Plasmodium Purine Metabolism and Its Inhibition by Nucleoside and Nucleotide Analogues

International audienceMalaria still affects around 200 million people and is responsible for more than 400,000 deaths per year, mostly children in subequatorial areas. This disease is caused by parasites of the Plasmodium genus. Only a few WHO-recommended treatments are available to prevent or cure plasmodial infections, but genetic mutations in the causal parasites have led to onset of resistance against all commercial antimalarial drugs. New drugs and targets are being investigated to cope with this emerging problem, including enzymes belonging to the main metabolic pathways, while nucleoside and nucleotide analogues are also a promising class of potential drugs. This review highlights the main metabolic pathways targeted for the development of potential antiplasmodial therapies based on nucleos(t)ide analogues, as well as the different series of purine-containing nucleoside and nucleotide derivatives designed to inhibit Plasmodium falciparum purine metabolism.

Targeting purine metabolizing enzymes from Plasmodium falciparum : Design and Study of bio-actives derivatives

Le paludisme, problème de santé publique mondial, est dû à plusieurs parasites possédant la caractéristique de n'avoir qu'une voie de biosynthèse nucléotidique : la voie de récupération. Dans le cadre d'une conception rationnelle d'inhibiteurs d'enzymes impliqués dans le cycle purique chez Plasmodium Falciparum (un des parasites responsable du paludisme), plusieurs composés ont donné des résultats prometteurs. Le projet de thèse sera consacré d'une part à l'optimisation structurale de ces composé-hits en interaction avec une équipe de biologistes (SAR) et une équipe de structuralistes (relation structure fonction activité), et d'autre part à la mise au point de méthodes de dosages LC/MS/MS pour identifier et étudier les cibles biologiques, et révéler l'impact des nouveaux composés sur le métabolisme purique.Malaria, a global public health problem, is due to several parasites which are characterized by presenting only one nucleotide biosynthesis pathway : the recovery path. As part of a rational design of inhibitors of enzymes involved in purine cycle of Plasmodium Flaciparum (one of parasites responsible for malaria), several compounds have shown promising results. This PhD project will focus firstly on the structural optimization of these hits, in interaction with a team of biologists (SAR) and of structuralists (structure-fonction-activity relationship), and secundly on the development of LC/MS/MS dosage methods to identify and study the biological targets, and reveal the impact of the omptimized compounds on the purine metabolism

Synthesis of N-methylene phosphonate aziridines: Reaction scope and mechanistic insights

International audienceA series of N-carbamoyl aziridines has been treated by diethyl phosphite in presence of n-BuLi to afford α-methylene phosphonate aziridines in modest yields. The study of the reaction's scopes and the analysis of byproducts indicated that this transformation proceeds via a unique mechanism. The mechanism that produces the α-methylene phosphonate relies in the use of BuLi, where both the lithium ion and then the presence of the nucleophilic butyl is essential. In addition, the nature of the final compound, either α-methylene phosphonate or α-methylene-gem-bisphosphonate derivatives containing an aziridine motif, is highly dependent on the nature of the base used

Synthèse et Activité antipaludique de nouveaux analogues d’acyclonucléotides

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New series of acyclic nucleoside phosphonates as potent antimalarials

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Synthesis of acyclic nucleoside phosphonates as potent antimalarials

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β-Hydroxy- and β-Aminophosphonate Acyclonucleosides as Potent Inhibitors of Plasmodium falciparum Growth

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Synthesis of acyclic nucleoside phosphonates as potent antimalarials

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New series of acyclic nucleoside phosphonates as potent antimalarials

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Divalent Amino-Acid-Based Amphiphilic Antioxidants: Synthesis, Self-Assembling Properties, and Biological Evaluation

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