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Castanet-Tolosan, France

Meunier B.,Palumed | Meunier B.,CNRS Coordination Chemistry | Robert A.,CNRS Coordination Chemistry
Accounts of Chemical Research | Year: 2010

Heme is not only just the binding site responsible for oxygen transport by hemoglobin, but it is also the prosthetic group of many different heme-containing enzymes, such as cytochromes P450, peroxidases, catalase, and several proteins involved in electron transfer. Heme plays a key role in the mechanism of action of many different antimalarial drugs. In degrading the host's hemoglobin, the malaria parasite Plasmodium and several other heme-eating parasites are faced with this redox-active metal complex. Heme is able to induce the toxic reductive cascade of molecular oxygen, which leads to the production of destructive hydroxyl radicals. Plasmodium detoxifies heme by converting it into a redox-inactive iron(III) polymer called hemozoin. Artemisinin, a natural drug containing a biologically important 1,2,4-trioxane structure, is now the first-line treatment for multidrug-resistant malaria. The peroxide moiety in artemisinin reacts in the presence of the flat, achiral iron(II)-heme; the mechanism does not reflect the classical "key and lock" paradigm for drugs. Instead, the reductive activation of the peroxide function generates a short-lived alkoxy radical, which quickly rearranges to a C-centered primary radical. This radical alkylates heme via an intramolecular process to produce covalent heme-drug adducts. The accumulation of non-polymerizable redox-active heme derivatives, a consequence of heme alkylation, is thought to be toxic for the parasite. The alkylation of heme by artemisinin has been demonstrated in malaria-infected mice, indicating that heme is acting as the trigger and target of artemisinin. The alkylation of heme by artemisinin is not limited to this natural compound: the mechanism is invoked for a large number of antimalarial semisynthetic derivatives. Synthetic trioxanes or trioxolanes also alkylate heme, and their alkylation ability correlates well with their antimalarial efficacy. In addition, several reports have demonstrated the cytotoxicity of artemisinin derivatives toward several tumor cell lines. Deoxy analogues were just one-fiftieth as active or less, showing the importance of the peroxide bridge. The involvement of heme in anticancer activity has thus also been proposed. The anticancer mechanism of endoperoxide-containing molecules, however, remains a challenging area, but one that offers promising rewards for research success. Although it is not a conventional biological target, heme is the master piece of the mechanism of action of peroxide-containing antimalarial drugs and could well serve as a target for future anticancer drugs. © 2010 American Chemical Society.

Boissier J.,University of Perpignan | Boissier J.,CNRS Host-Pathogen-Environment Interactions Laboratory | Portela J.,University of Perpignan | Portela J.,CNRS Host-Pathogen-Environment Interactions Laboratory | And 4 more authors.
Comptes Rendus Chimie | Year: 2012

Schistosomiasis is a chronic life-threatening parasitic disease concerning more than 200 million people in the World. Little attention has been paid to schistosomiasis over the last 30 years, and praziquantel is the only drug in use to control this disease. In the absence of a vaccine, there is a real need for new drugs in order both to improve the efficacy of the treatment and to delay the development of praziquantel resistant schistosomes. The present note reports the significant reduction of the worm burden after oral administration of trioxaquine PA1259 to mice infected by Schistosoma mansoni. © 2011 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

After a brief survey of the current situation concerning the discovery of new drugs in the field of malaria or bacterial infections, we describe the preparation of hybrid molecules as new anti-infective agents: trioxaquines as antimalarials and Vancomyquines® as antibiotics. These hybrid molecules are active on malarial parasites or bacteria that are resistant to classical drugs that are currently used. © 2009 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Ceccom J.,Toulouse 1 University Capitole | Cosledan F.,Palumed | Halley H.,Toulouse 1 University Capitole | Halley H.,French National Center for Scientific Research | And 6 more authors.
PLoS ONE | Year: 2012

Alzheimer's disease (AD) is a neurodegenerative syndrom involving many different biological parameters, including the accumulation of copper metal ions in Aβ amyloid peptides due to a perturbation of copper circulation and homeostasis within the brain. Copper-containing amyloids activated by endogenous reductants are able to generate an oxidative stress that is involved in the toxicity of abnormal amyloids and contribute to the progressive loss of neurons in AD. Since only few drugs are currently available for the treatment of AD, we decided to design small molecules able to interact with copper and we evaluated these drug-candidates with non-transgenic mice, since AD is mainly an aging disease, not related to genetic disorders. We created a memory deficit mouse model by a single icv injection of Aβ1-42 peptide, in order to mimic the early stage of the disease and the key role of amyloid oligomers in AD. No memory deficit was observed in the control mice with the antisense Aβ42-1 peptide. Here we report the capacity of a new copper-specific chelating agent, a bis-8-aminoquinoline PA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model. © 2012 Ceccom et al.

Portela J.,University of Perpignan | Portela J.,CNRS Host-Pathogen-Environment Interactions Laboratory | Boissier J.,University of Perpignan | Boissier J.,CNRS Host-Pathogen-Environment Interactions Laboratory | And 7 more authors.
PLoS Neglected Tropical Diseases | Year: 2012

Schistosomiasis is among the most neglected tropical diseases, since its mode of spreading tends to limit the contamination to people who are in contact with contaminated waters in endemic countries. Here we report the in vitro and in vivo anti-schistosomal activities of trioxaquines. These hybrid molecules are highly active on the larval forms of the worms and exhibit different modes of action, not only the alkylation of heme. The synergy observed with praziquantel on infected mice is in favor of the development of these trioxaquines as potential anti-schistosomal agents. © 2012 Portela et al.

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