinin combination therapy (ACT) has become the first line of chemotherapy. Because the threat of resistance is always on the horizon, it is imperative to continually identify new treatments, comprising both advanced analogues of all antimalarial drugs, especially artemisinin, and the exploration of novel combinations, ideally with distinct mechanisms of action. Here we report for the first time the synthesis of a series of two-carbon-linked artemisinin-derived dimers, their unique structural features, and demonstration of their antimalarial efficacy via single oral dose administration in two 60-day survival studies of Plasmodium berghei infected mice. Several of the new endoperoxide chemical entities consistently demonstrated excellent antimalarial efficacy, and combinations with two non-peroxide antimalarial drugs have been studied.

| 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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| S-EPMC3393438 | biostudies-literature

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DNA binding by the antimalarial compound artemisinin.

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

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| S-EPMC1134711 | biostudies-other

Drug resistance genomics of the antimalarial drug artemisinin.

Project description:Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast Asia are showing that artemisinin-based treatments are beginning to lose their effectiveness, adding renewed urgency to the search for the genetic determinants of parasite resistance to this important drug class. We review the genetic and genomic approaches that have led to an improved understanding of artemisinin resistance, including the identification of resistance-conferring mutations in the P. falciparum kelch13 gene.

| S-EPMC4283579 | biostudies-literature

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