A plant-derived morphinan as a novel lead compound active against malaria liver stages.Reportar como inadecuado

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* Corresponding author 1 Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires 2 Laboratoire de Chimie et Biochimie des Substances Naturelles 3 Service de chirurgie digestive et hépato-bilio-pancréatique CHU Pitié-Salpétrière 4 Department of Medical Microbiology 5 Laboratoire de Pharmacognosie Appliquée aux Maladies Infectieuses 6 Parasitologie et modèles expérimentaux

Abstract : BACKGROUND: The global spread of multidrug-resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s. METHODS AND FINDINGS: Using bioassay-guided fractionation based on the parasite-s hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro P. falciparum and P. yoelii and in vivo P. yoelii. Tazopsine fully inhibited the development of P. yoelii 50% inhibitory concentration IC50 3.1 muM, therapeutic index TI 14 and P. falciparum IC50 4.2 muM, TI 7 hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine NCP-tazopsine, with similar inhibitory activity was selected for its lower toxicity IC50 3.3 muM, TI 46, and IC50 42.4 muM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively. Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages. CONCLUSIONS: A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs.

Autor: Maëlle Carraz - Akino Jossang - Jean-François Franetich - Anthony Siau - Liliane Ciceron - Laurent Hannoun - Robert Sauerwein -

Fuente: https://hal.archives-ouvertes.fr/


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