title: Inhibition of Plasmodium falciparum fatty acid biosynthesis: evaluation of FabG, FabZ, and FabI as drug targets for flavonoids.
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.
authors.affiliation: University of Zurich, Institute of Organic Chemistry, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. deniz.tasdemir@pharmacy.ac.uk
authors.forename: Deniz
authors.initials: D
authors.lastname: Tasdemir
authors.forename: Gabriela
authors.initials: G
authors.lastname: Lack
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Peter
authors.initials: P
authors.lastname: Rüedi
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.forename: Remo
authors.initials: R
authors.lastname: Perozzo
mesh_terms: D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives / Q000737:chemistry; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005227:Fatty Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D047309:Flavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D047311:Luteolin / Q000737:chemistry; D010636:Phenols / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D059808:Polyphenols; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D005227:Fatty Acids; D047309:Flavones; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; C417939:catechin gallate; D002738:Chloroquine; D002392:Catechin; D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D006836:Hydro-Lyases; C036180:beta-hydroxyacyl-(acyl-carrier-protein)dehydrase; D047311:Luteolin