Letteratura scientifica selezionata sul tema "N-Heterocyclic iminium salts"

1,3-Dimethyl-5-imino-imidazolidine-2,4-dione (7a) undergoes thiolysis (H2S) to give the corresponding imidazolidine-2,4-dione-5-thione derivative 6. The 5-N-methylimino analogue 7b can be obtained from 7a by methylation. Further methylation of 7b affords the crude iminium salt 8c from which the heterocyclic orthoamide derivatives 10, 11 can be prepared. The heterocyclic amide acetal 9a can be obtained from 7a and dimethyl sulfate in methanol and subsequent addition of sodium methanolate in a one-pot reaction. The aminal ester 10 is converted to the amide acetal 9a on treatment with hydrogen chloride in methanol

An improved procedure for the preparation of trimethoxyacetonitrile (3a) starting from trichloroacetonitrile and sodium methanolate is described. Carbanions, obtained by the action of sodium hydride on nitriles, ethyl acetate and methylketones, react with trialkoxyacetonitriles 3 to give α- imino-orthocarboxylic acid trialkylesters 12, 14 and 20, which form an equilibrium with the tautomeric enamines 13, 15 and 21. The enamines 21 react with N,N-dimethylformamide dimethylacetal (24) to give amidines 25 which are cyclized to pyridinium salts 28 and 29 on treatment with benzyl bromide and acetyl chloride, respectively. The reaction of the enaminonitrile 13a with the orthoamide derivative of phenylpropiolic acid 30 affords the pyridine-2-orthocarboxylic acid trimethylester 31. The N,O-protected 4-hydroxy-piperidine 35 can be deprotonated by means of sec-butyl lithium. The carbanions thus formed are trapped with D2O, dimethyl sulfate, phenylisocyanate, CO2, and dimethyl carbonate delivering the piperidine derivatives 37 - 41. The heterocyclic orthoester 43 can be prepared analogously from 35 and 3a. The piperidine derivatives 44, 46 and 47 are prepared from the N,O-protected piperidines 39 and 41.

La vectorisation de médicaments a mis en exergue de réelles innovations pharmacologiques et pharmacocinétiques. Néanmoins, peu d’études originales ont été menées sur les vecteurs à visée antiparasitaire. Seuls des médicaments pour lesquels les parasites ont développé des mécanismes de résistance, ont été utilisés en vectorisation. Les conditions et coûts de préparation de ces nanoformulations sont également un frein majeur à leur future production. L’enjeu consistait donc à développer des nanovecteurs permettant la délivrance de nouvelles classes d’antiparasitaires, tout en s’appuyant sur une stratégie de synthèse « click » à la fois accessible et innovante. Dans un premier temps, le potentiel antipaludique de nouveaux sels d’iminium N-hétérocycliques a été évalué sur Plasmodium falciparum, responsable du paludisme. Les sels de bis-aminopyridiniums se sont avérés être les plus prometteurs avec des activités de l’ordre du sub-micromolaire et un mécanisme d’action original probablement lié à leurs forts pouvoirs rédox. Dans un deuxième temps, la vectorisation de ces candidats bis-aminopyridinium a été entreprise par la préparation de nanovecteurs de type conjugués polymère-médicament. Ces derniers ont été obtenus via une stratégie simple consistant en l’utilisation du bis-aminopyridinium comme initiateur de la polymérisation de son propre nanovecteur. L’étude des RSA a souligné l’importance d’un premier bloc acrylate et d’un arrangement sphérique sur l’activité. Ainsi, un système tribloc soluble, biodégradable et furtif, de tailles inferieures à 100 nm, vectorisant 5 mol% de principe actif, a permis le maintien d’une bonne activité antiplasmodiale, sans effet cytotoxique
Drug delivery has emphasised real pharmacological and pharmacokinetic advancements. Nevertheless, few in-depth and original studies have been conducted on antimalarial vectors. Only approved drugs, for which the parasites have developed resistance mechanisms, have been used in vectorization. The conditions and costs of preparation of these nanoformulations constitute a major barrier to their future production. This project aimed at developing nanovectors for the delivery of new antiparasitic drugs, while relying on a both accessible and innovative "click" synthesis strategy. First, the antimalarial efficiency of new N-heterocyclic iminium salts was evaluated on Plasmodium falciparum, responsible for malaria. Bis-aminopyridinium salts proved to be the most promising candidates with sub-micromolar antiplasmodial activities and an original mechanism of action, probably related to their strong redox properties. Secondly, the vectorization of these bis-aminopyridinium drug candidates was undertaken through preparation of polymer-drug conjugate nanovectors. The latter were obtained via a simple strategy, consisting in the use of the bis-aminopyridinium salt as polymerization initiator of its own nanovector. The SAR study underlined the need for a first acrylate block and spherical arrangements on the activity. Hence, a soluble, biodegradable, and stealth triblock system with sizes lower than 100 nm and enabling the delivery of 5 mol% of drug, showed effective antiplasmodial activity, without any cytotoxic effect