Tasdemir, D., Lack, G., Brun, R., Rüedi, P., Scapozza, L. and Perozzo, R. (2006) Inhibition ofPlasmodiumfalciparumFatty Acid Biosynthesis: Evaluation of FabG, FabZ, and FabI as Drug Targets for Flavonoids. Journal of Medicinal Chemistry, 49 (11). pp. 3345-3353. 10.1021/jm0600545.
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After the discovery of a potent natural flavonoid glucoside as a potent inhibitor of FabI, a large flavonoid library was screened against three important enzymes (i.e., FabG, FabZ, and FabI) involved in the fatty acid biosynthesis of P. falciparum. Although flavones with a simple hydroxylation pattern (compounds 4-9) showed moderate inhibitory activity toward the enzymes tested (IC50 10-100 μM), the more complex flavonoids (12-16) exhibited strong activity toward all three enzymes (IC50 0.5-8 μM). Isoflavonoids 26-28 showed moderate (IC50 7-30 μM) but selective activity against FabZ. The most active compounds were C-3 gallic acid esters of catechins (32, 33, 37, 38), which are strong inhibitors of all three enzymes (IC50 0.2-1.1 μM). Kinetic analysis using luteolin (12) and (-)-catechin gallate (37) as model compounds revealed that FabG was inhibited in a noncompetitive manner. FabZ was inhibited competitively, whereas both compounds behaved as tight-binding noncompetitive inhibitors of FabI. In addition, these polyphenols showed in vitro activity against chloroquine-sensitive (NF54) and -resistant (K1) P. falciparum strains in the low to submicromolar range. © 2006 American Chemical Society.
|Departments, units and centres:||Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry|
|Journal or Publication Title:||Journal of Medicinal Chemistry|
|Deposited By:||Library Staff|
|Deposited On:||09 Mar 2012 17:56|
|Last Modified:||09 Mar 2012 17:56|
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