Fiche publication
Date publication
février 2017
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth
,
Dr ELHABIRI Mourad
Tous les auteurs :
Krieg R, Jortzik E, Goetz AA, Blandin S, Wittlin S, Elhabiri M, Rahbari M, Nuryyeva S, Voigt K, Dahse HM, Brakhage A, Beckmann S, Quack T, Grevelding CG, Pinkerton AB, Schönecker B, Burrows J, Davioud-Charvet E, Rahlfs S, Becker K
Lien Pubmed
Résumé
In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC 1-5 nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites.
Mots clés
Amines, chemistry, Animals, Anopheles, parasitology, Anti-Infective Agents, pharmacology, Antiparasitic Agents, chemistry, Cell Death, drug effects, Cell Proliferation, drug effects, Female, Germ Cells, drug effects, Inhibitory Concentration 50, Life Cycle Stages, drug effects, Malaria, parasitology, Mice, Models, Biological, Parasites, drug effects, Plasmodium berghei, drug effects, Plasmodium falciparum, drug effects, Schistosoma mansoni, drug effects, Steroids, chemistry, Toxicity Tests, Acute
Référence
Nat Commun. 2017 Feb 17;8:14478
