Inhibition ofPlasmodiumfalciparumFatty 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.

<i>In vitro</i> and <i>in vivo</i> antiplasmodial activity of extracts from <i>Polyalthia suaveolens, Uvaria angolensis and Monodora tenuifolia</i> (Annonaceae)

“…They might be individually and/or collectively responsible for the exhibited antiplasmodial activity. Indeed, these groups of compounds were previously reported to have significant inhibitory effects on P. falciparum (Kaur et al, 2009;JimenezRomero et al, 2008;Tasdemir et al, 2006). Functional terminal lactones or butenolide often characterize the acetogenins (Li et al, 2008).…”

X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy

“…These researchers also reported the discovery of a rhodanine class of small molecule binders to PfENR, with the most efficacious member of this class approximating the activity of triclosan (58). Building on initial investigations into plant polyphenols as antibacterial FAS-II inhibitors (59), other researchers have independently examined natural product inhibitors of PfENR where a common structural theme is the presence of one or more phenolic moieties (60,61). Interestingly, select members of the green tea catechin family were high nanomolar inhibitors of PfENR alone while also potentiating the efficacy of triclosan inhibition proposedly through the formation of a PfENR⅐catechin⅐triclosan complex (62).…”

Synthesis and Biological Activity of Novel

“…The diastereomeric mixture of alkene (15) was reacted in the next step in a cross-metathesis reaction with vinylboronic acid pinacol ester (17). Unsure about the effect of the diene moiety on the reaction, we were pleased to find that the cross-metathesis proceeded well according to TLC analysis.…”

“…Interestingly, FabG is the only enzyme in the catalytic cycle that undergoes a substantial conformational change upon binding of its cofactor which could offer additional opportunities for drug development [16]. However, this enzyme is not rate limiting in the catalytic cycle which possibly explains why the few reported inhibitors of FabG only show moderate antibiotic activity [17]. In the next step, the alcohol of the -hydroxyacetyl-ACP complex is eliminated by FabA or FabZ to give trans-2-acetyl-ACP.…”