Chloroquine-resistant Strains Of Plasmodium Falciparum Research Articles

Phenolic composition and prospective anti-infectious properties of Atriplex lindleyi

ObjectiveTo investigate the antiplasmodial, antimicrobial, radical scavenging effects and to identifiy the phenolic constituents of Atriplex lindleyi (A. lindleyi). MethodsA. lindleyi extracts and some isolated compounds were tested in vitro against the chloroquine-resistant strains of Plasmodium falciparum. The radical scavenging activity was quantified by using 2,2-diphenyl-2-picrylhydrazyl nitrogen-centered free radical. The IC50 of each extract was compared with references. The in vitro anti-infectious activity of extracts was evaluated against representative Gram-positive and Gram-negative bacterial strains [Staphylococcus aureus CIP 4.83, Enterococcus hirae CIP 5855, Pseudomonas aeruginosa (P. aeruginosa) CIP 82118, Escherichia coli CIP 53126], and fungal species [(Candida albicans (C. albicans) IP 48.72, Aspergillus niger IP 1431.83]. Ethanol extract was investigated for chemical composition through column and high performance liquid chromatography. The isolated compounds were identified by mass spectrometry and nuclear magnetic resonance. ResultsQuercetin-7-O-arabinopyranoside-3-O-neohesperidosides (1), quercetin-3-O-arabinopyranosyl(1→6) glucopyranoside (2), quercetin-3-O-glucopyranoside-7-O-rhamnopyranoside (3), quercetin-3-O-glucopyranoside-7-O-arabinoside (4), schaftoside (5), quercetin-7-O-glucopyranoside (6) were isolated for the first time from the ethanol extract of A. lindleyi aerial parts in addition to isorhamnetin-3-O-β-glucopyranoside (7) and quercetin (8). The extracts exhibited moderate antiplasmodial activity with IC50≈ranging from 10–50 μg/mL. Quercetin was the most potent compound with IC50 of 9 µg/mL. P. aeruginosa and C. albicans were the most susceptible organisms. ConclusionsThe study implies that A. lindelyi can contribute to the fight against malaria, and be useful as prophylactic against C. albicans and P. aeruginosa.

Antimalarial and Antiproliferative Cassane Diterpenes of Caesalpinia sappan.

Bioassay-guided fractionation of a methanol extract of the seeds of Caesalpinia sappan led to the isolation of 12 new cassane-type diterpenes, caesalsappanins A-L (1-12). Their structures were elucidated on the basis of NMR and HRESIMS analysis, and the absolute configuration of compound 1 was determined by single-crystal X-ray crystallography. All isolated compounds were tested against a chloroquine-resistant Plasmodium falciparum strain for antiplasmodial activities and against a small panel of human cancer cell lines for antiproliferative activities. Compounds 7 and 8 displayed antimalarial activity against the chloroquine-resistant K1 strain of P. falciparum with IC50 values of 0.78 and 0.52 μM and selectivity indices of 17.6 and 16.4, respectively. Compound 10 showed antiproliferative activity against the KB cancer cell line with an IC50 value of 7.4 μM.

D-Glucose-Derived 1,2,4-Trioxepanes: Synthesis, Conformational Study, and Antimalarial Activity.

New enantiomerically pure 1,2,4-trioxepanes 10a,b/11a,b were synthesized from D-glucose. Their conformational behavior was studied by low-temperature NMR and substantiated by DFT calculations. On evaluation of in vitro antimalarial activity, the adamantyl derivative 11b showed IC50 values in the low micromolar range, particularly against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 ± 0.12 μM).

Synthesis, antimalarial activity and molecular docking of hybrid 4-aminoquinoline-1,3,5-triazine derivatives

A series of novel hybrid 4-aminoquinoline 1,3,5-triazine derivatives was synthesized in a five-steps reaction and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Entire synthetic derivatives showed higher antimalarial activity on the sensitive strain while two compounds, viz., 9a and 9c displayed good activity against both the strains of P. falciparum. The observed activity was further substantiated by docking study on both wild and qradruple mutant type P. falciparum dihydrofolate reductase-thymidylate synthase (pf-DHFR-TS).

Powerful Antioxidant and Pro-Oxidant Properties of Cassia roxburghii DC. Leaves Cultivated in Egypt in Relation to Their Anti-Infectious Activities

Leaf extracts of Cassia roxburghii DC., prepared in petroleum ether, chloroform, ethyl acetate, butanol, and methanol/water (70:30, v/v), were evaluated as antioxidant, pro-oxidant, anti-infectious, and cytotoxic agents. The major metabolite of each extract was identified by chromatographic and spectroscopic means. The redox properties were assessed with a battery of assays, which revealed that the ethyl acetate extract demonstrated an interesting scavenging activity of DPPH and superoxide radicals and an ascorbic acid-like pro-oxidant activity. All the tested extracts showed moderate antiplasmodial activity against a chloroquine-resistant strain of Plasmodium falciparum, by possible disruption of parasite fine redox balance. Cytotoxicity was evaluated against a human breast cancer cell line. The antimicrobial activities of the extracts were estimated against representative bacterial strains (Staphylococcus aureus, Enterococcus hirae, Pseudomonas aeruginosa, Escherichia coli) and fungal species (Candida albicans, Aspergillus niger). The ethylacetate extract possessed the highest redox properties and exhibited the highest antiplasmodial activity; there was no correlation between antibacterial activity and the redox properties of the extracts.

Evaluation of antiplasmodial and antileishmanial activities of herbal medicine Pseudelephantopus spiralis (Less.) Cronquist and isolated hirsutinolide-type sesquiterpenoids

Ethnopharmacological relevancePseudelephantopus spiralis (Less.) Cronquist is distributed in the Caribbean, Mesoamerica and Latin America. Preparations of the plant are traditionally used in Latin America for the treatment of various diseases including fever, malaria, and spleen or liver inflammations. Materials and methodsAerial parts of P. spiralis were extracted with either ethanol or distilled water. Seven hirsutinolide-type sesquiterpenoids were isolated: 8-acetyl-13-ethoxypiptocarphol (1), diacetylpiptocarphol (2), piptocarphins A (3), F (4) and D (5), (1S*,4R*,8S*,10R*)-1,4-epoxy-13-ethoxy-1,8,10-trihydroxygermacra-5E,7(11)-dien-6,12-olide (6), and piptocarphol (7). Extracts and isolated compounds (2, 3, 5–7) were screened for their in vitro antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FcM29-Cameroon and antileishmanial activity against three stages of Leishmania infantum. Their cytotoxicities were also evaluated against healthy VERO cell lines and J774A.1 macrophages, the host cells of the Leishmania parasites in humans. ResultsAqueous extracts showed a greater inhibitory effect than alcoholic extracts, with IC50 on P. falciparum of 3.0µg/mL versus 21.1µg/mL, and on L. infantum of 13.4µg/mL versus >50µg/mL. Both extracts were found to be cytotoxic to VERO cells (CC50<3µg/mL). Sesquiterpene lactones 2 and 3 showed the best activity against both parasites but failed in selectivity. Carbon 8 hydroxylated hirsutinolides 5–7 presented the particularity of exhibiting two conformers observed in solution during extensive NMR analyses in CD3OD and UHPLC-MS. The presence of a hydroxyl function at C-8 decreased the activity of 5–7 on the two parasites and also on VERO cells. ConclusionThe antiplasmodial activity displayed by the aqueous extract explains the traditional use of P. spiralis in the treatment of malaria. This activity seems to be attributable to the presence of sesquiterpene lactones 2 and 3, the most active against P. falciparum. Aqueous extract and compounds 2, 3 and 6 were also active against L. infantum but lacked in selectivity due to their cytotoxicity towards macrophages. Exploring the safety and antiplasmodial efficacy of this traditional remedy will require further toxicological and in vivo studies in the light of the cytotoxicity towards healthy cell lines displayed by the aqueous extract and compounds 2 and 3.

Synthesis, characterization and pharmacological evaluation of ferrocenyl azines and their rhodium(I) complexes

Ferrocenyl azines containing salicylaldimine motifs were prepared by Schiff-base condensation of salicylaldehyde hydrazones and (dimethylamino)methyl ferrocenecarboxaldehyde. Their corresponding Rh(I) complexes were prepared by reaction of the various ferrocenyl azines with [RhCl(COD)]2 (where COD = 1,5-cyclooctadiene) to yield heterobimetallic complexes. The compounds were characterized using standard spectroscopic and analytical techniques. The characterization data suggests that the ferrocenyl azine acts as a bidentate donor. The rhodium(I) centre binds to the imine nitrogen and phenolic oxygen of the salicylaldimine, forming a neutral complex. The compounds were screened against the NF54 chloroquine-sensitive (CQS) and K1 chloroquine-resistant (CQR) strains of Plasmodium falciparum. The ferrocene-containing salicylaldimines exhibited weak to moderate activity across both parasite strains. The heterometallic complexes exhibited enhanced activity compared to the ferrocenyl azines in both strains. Most of the compounds exhibited enhanced activity in the resistant strain compared to the sensitive strain. Inhibition of haemozoin formation was considered as a possible mechanism of action of these compounds and indeed they exhibited β-haematin inhibition activity, albeit weaker than chloroquine. All compounds were also screened against the G3 strain of Trichomonas vaginalis. The compounds inhibited no more than 50% parasite growth at the tested concentration. One complex exhibited moderate cytotoxicity against WHCO1 oesophageal cancer cells.

English

Tanzania has over 12,000 plant species, some of which are endemic and have potential to yield useful medicines. This study seeks to document such plants used as traditional medicines for treatment of malaria in Kagera region of northwestern Tanzania and Lindi region in south eastern Tanzania. The study also reports on the antiplasmodial activity against chloroquine-resistant Plasmodium falciparum (Dd2) strain of some of the documented plants using the parasite lactate dehydrogenase method. A total of 108 plant species, among which the families Compositae (14; 12.96%), Fabaceae (12; 11.11%), Euphorbiaceae (8; 7.41%), Melastomataceae (6; 5.56%) and Myrtaceae (4; 3.70%) were documented. Sixteen (16; 44.4%) of 36 extracts from 31 plant species that were tested inhibited malaria parasites growth by more than 50%. Bersema abyssinica stem bark extract was the most active with 86.67% inhibition rate followed by Bridelia micrantha stem bark extract with 71.87% inhibition rate. These results confirm the potential for plants used in traditional medicine to yield active antimalarial compounds. Further in vitro and in vivo screening supported by bioassay-guided isolation of active compounds from plants showing good safety margin is suggested. Key words: Ethnobotanical survey, medicinal plants, malaria, treatment, in vitro antiplasmodial, Tanzania.

Minor secondary metabolites from the bark of Entandrophragma congoënse (Meliaceae)

Two new tirucallane-type triterpenoids were isolated from the bark of Entandrophragma congoënse (Meliaceae) along with five known compounds gladoral A, bipendensin, 4-hydroxymethyl-3,5-dimethyldihydrofuran-2(3H)-one, scopoletin and 5,7-dimethoxy-6-hydroxycoumarin. Their structures were elucidated by means of spectroscopic analyses including 1D and 2D-NMR spectroscopy, high resolution mass spectrometric data as well as the comparison of data with those reported in the literature. The tested compounds (1–4) displayed moderated antiplasmodial activity against erythrocytic stages of chloroquine-resistant Plasmodium falciparum strain NF54 and low cytotoxicity on L6 cell lines. All the isolated compounds are reported for the first time from the genus Entandrophragma.

Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice.

Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity.

Synthesis, Docking, In Vitro and In Vivo Antimalarial Activity of Hybrid 4-aminoquinoline-1,3,5-triazine Derivatives Against Wild and Mutant Malaria Parasites.

A new series of hybrid 4-aminoquinoline-1,3,5-triazine derivatives was synthesized by a four-step reaction. Target compounds were screened for in vitro antimalarial activity against chloroquine-sensitive (3D-7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Compounds exhibited, by and large, good antimalarial activity against the resistant strain, while two of them, that is 8g and 8a, displayed higher activity against both the strains of P.falciparum. Additionally, docking study was performed on both wild (1J3I.pdb) and quadruple mutant (N51I, C59R, S108N, I164L, 3QG2.pdb) type pf-DHFR-TS to highlight the structural features of hybrid molecules.

Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model.

BackgroundEven though malaria is a completely preventable and treatable disease, it remains a threat to human life and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. According to the World Malaria Report 2013, in 2012 there were an estimated 207 million malaria cases and 627,000 deaths. Thus, the discovery and development of new, effective anti-malarial drugs are required. To achieve this goal, the Department of Chemistry at the University of the Free State has synthesized a number of novel amino-alkylated chalcones and analogues, which showed in vitro anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. The lead compound (NP046) was selected for a comprehensive pharmacokinetic (PK) and in vivo efficacy evaluation in a mouse model.MethodsIn vivo efficacy: Water solutions of NP046 were administered orally at 50 and 10 mg/kg using oral gavage and IV at 5 and 1 mg/kg via the dorsal penile vein to Plasmodium berghei (ANKA strain) infected male C57BL/6 mice (n = 5), once a day for four days. Blood samples were collected via tail bleeding in tubes containing phosphate buffer saline (PBS) on day five to determine the % parasitaemia by flow cytometry.In vivo PK: NP046 solutions in water were administered orally (50 and 10 mg/kg) and IV (5 mg/kg) to male C57BL/6 mice (n = 5). Blood samples were collected via tail bleeding into heparinized tubes and analysed using a validated LC-MS/MS assay. Data obtained from the concentration-time profile was evaluated using Summit PK software to determine the PK parameters of NP046.ResultsNP046 inhibited parasite growth for the oral and IV groups. Better parasite growth inhibition was observed for the IV group. The PK evaluation of NP046 showed low oral bioavailability (3.2% and 6% at 50 mg/kg and 10 mg/kg dose, respectively and a moderate mean half-life ranging from 3.1 to 4.4 hours.ConclusionEven though the oral bioavailability of NP046 is low, its percentage parasite growth inhibition is promising, but in order to improve the oral bioavailability, structure-activity-relationship (SAR) optimization studies are currently being conducted.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-14-8) contains supplementary material, which is available to authorized users.

Antimalarial Activity of Various Bisbenzylisoquinoline and AporphineBenzylisoquinoline Alkaloids and their Structure-Activity Relationships against Chloroquine – Sensitive and Resistant Plasmodium falciparum Malaria in vitro

The antimalarial activity of some bisbenzylisoquinoline (BBIQ) alkaloids were studied using in vitro culture of both chloroquine (CQ)-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The combination of chloroquine and tetrandrine gave a 44 fold potentiation of malarial killing. Fangchinoline, hernandezine, pycnamine, berbamine and isotetrandrine had similar antimalarial activity as tetrandrine against the sensitive strain of P. falciparum malaria. Hernandezine, isotetrandrine, berbamine, fangchinoline and methoxyadiantifoline had similar antimalarial activity as tetrandrine against a strain of chloroquine-resistant falciparum malaria. Based on structure/ activity analysis, we concluded that the stereochemistry of C-1E¹ (S ring) of the BBIQ structure played an important role in selective action against resistant malaria. The stereochemistry of C-1 (left ring) and a substituent of C-12 appeared to have little influence on the selectivity. The point of attachment of the ether bridges to the rings also exerts an important influence on selective antimalarial activity. Tetrandrine (TT) penetrates both the erythrocyte and parasite membranes and inhibits the synthesis and activity of the (MDR) pump and likely the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) since it inhibits the calcium channel. These observations likely account for the fact TT potentiates the activity of chloroquine more than 40 fold against chloroquine resistant falciparum malaria.

Antiplasmodial activity of short peptide-based compounds

Three series of short peptide-based compounds were synthesized, which upon evaluation against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains ofPlasmodium falciparum in vitro, produced IC50values ranging between 1.4–4.7 μg mL−1.

Improved antiparasitic activity by incorporation of organosilane entities into half-sandwich ruthenium(II) and rhodium(III) thiosemicarbazone complexes.

A series of ferrocenyl- and aryl-functionalised organosilane thiosemicarbazone compounds was obtained via a nucleophilic substitution reaction with an amine-terminated organosilane. The thiosemicarbazone (TSC) ligands were further reacted with either a ruthenium dimer [(η(6-i)PrC6H4Me)Ru(μ-Cl)Cl]2 or a rhodium dimer [(Cp*)Rh(μ-Cl)Cl]2 to yield a series of cationic mono- and binuclear complexes. The thiosemicarbazone ligands, as well as their metal complexes, were characterised using NMR and IR spectroscopy, and mass spectrometry. The molecular structure of the binuclear ruthenium(ii) complex was determined by single-crystal X-ray diffraction analysis. The thiosemicarbazones and their complexes were evaluated for their in vitro antiplasmodial activities against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) Plasmodium falciparum strains, displaying activities in the low micromolar range. Selected compounds were screened for potential β-haematin inhibition activity, and it was found that two Rh(iii) complexes exhibited moderate to good inhibition. Furthermore, the compounds were screened for their antitrichomonal activities against the G3 Trichomonas vaginalis strain, revealing a higher percentage of growth inhibition for the ruthenium and rhodium complexes over their corresponding ligand.

Seeds of Peganum Harmala L. Chemical Analysis, Antimalarial and Antioxidant Activities, and Cytotoxicity Against Human Breast Cancer Cells

The present study evaluated the levels of total phenolics, flavonoids, tannins and anthocyanins from Peganum harmala L. seeds and determined their antioxidant, antiplasmodial and anticancer potentials. Antioxidant activity was determined by DPPH and ABTS assays. Extracts of P. harmala seeds from Oudref and Djerba (two places in Tunisia) were obtained by successive extraction solvents: petroleum ether, chloroform, ethyl acetate, ethanol and water. Their composition was evaluated for phenolics (gallic acid equivalent 2.48 to 72.52 g/kg), tannins (catechin equivalent 0 to 25.27 g/kg), anthocyanins (cyanidin equivalent 0 to 20.56 mg/kg) and flavonoids (quercetin equivalent 0 to 3.12 g/kg). Ethanolic extract exerted the highest activities against a chloroquine-resistant strain of Plasmodium falciparum (IC₅₀=23 mg/L), against human breast cancer cells MCF7 (IC₅₀=32 mg/L) and against free radical (IC₅₀=19.09±3.07 mg/L). Correlations were studied between each chemical family and the three activities. Total phenolics content exhibited the highest correlation with antiplasmodial activity (R²=0.92) and with anticancer activity (R²=0.86), respectively.

1H-1,2,3-triazole tethered isatin-ferrocene conjugates: Synthesis and in vitro antimalarial evaluation.

1H-1,2,3-triazole tethered isatin-ferrocene conjugates were synthesized and evaluated for their antiplasmodial activities against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The conjugates 5f and 5h with an optimum combination of electron-withdrawing halogen substituent at C-5 position of isatin ring and a propyl chain, introduced as linker, proved to be most potent and non-cytotoxic among the series with IC50 values of 3.76 and 4.58 μM against 3D7 and W2 strains, respectively.

6α-Hydroxy-α-toxicarol and (+)-tephrodin with antiplasmodial activities from Tephrosia species

The CH2Cl2/MeOH (1:1) extract of the roots of Tephrosia villosa showed good antiplasmodial activity against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 values of 3.1±0.4 and 1.3±0.3μg/mL, respectively. Chromatographic separation of the extract yielded a new rotenoid, 6α-hydroxy-α-toxicarol, along with five known rotenoids, (rotenone, deguelin, sumatrol, 12a-hydroxy-α-toxicarol and villosinol). Similar treatment of the extract of the stem of Tephrosia purpurea (IC50=4.1±0.4 and 1.9±0.2μg/mL against D6 and W2 strains of P. falciparum, respectively) yielded a new flavone having a unique substituent at C-7/C-8 [trivial name (+)-tephrodin], along with the known flavonoids tachrosin, obovatin methyl ether and derrone. The relative configuration and the most stable conformation in (+)-tephrodin was determined by NMR and theoretical energy calculations. The rotenoids and flavones tested showed good to moderate antiplasmodial activities (IC50=9−23μМ). Whereas the cytotoxicity of rotenoids is known, the flavones (+)-tephrodin and tachrosin did not show significant cytotoxicity (IC50>100μМ) against mammalian African monkey kidney (vero) and human larynx carcinoma (HEp2) cell lines.

Synthesis and Evaluation of a Carbosilane Congener of Ferroquine and Its Corresponding Half-Sandwich Ruthenium and Rhodium Complexes for Antiplasmodial and β-Hematin Inhibition Activity

A silicon-containing congener of ferroquine (1) was synthesized by incorporating an organosilicon motif in the lateral side chain of ferroquine. Compound 1 was then further reacted with dinuclear half-sandwich transition-metal precursors [Ru(Ar)(μ-Cl)Cl]2 (Ar = η6-p-iPrC6H4Me, η6-C6H6, η6-C6H5OCH2CH2OH), [Rh(COD)(μ-Cl)]2, and [RhCp*(μ-Cl)Cl]2, to yield a series of heterometallic organometallic complexes (2–6). Compound 1 coordinates selectively in a monodentate manner to the transition metals via the quinoline nitrogen of the aminoquinoline scaffold. All of the compounds were characterized using various analytical and spectroscopic techniques, and the molecular structure of compound 1 was elucidated by single-crystal X-ray diffraction analysis. Furthermore, the in vitro antiplasmodial activity of compounds 1–6 was established against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the malaria parasite Plasmodium falciparum.

3-Oxo-14α,15α-epoxyschizozygine: A new schizozygane indoline alkaloid from Schizozygia coffaeoides

The stem bark extract of Schizozygia coffaeoides (Apocynaceae) showed moderate antiplasmodial activity (IC50=8–12μg/mL) against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Chromatographic separation of the extract led to the isolation of a new schizozygane indoline alkaloid, named 3-oxo-14α,15α-epoxyschizozygine. In addition, two dimeric anthraquinones, cassiamin A and cassiamin B, were identified for the first time in the family Apocynaceae. The structures of the isolated compounds were deduced on the basis of spectroscopic evidence. The schizozygane indole alkaloids showed good to moderate antiplasmodial activities (IC50=13–52μМ).