Highest Antiplasmodial Activity Research Articles

Anti-Plasmodial Assessment of Four Different Iranian Propolis Extracts.

Eradication of malaria will depend on discovery of new intervention tools such as anti-malarial drugs. Due to the increasing interest in the application of propolis against significant clinical pathogenic agents, the aim of the present investigation was to evaluate the anti-plasmodial effect of Iranian propolis extracts against chloroquine (CQ)-sensitive Plasmodium falciparum 3D7 and Plasmodium berghei (ANKA strain). Crude samples of honeybee (Apis mellifera) propolis were collected from four provinces in northern (Kalaleh, Golestan), northeastern (Chenaran, Razavi Khorasan), central (Taleghan, Alborz) and western (Morad Beyg, Hamedan) areas of Iran with different types of flora. The dried propolis samples were extracted with three different solvents, including ethanol 70% (EtOH), ethyl acetate (EA) and dichloromethane (DCM). All extracts were shown to have in vitro anti-plasmodial activity with IC50 ranging from 16.263 to 80.012 µg/mL using parasite lactate dehydrogenase (pLDH) assay. The DCM extract of Morad Beyg propolis indicated the highest anti-plasmodial activity (IC50: 16.263 ± 2.910 μg/mL; P = 0.027, Kruskal-Wallis H-test). The samples were also evaluated in mice for their in vivo anti-plasmodial effect. The curative effect against established infection (Rane test) showed that both extracts at all doses (50, 100, and 200 mg/kgBW) produced anti-plasmodial activity against the parasite. Furthermore, using gas chromatography-mass spectrometry (GC-MS), the quantity of flavonoids in DCM and EtOH 70% extracts were found to be 7.42% and 3.10%, respectively. The potent anti-plasmodial activity of both EtOH 70% and DCM extracts of the propolis of Morad Beyg, Hamedan suggests further analyses of individual components to assess its utilization as anti-malarial drugs.

Antiplasmodial Activity, Cytotoxicity and Structure-Activity Relationship Study of Cyclopeptide Alkaloids.

Cyclopeptide alkaloids are polyamidic, macrocyclic compounds, containing a 13-, 14-, or 15-membered ring. The ring system consists of a hydroxystyrylamine moiety, an amino acid, and a β-hydroxy amino acid; attached to the ring is a side chain, comprised of one or two more amino acid moieties. In vitro antiplasmodial activity was shown before for several compounds belonging to this class, and in this paper the antiplasmodial and cytotoxic activities of ten more cyclopeptide alkaloids are reported. Combining these results and the IC50 values that were reported by our group previously, a library consisting of 19 cyclopeptide alkaloids was created. A qualitative SAR (structure-activity relationship) study indicated that a 13-membered macrocyclic ring is preferable over a 14-membered one. Furthermore, the presence of a β-hydroxy proline moiety could correlate with higher antiplasmodial activity, and methoxylation (or, to a lesser extent, hydroxylation) of the styrylamine moiety could be important for displaying antiplasmodial activity. In addition, QSAR (quantitative structure-activity relationship) models were developed, using PLS (partial least squares regression) and MLR (multiple linear regression). On the one hand, these models allow for the indication of the most important descriptors (molecular properties) responsible for the antiplasmodial activity. Additionally, predictions made for interesting structures did not contradict the expectations raised in the qualitative SAR study.

Biological Potentials of Ginger Associated <i>Streptomyces</i> Compared with Ginger Essential Oil

Medicinal plants and associated microorganisms are recognized to have beneficial relationship. These two organisms are well known for their ability to produce bioactive secondary metabolites which the similarity has been demonstrated in a few works. This study had for objective to assess biological potentials of actinomycetes isolated from ginger rhizomes and its rhizospheric soil and to determine their similarity and efficiency with ginger essential oil. Among the 63 actinomycetes strains isolated from the rhizomes and rhizospheric soils of two ginger countries plantations of Soavinandriana Itasy-Madagascar, biological activity tests showed that 16 strains (2 endophytes and 14 from rhizospheric soils of ginger) exhibited antimicrobial activity against at least one germ. The strains are more active against Gram+ bacteria and fungi than Gram- bacteria. Only, one strain isolated from ginger rhizospheric soil of the site n°2 (AHO 18) inhibited the development of all tests germs. The tests conducted on six representative strains selected on the basis of antimicrobial assay showed that extracts from the isolates AHO 3 and AHO 43 have strong antiproliferative activity on cells HT-20 (colon cancer) with IC50 values of 5µg/ml and 2,2μg/ml, respectively; strong antimalaria activity against the chloroquino-resistant <i>Plasmodium falciparum</i> strain (IC50=1,25μg/ml for AHO 3 extract and 2,5&lt;IC50&lt;5µg/ml for AHO 43 extract) and antioxidant activity (IC50=15mg/ml for AHO 3 extract and 10,6mg/ml for AHO 43 extract). The 2 isolates based on phenotypic and molecular characterization using their 16S rRNA gene were identified as <i>Streptomyces chrysomallus</i> (isolate AHO 3) and <i>Streptomyces sp</i> (isolate AHO 43). Moreover, the two essential oils of ginger tested showed antimicrobial activity against all tests germs used and antioxidant activity. Only, ginger essential oil from the site n°2 exhibited moderate antiproliferative potential (IC50=14μg/ml) on colon cancer cells and high antiplasmodial activity (2,5&lt;IC50&lt;5µg/ml). <i>Streptomyces sp</i> showed similar and strong biological activities than those of ginger essential oil from the site n°2. Chemical screening of the <i>Streptomyces sp</i> extract and the essential oil H2 revealed the common presence of terpens and phenolic compounds.

Fern-synthesized nanoparticles in the fight against malaria: LC/MS analysis of Pteridium aquilinum leaf extract and biosynthesis of silver nanoparticles with high mosquitocidal and antiplasmodial activity.

Malaria remains a major public health problem due to the emergence and spread of Plasmodium falciparum strains resistant to chloroquine. There is an urgent need to investigate new and effective sources of antimalarial drugs. This research proposed a novel method of fern-mediated synthesis of silver nanoparticles (AgNP) using a cheap plant extract of Pteridium aquilinum, acting as a reducing and capping agent. AgNP were characterized by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD). Phytochemical analysis of P. aquilinum leaf extract revealed the presence of phenols, alkaloids, tannins, flavonoids, proteins, carbohydrates, saponins, glycosides, steroids, and triterpenoids. LC/MS analysis identified at least 19 compounds, namely pterosin, hydroquinone, hydroxy-acetophenone, hydroxy-cinnamic acid, 5, 7-dihydroxy-4-methyl coumarin, trans-cinnamic acid, apiole, quercetin 3-glucoside, hydroxy-L-proline, hypaphorine, khellol glucoside, umbelliferose, violaxanthin, ergotamine tartrate, palmatine chloride, deacylgymnemic acid, methyl laurate, and palmitoyl acetate. In DPPH scavenging assays, the IC50 value of the P. aquilinum leaf extract was 10.04 μg/ml, while IC50 of BHT and rutin were 7.93 and 6.35 μg/ml. In mosquitocidal assays, LC50 of P. aquilinum leaf extract against Anopheles stephensi larvae and pupae were 220.44 ppm (larva I), 254.12 ppm (II), 302.32 ppm (III), 395.12 ppm (IV), and 502.20 ppm (pupa). LC50 of P. aquilinum-synthesized AgNP were 7.48 ppm (I), 10.68 ppm (II), 13.77 ppm (III), 18.45 ppm (IV), and 31.51 ppm (pupa). In the field, the application of P. aquilinum extract and AgNP (10 × LC50) led to 100 % larval reduction after 72 h. Both the P. aquilinum extract and AgNP reduced longevity and fecundity of An. stephensi adults. Smoke toxicity experiments conducted against An. stephensi adults showed that P. aquilinum leaf-, stem-, and root-based coils evoked mortality rates comparable to the permethrin-based positive control (57, 50, 41, and 49 %, respectively). Furthermore, the antiplasmodial activity of P. aquilinum leaf extract and green-synthesized AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of P. falciparum. IC50 of P. aquilinum were 62.04 μg/ml (CQ-s) and 71.16 μg/ml (CQ-r); P. aquilinum-synthesized AgNP achieved IC50 of 78.12 μg/ml (CQ-s) and 88.34 μg/ml (CQ-r). Overall, our results highlighted that fern-synthesized AgNP could be candidated as a new tool against chloroquine-resistant P. falciparum and different developmental instars of its primary vector An. stephensi. Further research on nanosynthesis routed by the LC/MS-identified constituents is ongoing.

New derivatives of bicyclic diamines with antiprotozoal activity

ω-Aminoacyl and -alkyl derivatives of 4-(dialkylamino)bicyclo[2.2.2]octan-2-amines and of 5-(dialkylamino)-2-azabicyclo[3.2.2]nonanes were prepared and their activities were examined in vitro against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). The results of the biological tests of the newly synthesized compounds were compared with the activities of already synthesized compounds and of drugs in use. Lots of the newly synthesized compounds showed promising antiprotozoal properties and selectivity, some of them exhibited even higher antiplasmodial activity than chloroquine. Structure–activity relationships were discussed.

Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum.

The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-aminoquinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.

Highly antiplasmodial non-natural oxidative products of dioncophylline A: synthesis, absolute configuration, and conformational stability.

Four new compounds, the monomeric dioncotetralones A (6 a) and B (6 b) and the dimeric compounds jozimine A3 (7) and jozimine A4 (9), were semi-synthesized from the natural product dioncophylline A (4) and its 5'-O-demethylated derivative (5), respectively, under phenol oxidative reaction conditions. Dioncotetralones A (6 a) and B (6 b) possess an unprecedented Z-configured double bond, in contrast to the classic biaryl axis that is present in the precursor dioncophylline A (4), and an additional stereogenic center at the C2' atom was generated due to the dearomatization. The resulting steric repulsion forced the expected planar double bond into a helical distorted conformation. The homocoupling of 5 yielded compounds 7 and 9, the latter of which is the first sp(3) -sp(2) coupled product of a monomeric naphthylisoquinoline with a reduced one and, thus, contains a newly generated stereogenic center. The full stereostructures of 6 a, 6 b, 7, and 9 were successfully elucidated by the interplay of spectroscopic methods (1D/2D NMR and electronic circular-dichroism spectroscopy) in combination with quantum-chemical calculations. In addition, compounds 6 a and 7 exhibited high antiplasmodial activities with excellent half-maximal inhibitory concentration values.

Antiplasmodial activity of medicinal plants from Chhotanagpur plateau, Jharkhand, India

BackgroundThe alarmingly increasing problem of drug resistance in treatment of malaria has led to an urgent need for identifying new anti-malarial drugs for both prophylaxis and chemotherapy. Aim of the studyThe present study presents a systematic exploration of the ex vivo blood stage antiplasmodial potential of medicinal plants to corroborate their traditional usage against malaria in Jharkhand, India. MethodsAn ethnobotanical survey in and around Ranchi was done to grasp the traditional knowledge of medicinal plants used by local healers for malaria, other fevers and for other medicinal purposes like, antiamoebic, antihelmenthic, antidote to poisons, etc. Following the survey, the selected 22 plant samples were extracted in ethanol for studying ex vivo SYBR Green I fluorescence assay based anti-plasmodial activity against both chloroquine-sensitive Pf3D7 and chloroquine resistant PfINDO strains of Plasmodium falciparum grown in human red blood cell cultures. Cytotoxicity was determined against HeLa and L929 cells using MTT assay. Further the most potent extract was chromatographed on reverse phase HPLC towards antiplasmodial activity guided purification of metabolites. ResultsOf the 22 plant species assayed, the highest antiplasmodial activity (Pf3D7IC50≤5µg/ml) was seen in leaf ethanol extracts of Corymbia citriodora (Hook.) K.D.Hill & L.A.S.Johnson, Calotropis procera (Aiton) Dryand. and Annona squamosa L. and bark ethanol extract of Holarrhena pubescens Wall. ex G.Don. Leaf ethanol extract of H. pubescens, bark ethanol extract of Pongamia pinnata (L.) Pierre and whole plant ethanol extract of Partheniumhysterophorus L. showed promising activity (IC50 6–10µg/ml). Good antiplasmodial activity (IC50: 11–20µg/ml) was observed in leaf ethanol extract of Bryophyllum pinnatum (Lam.) Oken and whole plant ethanol extract of Catharanthus roseus (L.) G.Don. The extracts of plants showing highest to good antiplasmodial activity exhibited HeLa/Pf3D7 selectivity indices of the order of 20–45. Bioassay guided fractionation of P. hysterophorus led to fivefold enrichment of antiplasmodial activities (IC50 ~450ng/ml) in some fractions. ConclusionThese results provide confirmation to the traditional usage of some medicinal plants against malaria in areas around Ranchi, Jharkhand.

Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action.

BackgroundGiven the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated.MethodsSix diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (HssLDH) or plasmodial lactate dehydrogenase (PfLDH) enzymes, and, a β-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro.ResultsAll tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC50) values below 1 μΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of PfLDH; specificity between the residues involved in H-bonds of the PfLDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of PfLDH. CQAn33 and CQAn37 inhibited β-haematin formation with either a similar or a 2-fold higher IC50 value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive.ConclusionsThe presence of an alkyne group and the size of the side chain affected anti-P. falciparum activity in vitro. Docking studies suggested a mechanism of action other than PfLDH inhibition. The β-haematin assay suggested the presence of an additional mechanism of action of CQAn33 and CQAn37. Tests with CQAn34, CQAn37, CQAn39 and CQAn45 confirmed previous results against P. berghei malaria in mice, and CQAn33, 39 and 45 were active against CQ-resistant parasites, but CQAn28 and CQAn34 were not. The result likely reflects structure-activity relationships related to the resistant phenotype.

HPLC-based activity profiling for antiplasmodial compounds in the traditional Indonesian medicinal plant Carica papaya L

Ethnopharmacological relevanceLeaf decoctions of Carica papaya have been traditionally used in some parts of Indonesia to treat and prevent malaria. Leaf extracts and fraction have been previously shown to possess antiplasmodial activity in vitro and in vivo. Materials and methodsAntiplasmodial activity of extracts was confirmed and the active fractions in the extract were identified by HPLC-based activity profiling, a gradient HPLC fractionation of a single injection of the extract, followed by offline bioassay of the obtained microfractions. For preparative isolation of compounds, an alkaloidal fraction was obtained via adsorption on cationic ion exchange resin. Active compounds were purified by HPLC–MS and MPLC–ELSD. Structures were established by HR-ESI-MS and NMR spectroscopy. For compounds 5 and 7 absolute configuration was confirmed by comparison of experimental and calculated electronic circular dichroism (ECD) spectroscopy data, and by X-ray crystallography. Compounds were tested for bioactivity in vitro against four parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum), and in the Plasmodium berghei mouse model. ResultsProfiling indicated flavonoids and alkaloids in the active time windows. A total of nine compounds were isolated. Four were known flavonols – manghaslin, clitorin, rutin, and nicotiflorin. Five compounds isolated from the alkaloidal fraction were piperidine alkaloids. Compounds 5 and 6 were inactive carpamic acid and methyl carpamate, while three alkaloids 7–9 showed high antiplasmodial activity and low cytotoxicity. When tested in the Plasmodium berghei mouse model, carpaine (7) did not increase the survival time of animals. ConclusionsThe antiplasmodial activity of papaya leaves could be linked to alkaloids. Among these, carpaine was highly active and selective in vitro. The high in vitro activity could not be substantiated with the in vivo murine model. Further investigations are needed to clarify the divergence between our negative in vivo results for carpaine, and previous reports of in vivo activity with papaya leaf extracts.

In vitro studies on the sensitivity pattern of Plasmodium falciparum to anti-malarial drugs and local herbal extracts.

BackgroundThe resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents.ResultsSensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia (‘Ejirin’) Diospyros monbuttensis (‘Egun eja’) and Morinda lucida (‘Oruwo’) was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P<0.05), artemisinin and quinine (P<0.05) and quinine and mefloquine (P<0.05). A negative correlation was observed between the responses to chloroquine and mefloquine (P>0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2nM) while the lowest was obtained from M. lucida (IC50 =25nM).ConclusionsNatural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs.

Amino derivatives of indolone-N-oxide: Preparation and antiplasmodial properties

There is an urgent need for new antimalarial drugs with novel mechanisms of action on novel targets. Indolone-N-oxides (INODs) display antimalarial properties in vitro and in vivo, but identified leads such as 6-(4-chloro-phenyl)-5-oxy-[1,3]dioxolo[4,5-f]indol-7-one 1, suffer from very poor aqueous solubility. In this study, structural modifications have been made by introducing various amino and bulky groups to produce sufficiently water soluble and active compounds for further pharmacological and pharmacokinetic studies. We report here the preparation of twelve novel amino derivatives and their antiplasmodial activities including those of two other structurally known compounds. The 5-methoxy-2-(4-morpholin-4-yl-phenyl)-1-oxy-indol-3-one, 9, has the highest antiplasmodial activity in vitro (IC50 = 6.5 nM; FcB1 strain) and selectivity index (SI (CC50 MCF7/IC50 FcB1) = 4538.5). The 6-amino-2-(4-chloro-phenyl)-1-oxy-indol-3-one, 14, (IC50 = 183 nM; SI = 60), is an excellent candidate for further mechanistic studies. Indeed, this is structurally the closest analogue to the current lead, 1, bearing an NH2 group at R2 offering possibilities for functionalization and labeling.

Antiplasmodial Activity of the Root Extracts of Cochlospermum tinctorium in Mice Experimentally Infected with Clinical Isolates of Plasmodium berghei berghei (NK 65)

Aims: To determine in vivo the antiplasmodial activity of two chromatographic fractions obtained from Cochlospermum tinctorium A. Rich root bark extract against Plasmodium berghei berghei in mice. Methodology: Two chromatographic fractions were obtained from the crude methanolic extract of C. tinctorium root bark using petroleum ether (Fraction 1) and ethanol (Fraction 2) which were tested to determine their antiplasmodial activity in Swiss Albino mice infected with P. berghei berghei. Fraction 1 was administered at dose levels of 50, 100 and 200mg/kg/day, while fraction 2 was administered at dose levels of 25, 50 and 100 mg/kg/day. Chloroquine at 5 mg/kg per day was used as positive control and 0.2 ml normal saline was applied per day as sham. Results: Fraction 1had a percentage antiplasmodial activity of 80.67%, 64.14% and 69.71% for the dose level of 50, 100 and 200 mg/kg respectively. Data shows that fraction 1 treatment was not dose dependent as the lowest dosage of 50 mg/kg/day produced the highest percentage antiplasmodial activity of 80.67%, while 5 mg/kg chloroquine gave 100% cure. The effects of all treatments were significantly different (p&lt;0.05). Fraction 2 produced a dose dependent antiplasmodial activity of 62.42%, 65.70% and 98.17% in infected mice treated with 25, 50 and 100 mg/kg/day of the fraction respectively in direct proportion. Only the 100 mg/kg fraction antiplasmodial activity was not significantly different (p&gt;0.05) from that of 5 mg/kg chloroquine. The Median survival time post infection for infected mice treated with sham was 11 days, for infected mice treated with 50, 100 and 200mg/kg of fraction 1, the median survival time was 15.5, 15.5 and 19 days respectively, the log-rank (Mantle-Cox) test value of p&lt;0.05 showed that survival curves are significantly different. The median survival time post infection for mice treated with 0.2ml normal saline per day was 11days, for mice treated with 25, 50 and 100mg/kg of fraction 2 the median survival time post infection was 19, 18.5 and 18 days respectively, Log-rank (Mantle-Cox) test value of p&lt;0.05 indicates that survival curves are significantly different. The high antiplasmodial activity of 100 mg/kg fraction 1 was countered by its low survival time indicating a probable increase in toxicity to the mice with increase in dosage. The mean Packed Cell Volume (PCV) for infected mice treated with 50, 100 and 200 mg/kg fraction 1, the mean PCV was 36.83%, 32.42% and 37.96% respectively, while infected mice treated with25, 50 and 100mg/kg the mean PCV was 40.22%, 27.50% and 43.04% respectively. Since the mean PCV for infected mice treated with sham was 29.50%and 43.40% for 5mg/kg chloroquine treated mice, both fractions of C. tinctorium possess anaemia ameliorating property. However, only that of 25 and 100 mg/kg fraction 2 were the same as that of 5 mg/kg chloroquine (p&gt;0.05).There was however no significant difference (p&gt;0.05) in the mean percentage antiplasmodial activity of fraction 2 (65.26%) which was higher than that of fraction 1 (62.90%). Conclusion: C. tinctorium root bark extractpossess antimalarial and anaemia ameliorating properties which validates its use in traditional medicine for the treatment of malaria.

Synthesis and evaluation of new polynuclear organometallic Ru(ii), Rh(iii) and Ir(iii) pyridyl ester complexes as in vitro antiparasitic and antitumor agents

New polynuclear organometallic Platinum Group Metal (PGM) complexes containing di- and tripyridyl ester ligands have been synthesised and characterised using analytical and spectroscopic techniques including (1)H, (13)C NMR and infrared spectroscopy. Reaction of these polypyridyl ester ligands with either [Ru(p-cymene)Cl2]2, [Rh(C5Me5)Cl2]2 or [Ir(C5Me5)Cl2]2 dimers yielded the corresponding di- or trinuclear organometallic complexes. The polyaromatic ester ligands act as monodentate donors to each metal centre and this coordination mode was confirmed upon elucidation of the molecular structures for two of the dinuclear complexes. The di- and trinuclear PGM complexes synthesized were evaluated for inhibitory effects on the human protozoal parasites Plasmodium falciparum strain NF54 (chloroquine sensitive), Trichomonas vaginalis strain G3 and the human ovarian cancer cell lines, A2780 (cisplatin-sensitive) and A2780cisR (cisplatin-resistant) cell lines. All of the complexes were observed to have moderate to high antiplasmodial activities and the compounds with the best activities were evaluated for their ability to inhibit formation of synthetic hemozoin in a cell free medium. The in vitro antitumor evaluation of these complexes revealed that the trinuclear pyridyl ester complexes demonstrated moderate activities against the two tumor cell lines and were also less toxic to model non-tumorous cells.

In vitro antiplasmodial activity of some medicinal plants of Burkina Faso

Malaria remains a major public health problem due to the emergence and spread of Plasmodium falciparum drug resistance. There is an urgent need to investigate new sources of antimalarial drugs which are more effective against Plasmodium falciparum. One of the potential sources of antimalarial drugs is traditional medicinal plants. In this work, we studied the in vitro antiplasmodial activity of chloromethylenic, methanolic, and MeOH/H2O (1/1) crude extracts and decoction obtained from eight medicinal plants collected in Burkina Faso and of total alkaloids for five plants. Extracts were evaluated in vitro for efficacy against Plasmodium falciparum strain K1, which is resistant to chloroquine, pyrimethamine and proguanil using the fluorescence-based SYBR Green I assay. The antiproliferative activity on human-derived hepatoma cell line HepG2 and Chinese hamster ovary (CHO) cells was evaluated using the 3-[4,5-dimethylthyazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) test in order to determine the selectivity index. Among the plant extracts tested for in vitro antiplasmodial activity, 16 were considered to be inactive (with IC50 > 10 μg/ml), six showed a moderate activity (5 < IC50 ≤ 10 μg/ml), and six were found to have a good in vitro activity with IC50 value ≤ 5 μg/ml. The highest antiplasmodial activity was found for extracts from: the alkaloid leaf extract and the chloromethylenic extracts of Combretum fragrans (IC50 = 3 μg/ml, IC50 = 5 μg/ml), the total alkaloids and the chloromethylenic leaf extracts of Combretum collinum (IC50 = 4 μg/ml), the MeOH/H2O leaf extract of Terminalia avicennioides (IC50 = 3.5 μg/ml), and the alkaloid leaf extract of Pavetta crassipes (IC50 = 5 μg/ml). Three other extracts showed moderate antiplasmodial activity (5 < IC50 ≤ 10 μg/ml): Terminalia avicennioides and Combretum fragrans methanolic extracts and Acacia kirkii alkaloid leaf extract (IC50 = 6.5, 9 and 10 μg/ml respectively). The Terminalia avicennioides crude MeOH/H2O (80:20 v/v) extract of the leaves was submitted to a successive liquid/liquid extraction with ethylacetate and n-butanol respectively. The extracts were investigated for in vitro antiplasmodial activity and antioxidant properties using DPPH(·), ABTS(+) and FRAP methods. The ethylacetate extract showed the best antiplasmodial activity (7 μg/ml) and the active constituent was isolated as ellagic acid by bioguided fractionation with an IC50 = 0.2 μM on Plasmodium falciparum and SI = 152. Besides, Terminalia avicennioides leaf extract and ellagic acid showed a good antioxidant activity. Our finding confirms the importance of investigating the antimalarial activity of plant species used in traditional medicine. Overall, two plants belonging to the Combretaceae family, Combretum fragrans and Combretum collinum appeared to be the best candidates and will be further investigated for their antiplasmodial properties, in order to isolate the molecules responsible for the antiplasmodial activity.

Di- and Trinuclear Ruthenium-, Rhodium-, and Iridium-Functionalized Pyridyl Aromatic Ethers: A New Class of Antiparasitic Agents

Two new di- and tripyridyl aromatic ether ligands (1 and 2) have been synthesized using the Williamson ether method. Functionalization of these ligands with either dichlorido(p-cymene)ruthenium(II), dichlorido(pentamethylcyclopentadienyl)rhodium(III), or dichlorido(pentamethylcyclopentadienyl)iridium(III) fragments yielded three di- and three trinuclear organometallic complexes (1a–c and 2a–c). Both ligands act as monodentate donors to each metal center via the pyridyl nitrogen atoms, and this coordination mode of the polyaryl ether ligands has been confirmed upon elucidation of the molecular structure of the dinuclear iridium complex 1c. All of the synthesized compounds were evaluated for inhibitory effects on the Plasmodium falciparum strain NF54 (chloroquine-sensitive) and found to have moderate to high antiplasmodial activities, with the trinuclear complexes displaying activities in the nanomolar range. The most active compounds were studied for their ability to inhibit formation of synthetic hemozoin...

Antiprotozoal activity of bicyclic diamines with a N-methylpiperazinyl group at the bridgehead atom

ω-Aminoacyl and -alkyl derivatives of 4-(4-methylpiperazin-1-yl)bicyclo[2.2.2]octan-2-amines and of 5-(4-methylpiperazin-1-yl)-2-azabicyclo[3.2.2]nonanes were prepared and their activities were examined in vitro against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). Some of the newly synthesized compounds showed very promising antiprotozoal activity and selectivity. A few of the alkylamino-2-azabicyclo[3.2.2]nonanes exhibited high antiplasmodial activity, whereas a single bicyclo[2.2.2]octane derivative was the most potent antitrypanosomal compound. The results of the newly synthesized compounds were compared with the activities of already synthesized compounds and of drugs in use. Structure–activity relationships were discussed.

Enantioselective synthesis of encecaline-derived potent antimalarial agents

The high antiplasmodial activity of racemic benzylamines rac-1 and rac-2 stimulated the synthesis of pure enantiomers. Ellman's chiral sulfinamides (S)-6 and (R)-6 were used as chiral auxiliaries. Condensation of prochiral ketone 5 with enantiomerically pure sulfinamides (S)-6 and (R)-6 and subsequent NaBH4 reduction provided predominantly unlike configured diastereomers (S,R)-8 and (R,S)-8 (ratio unlike-8:like-8 = 90:10). The same transformation of phenol 4 led to the diastereomeric sulfinamides (S,R)-12 and (S,S)-12 in the ratio 60:40. Acid hydrolysis of the diastereomerically pure sulfinamides followed by monobenzylation yielded the enantiomerically pure benzylamines (R)-1, (S)-1, (R)-2 and (S)-2. The enantiomeric purity of the products was proven by chiral HPLC and the absolute configuration by CD-spectroscopy. Generally, benzylamines with (R)-configuration show higher antiplasmodial activity than their corresponding (S)-configured enantiomers. Phenol (R)-2 represents a very potent lead against P. falciparum, with an IC50 value of only 0.026 μM against the NF54 strain. The very high eudismic ratio of 34 indicates the enantioselective interaction of phenol (R)-2 with a particular target protein of P. falciparum.

Jozimine A2: The First Dimeric Dioncophyllaceae‐Type Naphthylisoquinoline Alkaloid, with Three Chiral Axes and High Antiplasmodial Activity

A new dimeric naphthylisoquinoline alkaloid, jozimine A(2) (2), was isolated from the root bark of an Ancistrocladus species from the Democratic Republic of Congo. Its absolute stereostructure was determined by chemical, spectroscopic, and chiroptical methods, and confirmed by X-ray crystallography. Jozimine A(2) (2) is one of the as yet very rare naphthylisoquinoline dimers whose central biaryl axis is rotationally hindered. Moreover, it is the first natural dimer of a Dioncophyllaceae-type alkaloid, that is, lacking oxygen functions at C6, and bearing R configurations at C3 in its two isoquinoline portions. Despite this decreased steric hindrance, the outer biaryl axes are chiral, too, so that jozimine A(2) (2) has three consecutive stereogenic axes and, together with the four stereogenic centers, seven elements of chirality and is C(2)-symmetric. The new dimer exhibits excellent, and specific, antiplasmodial activity. To further confirm its stereostructure and for likewise testing the bioactivities of its (unnatural) atropo-diastereomer, compound 2 was prepared by semi-synthesis from the co-occurring (and likewise synthetically available) dioncophylline A (5), along with its atropo-diastereomer, 3'-epi-2.

&lt;em&gt;In Vitro&lt;/em&gt; Antiplasmodial Activity and Cytotoxicity of Leaf Extracts of &lt;em&gt;Jatropha Tanjorensis&lt;/em&gt; J.L. Ellis and Soroja

The in vitro antiplasmodial activity and cytotoxicity of extracts from Jatropha tanjorensis leaves was evaluated. The plant leaves were successively extracted into three (3) extract forms (aqueous extract, ethanolic extract and hydro-ethanolic (50:50 v/v)) using standard procedures. For quality control, high performance thin layer chromatography (HPTLC) was performed on extracts. Antiplasmodial activity was assessed in vitro by using a 3D7 chloroquine sensitive clone of NF-54 isolate of Plasmodium falciparum. Cytotoxicity of extracts against non-cancerous vero cell lines was determined with doxorubicin serving as the standard cytotoxic drug. The spectra from the chemical finger-print of the extracts revealed that the ethanolic extract contained eleven peaks in contrast to the hydro-ethanolic (eight peaks) and aqueous (six peaks) extracts. The ethanolic extract had the highest antiplasmodial activity (IC50 10.86 &#177; 1.52 ug/ml), low cytotoxicity (IC50 86.8 &#177; 4.8 ug/ml) and selectivity index (SI) of 8.0 when compared with the hydro-ethanolic (IC50plasmodial 48.0 &#177; 1.34 ug/ml, IC50vero cells 547 &#177; 9.4 ug/ml, and SI of 11.4) and aqueous (IC50plasmodial 44.0 &#177; 2.4 ug/ml; IC50vero cells &gt; 1000 ug/ml) extracts. The antiplasmodial activity of the crude ethanolic extract was however moderate when compared with the standard antimalaria drug chloroquine (IC50 0.087 &#177; 0.0003 ug/ml). The results therefore suggest moderate antiplasmodial activity and low cytotoxicity of ethanolic extract of Jatropha tanjorensis leaves against chloroquine sensitive strain of Plasmodium falciparum. The antiplasmodial activity of the plant leaves supports local claims on its efficacy in the treatment of malaria infection.