Antiplasmodial activity of nitroaromatic and quinoidal compounds: redox potential vs. inhibition of erythrocyte glutathione reductase

Prooxidant nitroaromatic and quinoidal compounds possess antimalarial activity, which might be attributed either to their formation of reactive oxygen species or to their inhibition of antioxidant enzyme glutathione reductase (GR, EC 1.6.4.2). We have examined the activity in vitro against Plasmodium falciparum of 24 prooxidant compounds of different structure (nitrobenzenes, nitrofurans, quinones, 1,1'-dibenzyl-4,4'-bipyridinium, and methylene blue), which possess a broad range of single-electron reduction potentials (E(1)(7)) and erythrocyte glutathione reductase inhibition constants (K(i(GR))). For a series of homologous derivatives of 2-(5'-nitrofurylvinyl)quinoline-4-carbonic acid, the relationship between compound K(i(GR)) and concentration causing 50% parasite growth inhibition (IC(50)) was absent. For all the compounds examined in this study, the dependence of IC(50) on their K(i(GR)) was insignificant. In contrast, IC(50) decreased with an increase in E(1)(7) and positive electrostatic charge of aromatic part of molecule (Z): log IC(50) (microM) = -(0.9846 +/- 0.3525) - (7.2850 +/- 1.2340) E(1)(7) (V) - (1.1034 +/- 0.1832) Z (r(2) = 0.8015). The redox cycling activity of nitroaromatic and quinoidal compounds in ferredoxin:NADP(+) reductase-catalyzed reaction and the rate of oxyhemoglobin oxidation in lysed erythrocytes increased with an increase in their E(1)(7) value. Our findings imply that the antiplasmodial activity of nitroaromatic and quinoidal compounds is mainly influenced by their ability to form reactive oxygen species, and much less significantly by the GR inhibition.     

Quantitative structure-activity relationships in prooxidant cytotoxicity of polyphenols: role of potential of phenoxyl radical/phenol redox couple

The aim of this work was to characterize the role of the potential of phenoxyl radical/phenol redox couple, E(7)(2), in the cytotoxicity of polyphenols. The cytotoxicity of polyphenols in bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK), and human promyelocytic leukemia cells (line HL-60) was partly inhibited by catalase, by the antioxidant N,N'-diphenyl-p-phenylene diamine and desferrioxamine, and potentiated by 1,3-bis-(2-chloro-ethyl)-1-nitrosourea, thus showing its prooxidant character. Dapsone, an inhibitor of myeloperoxidase, did not affect the cytotoxicity of polyphenols in HL-60 cells, whereas dicumarol, an inhibitor of DT-diaphorase, showed controversial effects on their cytotoxicity in FLK cells. Inhibitors of cytochromes P-450, alpha-naphthoflavone and izoniazide, decreased the cytotoxicity of several polyphenols, whereas 3,5-dinitrocatechol, an inhibitor of catechol-o-methyltransferase (COMT), increased it. The cytotoxicity of 13 polyhydroxybenzenes was described by the equations: logcL50 (microM) = -0.67 + 5.46E(7)(2) (V) - 0.16 logD (FLK), and logcL50 (microM) = -1.39 + 6.90E(7)(2) (V) - 0.20logD (HL-60), where cL50 is compound concentration for 50% cell survival, and D is octanol/water distribution coefficient at pH 7.0. The flavonoids comprise a separate series of compounds with lower cytotoxicity. The correlations obtained quantitatively confirm the parallelism between the polyphenol cytotoxicity and the rates of their single-electron oxidation, and point to the leading role of formation of the reactive oxygen species in their cytotoxicity. Depending on the examined system, this parallelism may be distorted due to the cytochrome P-450 and COMT-catalyzed transformation of polyphenols.     

Synthesis of totarol amino alcohol derivatives and their antiplasmodial activity and cytotoxicity

The previously unknown antiplasmodial activity of the plant derived natural product totarol is reported. Novel beta-amino alcohol derivatives based on this natural product were designed, synthesised and evaluated for in vitro antiplasmodial activity and cytotoxicity. These derivatives showed antiplasmodial IC50 values in the range of 0.6-3.0 microM and were equally active against a chloroquine-sensitive and resistant strain of Plasmodium falciparum, while showing little cytotoxicity against a mammalian cell line (CHO). In terms of lead development, two of the compounds based on substituted phenylpiperazine warrant further investigation as potential antiplasmodial leads. In addition to their selective antiplasmodial activity and lack of chloroquine cross-resistance, these compounds are structurally different to any of the available antimalarial drugs.     

Comparative antiplasmodial, leishmanicidal and antitrypanosomal activities of several biflavonoids

The antiplasmodial, leishmanicidal and antitrypanosomal activities of eight natural biflavonoids were estimated in vitro on a chloroquine-resistant strain of Plasmodium falciparum, axenically grown Leishmania donovani amastigotes and Trypanosoma cruzi trypomastigotes and Trypanosoma brucei rhodesiense bloodstream forms. Lanaroflavone showed the highest antiplasmodial activity (IC(50) = 0.48 microM), isoginkgetin was the most active leishmanicidal compound (IC(50) = 1.9 microM), whereas ginkgetin (IC(50) = 11 microM) and isoginkgetin (IC(50) = 13 microM) showed the best antitrypanosomal activity in our assays. The cytotoxicity and the selectivity indices for the most active compounds were also estimated. Lanaroflavone exhibited a high selectivity index value (SI = 159), indicating selective antiplasmodial activity.     

Indole alkaloids from Muntafara sessilifolia with antiplasmodial and cytotoxic activities

Four vobasinyl-iboga bisindole and one 2-acyl monomeric indole alkaloids were isolated from the stem bark of Muntafara sessilifolia along with eleven known compounds. Their structures and relative stereochemistry were elucidated on the basis of spectroscopic data including 1D and 2D NMR and mass spectrometry (MS). All isolated compounds were evaluated in vitro for antiplasmodial activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum, and for cytotoxicity against the human lung cell line MRC-5 and the rat skeletal muscle cell line L-6. 3'-Oxo-tabernaelegantine A exhibited antiplasmodial activity (4.4 μM IC(50)) associated with non-significant cytotoxicity (selectivity index of 48). Tabernaelegantine B and D displayed the highest cytotoxicity with IC(50) values of 0.47 and 1.89 μM on MRC-5 cells, and 0.42 and 2.7 μM on L-6 cells, respectively.     

Comparative quantitative structure toxicity relationships for flavonoids evaluated in isolated rat hepatocytes and HeLa tumor cells

Quantitative structure activity relationship (QSAR) equations were obtained to describe the cytotoxicity of 22 polyphenols using toxicity (logLD50) representing the concentration for 50% cell survival in 2 h for isolated rat hepatocytes, log P representing octanol/water partitioning, and/or E(p/2) representing redox potential. One- and two-parameter equations were derived for the quantitative structure toxicity relationships (QSTR) for polyphenol induced hepatocyte cytotoxicity: e.g. log C(hepatocyte) (microM)=-0.65(-0.08)log P+4.12(-0.15) (n=19, r(2)=0.80, s=0.33, P<1 x 10(-6)). One- and two-parameter QSAR equations were also derived to describe the inhibitory effects of 13 polyphenols on tumor cell growth when incubated with HeLa cells for 3 days: e.g. log C(tumor) (microM)=-0.34(+/-0.04)log P+2.40(+/-0.07) (n=11, r(2)=0.90, s=0.13, P<1 x 10(-5)). These findings point to lipophilicity as a major characteristic determining polyphenol cytotoxicity. The E(p/2) also played a significant role in polyphenol cytotoxicity towards both cell types: e.g. log C(hepatocyte) (microM)=-0.60(+/-0.06)log P+2.01(+/-0.43)E(p/2) (V)+3.86(+/-0.12) (n=9, r(2)=0.96, s=0.15, P<0.005). The involvement of log P and E(p/2) could be explained if polyphenol cytotoxicity involved the formation of radicals, which interacted with the mitochondrial inner membrane resulting in a disruption of the membrane potential.     

The antiplasmodial activity of norcantharidin analogs

The antiplasmodial activities of sixty norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum. Forty analogs returned IC(50) values <500 μM against at least one of the P. falciparum strains examined. The ring open compound 24 ((1S,4R)-3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is the most active aliphatic analog (D6 IC(50)=3.0±0.0 and W2 IC(50)=3.0±0.8 μM) with a 20-fold enhancement relative to norcantharidin. Surprisingly, seven norcantharimides also displayed good antiplasmodial activity with the most potent, 5 returning D6=8.9±0.9 and W2 IC(50)=12.5±2.2 μM, representing a fivefold enhancement over norcantharidin.     

In vitro antiplasmodial activities of semisynthetic N,N'-spacer-linked oligomeric ergolines

Starting from three monomeric ergolines (terguride 1, festuclavine 2, pergolide 3) N,N'-spacer-linked oligomeric derivatives were prepared using different aliphatic or arylalkyl spacers. The compounds have been evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive strain poW and the chloroquine-resistant clone Dd2 of Plasmodium falciparum. Additionally, the cytotoxic effects against mouse fibroblasts (NIH 3T3) in vitro, and human hepatocytes were evaluated. All monomers displayed only a weak antiplasmodial effect, but N-1,N-1'-spacer-linked dimerization substantially enhanced their antiplasmodial activity. The best activities were observed for compounds showing a distance of six carbon atoms between two monomers, which can be obtained by aliphatic or p-xylene linkers. The N-6,N-6'-spacer-linked depropylpergolide dimer 3i exhibited the highest antiplasmodial activity of all compounds tested (IC(50) values: 0.14 and 0.13 microM against poW and Dd2, respectively). Unfortunately, it displayed toxic effects against the mouse fibroblast cell line NIH 3T3 (IC(50): 0.1+/-0.09 microM) and also against human hepatocytes at 100 microM (LDH-leakage: 15.58+/-0.87 microkat/L; GSH-level: 8.15+/-0.78 nmol/10(6) cells). However, the N-1,N-1'-spacer-linked trimer of festuclavine (2f), and also the N-1,N-1'-spacer-linked tetramer of terguride (1g) possessed remarkable antiplasmodial activities (IC(50): 0.54 and 1.53 microM, respectively, against Dd2) lacking cytotoxicity.     

4-Thiophenoxy-2-trichloromethyquinazolines display in vitro selective antiplasmodial activity against the human malaria parasite Plasmodium falciparum

A series of original quinazolines bearing a 4-thiophenoxy and a 2-trichloromethyl group was synthesized in a convenient and efficient way and was evaluated toward its in vitro antiplasmodial potential. The series revealed global good activity against the K1-multi-resistant Plasmodium falciparum strain, especially with hit compound 5 (IC(50)=0.9 μM), in comparison with chloroquine and doxycycline chosen as reference-drugs. Both the in vitro cytotoxicity study which was conducted on the human HepG2 cell line and the in vitro antitoxoplasmic screening against Toxoplasma gondii indicate that this series presents an interesting selective antiplasmodial profile. Structure-activity- and toxicity relationships highlight that the trichloromethyl group plays a key role in the antiplasmodial activity and also show that the modulation of the thiophenol moiety influences the toxicity/activity ratio.     

Leishmanicidal cycloartane-type triterpene glycosides from Astragalus oleifolius

Two new cycloartane-type glycosides oleifoliosides A (1) and B (2) were isolated from the lower stem parts of Astragalus oleifolius. Their structures were identified as 3-O-[beta-xylopyranosyl-(1 --> 2)-alpha-arabinopyranosyl]-6-O-beta-xylopyranosyl-3beta,6alpha,16beta,24(S),25-pentahydroxycycloartane and 3-O-[beta-xylopyranosyl-(1 --> 2)-alpha-arabinopyranosyl]-6-O-beta-glucopyranosyl-3beta,6alpha,16beta,24(S),25-pentahydroxycycloartane, respectively, by means of spectroscopic methods (IR, 1D and 2D NMR, ESI-MS). Three known cycloartane glycosides cyclocanthoside E (3), astragaloside II (4) and astragaloside IV (5) were also isolated and characterized. All five compounds were evaluated for in vitro trypanocidal, leishmanicidal and antiplasmodial activities as well as their cytotoxic potential on primary mammalian (L6) cells. Except for the compound 5, all compounds showed notable growth inhibitory activity against Leishmania donovani with IC50 values ranging from 13.2 to 21.3 microg/ml. Only weak activity against Trypanosoma brucei rhodesiense was observed with the known compounds astragaloside II (4, IC50 66.6 microg/ml) and cyclocanthoside E (3, IC50 85.2 microg/ml), while all compounds were inactive against Trypanosoma cruzi and Plasmodium falciparum. None of the compounds were toxic to mammalian cells (IC50's > 90 microg/ml). This is the first report of leishmanicidal and trypanocidal activity of cycloartane-type triterpene glycosides.     

Isolation, characterization and antiplasmodial activity of steroidal alkaloids from Funtumia elastica (Preuss) Stapf

Bioassay-guided fractionation of the EtOH extract of the stem bark of Funtumia elastica resulted in the isolation of four steroidal alkaloids, holarrhetine (1), conessine (2), holarrhesine (3) and isoconessimine (4). Their structures were determined on the basis of 1D- and 2D-NMR techniques and mass spectrometry. Compounds 1-4 exhibited in vitro antiplasmodial activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum with IC50 values ranging from 0.97 to 3.39 microM. They showed weak cytotoxicity against a rat cell line L-6 with IC50 values ranging from 5.13 to 36.55 microM.     

Prooxidant toxicity of polyphenolic antioxidants to HL-60 cells: description of quantitative structure-activity relationships

Polyphenolic antioxidants exhibited a dose-dependent toxicity against human promyelocytic leukemia cells (HL-60). Their action was accompanied by malondialdehyde formation, and was partly prevented by desferrioxamine and the antioxidant N,N'-diphenyl-p-phenylene diamine. This points to a prooxidant character of their cytotoxicity. A quantitative structure-activity relationship (QSAR) has been obtained to describe the cytotoxicity of 13 polyphenolic antioxidants belonging to three different groups (flavonoids, derivatives of gallic and caffeic acid): log cL50 (microM) = (2.7829+/-0.2339)+(1.2734+/-0.4715) Ep/2 (V)-(0.3438+/-0.0582) log P (r2 = 0.8129), where cL50 represents the concentration for 50% cell survival, Ep/2 represents the voltammetric midpoint potential, and P represents the octanol/water partition coefficient. Analogous QSARs were obtained using enthalpies of single-electron oxidation of these compounds, obtained by quantum-mechanical calculations. These findings clearly point to two important characteristics determining polyphenol cytotoxicity, namely their ease of oxidation and their lipophilicity.     

Turkish freshwater and marine macrophyte extracts show in vitro antiprotozoal activity and inhibit FabI, a key enzyme of Plasmodium falciparum fatty acid biosynthesis.

The ethanolic extracts of a number of Turkish freshwater macrophytes (Potamogeton perfoliatus, Ranunculus tricophyllus and Cladophora glomerata) and marine macroalgae (Dictyota dichotoma, Halopteris scoparia, Posidonia oceanica, Scinaia furcellata, Sargassum natans and Ulva lactuca) were assayed for their in vitro antiprotozoal activity. Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum were used as test organisms. The cytotoxicity of the extracts was also assessed against primary rat skeletal myoblasts (L6 cells). Whereas none of the extracts were active against T. cruzi, all crude extracts displayed appreciable trypanocidal activity against T. brucei rhodesiense, with S. natans being the most active one (IC(50) 7.4microg/ml). Except for the marine alga H. scoparia, all extracts also possessed leishmanicidal potential. The best antileishmanial activity was exerted by U. lactuca and P. oceanica (IC(50)'s 5.9 and 8.0microg/ml, respectively). Five extracts that demonstrated inhibitory activity towards P. falciparum (IC(50)'s 18.1-48.8microg/ml) were simultaneously assayed against FabI, a crucial enzyme of the fatty acid system of P. falciparum, to find out whether FabI was their target. The extracts of C. glomerata and U. lactuca efficiently inhibited the FabI enzyme with IC(50) values of 1.0 and 4.0microg/ml, respectively. None of the extracts were cytotoxic towards mammalian L6 cells. This work reports for the first time antiprotozoal activity of some Turkish marine and freshwater algae, as well as a target-based antiplasmodial screening for the identification of P. falciparum FabI inhibitors from aquatic and marine macrophytes.     

In vitro antiplasmodial investigation of medicinal plants from El Salvador

In vitro antiplasmodial activities of extracts from Albizia saman, Fabaceae, Calea tenuifolia (C. zacatechichi), Asteraceae, Hymenaea courbaril, Fabaceae, Jatropha curcas, Euphorbiaceae, Momordica charantia, Cucurbitaceae, and Moringa oleifera, Moringaceae were evaluated. From the lipophilic extract of C tenuifolia five active flavones were obtained. 4',5-Dihydroxy-7-methoxyflavone [genkwanin] and 5-hydroxy-4',7-dimethoxyflavone [apigenin 4',7-dimethylether] exhibited the strongest antiplasmodial activity against a chloroquine-sensitive strain (poW) and a chloroquine-resistant strain (Dd2) of Plasmodium falciparum [IC50 values: 17.1-28.5 microM). Furthermore octadeca-9,12-dienoic acid [linoleic acid] [IC50] values of 21.8 microM (poW) and 31.1 microM (Dd2)] and octadeca-9,12,15-trienoic acid (alpha-linolenic acid) were isolated.     

Cryptolepine analogues containing basic aminoalkyl side-chains at C-11: synthesis, antiplasmodial activity, and cytotoxicity

A series of cryptolepine derivatives has been synthesized through the incorporation of short basic side-chains in the C-11 position of the 10H-indolo[3,2-b]quinoline scaffold. Their antiplasmodial activity was evaluated in vitro against the chloroquine resistant Plasmodium falciparum W2 strain, showing IC(50) values between 22 and 184 nM, while their cytotoxicity was assessed using HUVEC cells, revealing three compounds with a selectivity ratio higher than 10. The most selective of these derivatives, 4d, with a selectivity ratio of 46, was also the least cytotoxic of the series.     

Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli

The type II fatty acid pathway (FAS-II) is a validated target for antimicrobial drug discovery. An activity-guided isolation procedure based on Plasmodium falciparum enoyl-ACP reductase (PfFabI) enzyme inhibition assay on the n-hexane-, the CHCl(3-) and the aq MeOH extracts of the Turkish marine sponge Agelas oroides yielded six pure metabolites [24-ethyl-cholest-5alpha-7-en-3-beta-ol (1), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (2), 4,5-dibromopyrrole-2-carboxylic acid (3), (E)-oroidin (4), 3-amino-1-(2-aminoimidazoyl)-prop-1-ene (5), taurine (6)] and some minor, complex fatty acid mixtures (FAMA-FAMG). FAMA, consisting of a 1:2 mixture of (5Z,9Z)-5,9-tricosadienoic (7) and (5Z,9Z)-5,9-tetracosadienoic (8) acids, and FAMB composed of 8, (5Z,9Z)-5,9-pentacosadienoic (9) and (5Z,9Z)-5,9-hexacosadienoic (10) acids in approximately 3:3:2 ratio were the most active PfFabI inhibitory principles of the hexane extract (IC(50) values 0.35 microg/ml). (E)-Oroidin isolated as free base (4a) was identified as the active component of the CHCl(3) extract. Compound 4a was a more potent PfFabI inhibitor (IC(50) 0.30 microg/ml=0.77 microM) than the (E)-oroidin TFA salt (4b), the active and major component of the aq MeOH extract (IC(50) 5.0 microg/ml). Enzyme kinetic studies showed 4a to be an uncompetitive PfFabI inhibitor (K(i): 0.4+/-0.2 and 0.8+/-0.2 microM with respect to substrate and cofactor). In addition, FAMA and FAMD (mainly consisting of methyl-branched fatty acids) inhibited FabI of Mycobacterium tuberculosis (MtFabI, IC(50)s 9.4 and 8.2 microg/ml, respectively) and Escherichia coli (EcFabI, IC(50)s 0.5 and 0.07 microg/ml, respectively). The majority of the compounds exhibited in vitro antiplasmodial, as well as trypanocidal and leishmanicidal activities without cytotoxicity towards mammalian cells. This study represents the first marine metabolites that inhibit FabI, a clinically relevant enzyme target from the FAS-II pathway of several pathogenic microorganisms.     

Antiplasmodial hirsutinolides from Vernonia staehelinoides and their utilization towards a simplified pharmacophore

The dichloromethane extract of the leaves of Vernonia staehelinoides Harv. (Asteraceae) showed in vitro activity (IC(50) approximately 3 microg/ml) against the chloroquine-sensitive (D10) and the chloroquine-resistant (K1) strains of Plasmodium falciparum. Through conventional chromatographic techniques and bioassay-guided fractionation two structurally-related hirsutinolides displaying in vitro antiplasmodial activity (IC(50) approximately 0.2 microg/ml against D10) were isolated and identified by spectroscopic data. Compounds 1, 8 alpha-(2-methylacryloyloxy)-3-oxo-1-desoxy-1,2-dehydrohirsutinolide-13-O-acetate, and 2, 8 alpha-(5'-acetoxysenecioyloxy)-3-oxo-1-desoxy-1,2-dehydrohirsutinolide-13-O-acetate were found to be cytotoxic to mammalian Chinese Hamster Ovarian (CHO) cells at similar concentrations but proved to be attractive scaffolds for structure-activity relationship studies. Two main privileged substructures, a 2(5H)-furanone unit and a dihydrofuran-4-one unit, were identified as potential pharmacophores which may be responsible for the observed biological activity. Mucochloric and mucobromic acids were selected as appropriate 2(5H)-furanone substructures and these were shown to have comparable activity against the D10 and superior activity against the K1 strains relative to the hirsutinolide natural product. Mucochloric and mucobromic acids also show selective cytotoxicity to the malaria parasites compared to mammalian (CHO) cells in vitro. The antiplasmodial data obtained in respect of these two acids suggests that the 2(5H)-furanone substructure is a key pharmacophore in the observed antiplasmodial activity.     

Antioxidant properties of di-tert-butylhydroxylated flavonoids

Epidemiological evidence suggests an inverse relationship between dietary intake of flavonoids and cardiovascular risk. The biological activities of flavonoids are related to their antioxidative effects, but they also can be mutagenic, due to the prooxidant activity of the catechol pattern. To prevent these problems, we synthesized new flavonoids where one or two di-tert-butylhydroxyphenyl (DBHP) groups replaced catechol moiety at position 2 of the benzopyrane heterocycle. Two DBHP moieties can also be arranged in an arylidene structure or one DBHP fixed on a chalcone structure. Position 7 on the flavone and arylidene or position 4 on the chalcone was substituted by H, OCH(3), or OH. New structures were compared with quercetin and BHT in an LDL oxidation system induced by Cu(II) ions. Arylidenes and chalcones had the best activities (ED(50) = 0.86 and 0.21) compared with vitamin E, BHT, and quercetin (ED(50) = 10.0, 7. 4, and 2.3 microM). Activity towards stable free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) was measured by log Z and ECR(50) parameters. Synthesized flavones proved to be poor DPPH radical scavengers, the activity increasing with the number of DBHP units. In contrast, arylidenes and chalcones were stronger DPPH radical scavengers (log Z > 3, 0.3 < ECR(50) < 2.12) than BHT (log Z = 0.75, ECR(50) = 12.56) or quercetin (log Z = 2.76, ECR(50) = 0.43). Unlike quercetin, synthesized compounds neither chelated nor reduced copper, proving that these new flavonoids had no prooxidant activity in vitro.     

Antiplasmodial activity of sesquilignans and sesquineolignans from Bonamia spectabilis

Phytochemical re-investigation of the aerial parts of Bonamia spectabilis (Convolvulaceae) led to the isolation of four minor tetrahydrofuran-type sesquilignans (bonaspectins E-H) together with the known neolignan virolongin A and the known lignan rel-(7S,8R,7'R,8'R)-3,3',4,4',5,5'-hexamethoxylignan. Their structures were established on the basis of spectral data. These six compounds as well as further seven lignanoids from B. spectabilis, characterised previously, were tested for their antiplasmodial activity against a chloroquine-sensitive strain (PoW) and a chloroquine-resistant clone (Dd2) of Plasmodium falciparum. Bonaspectin C 4"-O-glucoside, its aglycone, and bonaspectin D 4"-O-glucoside revealed the highest antiplasmodial activities (IC50 values: 1.3, 2.0, 6.5 microM [PoW]; 1.7, 4.6, 3.7 microM [Dd2], respectively).     

Activity-guided isolation of antiplasmodial dihydrochalcones and flavanones from Piper hostmannianum var. berbicense

The bioassay-guided purification of an n-hexane extract from the leaves of Piper hostmannianum var. berbicense led to the isolation of four monoterpene or prenyl-substituted dihydrochalcones (1a, 1b, 2, 3) as well as the known compounds 2',6'-dihydroxy-4'-methoxydihydrochalcone (4), linderatone (5), strobopinin (6), adunctin E (7) and (-)-methyllinderatin (8). Their structures were established on the basis of NMR and X-ray analysis. (-)-Methyllinderatin, linderatone and 2',6'-dihydroxy-4'-methoxydihydrochalcone exhibited the most potent antiplasmodial activity with IC50 values of 5.64, 10.33 and 12.69 microM, respectively against both chloroquine-sensitive and resistant strains of Plasmodium falciparum (F32,FcB1). The activity of (-)-methyllinderatin was confirmed in vivo against Plasmodium vinckei petteri in mice (80% of reduction of parasitemia) at a dose of 20 mg/kg/day.