Abstract
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 microM), the more complex flavonoids (12-16) exhibited strong activity toward all three enzymes (IC50 0.5-8 microM). Isoflavonoids 26-28 showed moderate (IC50 7-30 microM) 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 microM). 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Oxoacyl-(Acyl-Carrier-Protein) Reductase
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Alcohol Oxidoreductases / antagonists & inhibitors*
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Alcohol Oxidoreductases / chemistry
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Catechin / analogs & derivatives
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Catechin / chemistry
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Cells, Cultured
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Chloroquine / pharmacology
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Drug Resistance
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Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*
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Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / chemistry
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Fatty Acids / antagonists & inhibitors*
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Fatty Acids / biosynthesis
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Flavones / chemical synthesis*
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Flavones / chemistry
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Flavones / pharmacology
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Flavonoids / pharmacology
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Humans
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Hydro-Lyases / antagonists & inhibitors*
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Hydro-Lyases / chemistry
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Kinetics
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Luteolin / chemistry
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Phenols / pharmacology
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Plasmodium falciparum / drug effects*
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Plasmodium falciparum / metabolism
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Polyphenols
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Structure-Activity Relationship
Substances
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Antimalarials
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Fatty Acids
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Flavones
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Flavonoids
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Phenols
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Polyphenols
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catechin gallate
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Chloroquine
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Catechin
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Alcohol Oxidoreductases
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3-Oxoacyl-(Acyl-Carrier-Protein) Reductase
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Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
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Hydro-Lyases
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beta-hydroxyacyl-(acyl-carrier-protein)dehydrase
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Luteolin