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Information Seminar Paper

Title

SYNTHESIS AND DETERMINATION OF ANTIMALARIAL ACTIVITY OF HYDROXYPYRIDINONE-CONTAINING CHLOROQUINE ANALOGUES

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Abstract

 Introduction: Recently, 3-hydroxypyridin-4-ones (HPOs) as iron (III) chelating agents have  been shown to possess antimalarial activity. In order to increase the antimalarial efficacy of HPOs, it was decided to synthesize analogues that were also similar to chloroquine. Thus a series of basic HPOs were designed, each possessing a quinoline ring.Methods: The hydroxyl group of 2-ethytl-3-hydroxypyran-4-one was benzylated using benzyl bromide, then it was converted to benzylated HPOs with ethylen diamine, in aqueous ethanol. The resulted pyridinones were reacted with the 4-Cl-substituted quinolines. Deprotection of hydroxyl group was achieved by catalytic hydrogenation to yield the corresponding bidentate chelators.Results: Identification and structural elucidation of compounds were achieved by 1HNMR, Mass spectra and elemental analysis. The pKa values of the ligands and their partition coefficients between 1-octanol/ water (pH 7.4) have been determined. The in vitro antimalarial activity of the basic HPOs was compared with N-alkyl pyridinone and desferrioxamine. All ligands inhibited the growth of the Plasmodium falciparum. The hydrophobic chelators are more active than hydrophilic. The synthesized compounds were found to have the lowest IC50 (5-10µM) values in comparison with N-alkyl pyridinone (50µM) and desferrioxamine (28µM).Conclusion: The synthesized compounds are more active against malarial parasites than the alkyl analogue and desferrioxamine and hence provide the most promising lead for basic hydroxypyridinone-containing chloroquine analogues as candidates for antimalarial compounds.

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