Trypanosomiasis and leishmaniasis are important parasitic diseases affecting millions of people in Africa, Asia, and South America. In a previous study, we identified several flavonoid glycosides as antiprotozoal principles from a Turkish plant. Here we surveyed a large set of flavonoid aglycones and glycosides, as well as a panel of other related compounds of phenolic and phenylpropanoid nature, for their in vitro activities against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani. The cytotoxicities of more than 100 compounds for mammalian L6 cells were also assessed and compared to their antiparasitic activities. Several compounds were investigated in vivo for their antileishmanial and antitrypanosomal efficacies in mouse models. Overall, the best in vitro trypanocidal activity for T. brucei rhodesiense was exerted by 7,8-dihydroxyflavone (50% inhibitory concentration [IC 50 ], 68 ng/ml), followed by 3-hydroxyflavone, rhamnetin, and 7,8,3,4-tetrahydroxyflavone (IC 50 s, 0.5 g/ml) and catechol (IC 50 , 0.8 g/ml). The activity against T. cruzi was moderate, and only chrysin dimethylether and 3-hydroxydaidzein had IC 50 s less than 5.0 g/ml. The majority of the metabolites tested possessed remarkable leishmanicidal potential. Fisetin, 3-hydroxyflavone, luteolin, and quercetin were the most potent, giving IC 50 s of 0.6, 0.7, 0.8, and 1.0 g/ml, respectively. 7,8-Dihydroxyflavone and quercetin appeared to ameliorate parasitic infections in mouse models. Generally, the test compounds lacked cytotoxicity in vitro and in vivo. By screening a large number of flavonoids and analogues, we were able to establish some general trends with respect to the structure-activity relationship, but it was not possible to draw clear and detailed quantitative structure-activity relationships for any of the bioactivities by two different approaches. However, our results can help in directing the rational design of 7,8-dihydroxyflavone and quercetin derivatives as potent and effective antiprotozoal agents.

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.

Recognition by rice plants (Oryza sativa) of the nonhost pathogen Pseudomonas syringae pv. syringae leads to an active response ultimately resulting in local acquired resistance against the rice blast fungus Pyricularia oryzae. An observable aspect of this defense response is the increased abundance of a set of transcripts. The accumulation of one of these transcripts, Pir7b, was dependent on the function of the bacterial lemA gene, which encodes part of a twocomponent regulatory system. This suggested that the lemA regulatory system controlled the production of an elicitor of Pir7b transcript accumulation. This elicitor, which we name syringolin, was purified to homogeneity and its structure was elucidated. Syringolin is a novel and unusual secreted peptide consisting of a 12-membered ring formed by the two non-proteinogenic amino acids 5methyl-4-amino-2-hexenoic acid and 3,4-dehydrolysine. The α-amino group of the latter is connected by a peptide bond to a valine that in turn is linked to a second valine via a urea moiety. Application of syringolin onto rice leaves elicited the accumulation of Pir7b as well as of other defense-related transcripts and induced resistance toward P. oryzae. Thus, syringolin is one of several determinants by which rice plants can perceive the nonhost pathogen P. syringae pv. syringae.

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Anti-plasmodial activity-guided fractionation of Phlomis brunneogaleata (Lamiaceae) led to the isolation of two new metabolites, the iridoid glycoside, brunneogaleatoside and a new pyrrolidinium derivative (2S,4R)-2-carboxy-4-(E)-p-coumaroy- and X-ray crystallography. Compounds 10 and 11 were determined to be the major anti-malarial principles of the crude extract (IC 50 values of 2.4 and 5.9 mg/mL, respectively). They also exhibited significant leishmanicidal activity (IC 50 = 1.1 and 4.1 mg/mL, respectively). The inhibitory potential of the pure metabolites against plasmodial enoyl-ACP reductase (FabI), which is the key regulator of type II fatty acid synthases (FAS-II) in P. falciparum, was also assessed. Compound 10 showed promising FabI inhibiting effect (IC 50 = 10 mg/mL) and appears to be the first anti-malarial natural product targeting FabI of P. falciparum.