Highest Antiplasmodial Activity Research Articles

Protein target similarity is positive predictor of in vitro antipathogenic activity: a drug repurposing strategy for Plasmodium falciparum

Drug discovery is an intricate and costly process. Repurposing existing drugs and active compounds offers a viable pathway to develop new therapies for various diseases. By leveraging publicly available biomedical information, it is possible to predict compounds’ activity and identify their potential targets across diverse organisms. In this study, we aimed to assess the antiplasmodial activity of compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library using in vitro and bioinformatics approaches. We assessed the in vitro antiplasmodial activity of the compounds using blood-stage and liver-stage drug susceptibility assays. We used protein sequences of known targets of the ReFRAME compounds with high antiplasmodial activity (EC50 < 10 uM) to conduct a protein-pairwise search to identify similar Plasmodium falciparum 3D7 proteins (from PlasmoDB) using NCBI protein BLAST. We further assessed the association between the compounds' in vitro antiplasmodial activity and level of similarity between their known and predicted P. falciparum target proteins using simple linear regression analyses. BLAST analyses revealed 735 P. falciparum proteins that were similar to the 226 known protein targets associated with the ReFRAME compounds. Antiplasmodial activity of the compounds was positively associated with the degree of similarity between the compounds’ known targets and predicted P. falciparum protein targets (percentage identity, E value, and bit score), the number of the predicted P. falciparum targets, and their respective mutagenesis index and fitness scores (R2 between 0.066 and 0.92, P < 0.05). Compounds predicted to target essential P. falciparum proteins or those with a druggability index of 1 showed the highest antiplasmodial activity.

2,4-disubstituted 6-fluoroquinolines as potent antiplasmodial agents: QSAR, homology modeling, molecular docking and ADMET studies

ObjectiveThis work was designed to study 2,4-disubstituted 6-fluoroquinolines as antiplasmodial agents by using in silico techniques, to aid in the design of novel analogs with high potency against malaria and high inhibition of Plasmodium falciparum translation elongation factor 2 (PfeEF2), a novel drug target. MethodsQuantitative structure-activity relationships (QSAR) of 2,4-disubstituted 6-fluoroquinolines were studied with the genetic function approximation technique in Material Studio software. The 3D structure of PfeEF2 was modeled in the SWISS-MODEL workspace through homology modeling. A molecular docking study of the modeled PfeEF2 and 2,4-disubstituted 6-fluoroquinolines was conducted with Autodock Vina in Pyrx software. Furthermore, the in silico pharmacokinetic properties of selected compounds were investigated. ResultsA robust, reliable and predictive QSAR model was developed that related the chemical structures of 2,4-disubstituted 6-fluoroquinolines to their antiplasmodium activities. The model had an internal squared correlation coefficient R2 of 0.921, adjusted squared correlation coefficient R2adj of 0.878, leave-one-out cross-validation coefficient Q2cv of 0.801 and predictive squared correlation coefficient R2pred of 0.901. The antiplasmodium activity of 6-fluoroquinolines was found to depend on the n5Ring, GGI9, TDB7u, TDB8u and RDF75i physicochemical properties: n5Ring, TDB8u and RDF75i were positively associated, whereas GGI9 and TDB7u were negatively associated, with the antiplasmodium activity of the compounds. Stable complexes formed between the compounds and modeled PfeEF2, with binding affinity ranging from −8.200 to −10.700 kcal/mol. Compounds 5, 11, 16, 22 and 24 had better binding affinities than quinoline-4-carboxamide (DDD107498), as well as good pharmacokinetic properties, and therefore may be better inhibitors of this novel target. ConclusionQSAR and docking studies provided insight into designing novel 2,4-disubstituted 6-fluoroquinolines with high antiplasmodial activity and good structural properties for inhibiting a novel antimalarial drug target.

Antimalarial potential of five Nigerian medicinal plants: Repository versus curative activities

The conventional management of malaria in most endemic areas is based on phytomedicine. It is commonly believed that prevention is better than cure when it comes to disease management. Therefore, medicinal plants commonly used for treatment in herbal medicine are also used for prevention purposes. Hence, it is important to investigate the efficacy of medicinal plants in relation to the timing of their use. To document the medicinal plants used for treating malaria, a structured questionnaire-based ethnobotanical survey was conducted in Omu-Aran, Kwara State, Nigeria. The survey revealed the use of 31 plant species from 24 families, with origin in Omu-Aran, in herbal antimalarial recipes. Some of the identified plants were subjected to in vivo antimalarial bioassays. The aqueous and dichloromethane: Methanol (1:1) extracts of the leaves and stem bark of Morinda lucida and Nauclea latifolia, as well as the leaf extracts of Chromolaena odorata, Tithonia diversifolia, and Lawsonia inermis were tested at doses of 100, 250 and 400 mg/kg against Plasmodium berghei Anka. The repository and curative tests were conducted to assess the residual and curative abilities of the extracts, respectively, with chloroquine as a reference drug. The tested extracts demonstrated better antiplasmodial activities in the repository tests, particularly the aqueous extracts. Only the organic extract of T. diversifolia at 100 mg/kg exhibited a high antiplasmodial activity with a percentage chemosuppression (PCS) value of 66.13%, while other extracts showed moderate (PCS: 30 &amp;ndash; 60%) to no activity (PCS: &lt;0%) in curative tests. In repository tests, only N. latifolia showed high activity with percentage chemoprophylaxis (PCP) values ranging from 61.51% to 81.69%, while other extracts generally showed moderate activities. Chloroquine showed strong chemosuppression (92.74 &amp;le; PCS &amp;le; 98.77) in curative tests but weak chemoprophylaxis (PCP &lt;30%). The efficacy tests showed that most of the investigated medicinal plants were more effective for prevention rather than for curative purposes.

Phytofabrication and characterization of Alchornea cordifolia silver nanoparticles and evaluation of antiplasmodial, hemocompatibility and larvicidal potential.

Purpose: The recent emergence of Plasmodium falciparum (Pf) parasites resistant to current artemisinin-based combination therapies in Africa justifies the need to develop new strategies for successful malaria control. We synthesized, characterized and evaluated medical applications of optimized silver nanoparticles using Alchornea cordifolia (AC-AgNPs), a plant largely used in African and Asian traditional medicine. Methods: Fresh leaves of A. cordifolia were used to prepare aqueous crude extract, which was mixed with silver nitrate for AC-AgNPs synthesis and optimization. The optimized AC-AgNPs were characterized using several techniques including ultraviolet-visible spectrophotometry (UV-Vis), scanning/transmission electron microscopy (SEM/TEM), powder X-ray diffraction (PXRD), selected area electron diffraction (SAED), energy dispersive X-ray spectroscopy (EDX), Fourier transformed infrared spectroscopy (FTIR), dynamic light scattering (DLS) and Zeta potential. Thereafter, AC-AgNPs were evaluated for their hemocompatibility and antiplasmodial activity against Pf malaria strains 3D7 and RKL9. Finally, lethal activity of AC-AgNPs was assessed against mosquito larvae of Anopheles stephensi, Culex quinquefasciatus and Aedes aegypti which are vectors of neglected diseases such as dengue, filariasis and chikungunya. Results: The AC-AgNPs were mostly spheroidal, polycrystalline (84.13%), stable and polydispersed with size of 11.77 ± 5.57nm. FTIR revealed the presence of several peaks corresponding to functional chemical groups characteristics of alkanoids, terpenoids, flavonoids, phenols, steroids, anthraquonones and saponins. The AC-AgNPs had a high antiplasmodial activity, with IC50 of 8.05μg/mL and 10.31μg/mL against 3D7 and RKL9 Plasmodium falciparum strains. Likewise, high larvicidal activity of AC-AgNPs was found after 24h- and 48h-exposure: LC50 = 18.41μg/mL and 8.97μg/mL (Culex quinquefasciatus), LC50 = 16.71μg/mL and 7.52μg/mL (Aedes aegypti) and LC50 = 10.67μg/mL and 5.85μg/mL (Anopheles stephensi). The AC-AgNPs were highly hemocompatible (HC50 > 500μg/mL). Conclusion: In worrying context of resistance of parasite and mosquitoes, green nanotechnologies using plants could be a cutting-edge alternative for drug/insecticide discovery and development.

Antimalarial and Cytotoxic Activity of Native Plants Used in Cabo Verde Traditional Medicine.

Medicinal plants have historically been a source of drugs in multiple applications, including the treatment of malaria infections. The Cabo Verde archipelago harbors a rich diversity of native plants, most of which are used for medicinal purposes. The present study investigated the in vitro antiplasmodial activities of four native plants from Cabo Verde (i.e., Artemisia gorgonum, Lavandula rotundifolia, Sideroxylon marginatum, and Tamarix senegalensis). Traditional preparations of these medicinal plants, namely aqueous extracts (infusions) and ethanolic extracts, were tested against both chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains using the SYBR Green detection method. The in vitro cytotoxicity was evaluated in Caco-2 and PLP2 cells using a sulforhodamine B colorimetric assay. An ethanolic extract of A. gorgonum and infusions of T. senegalensis exhibited high antiplasmodial activities (EC50 < 5 μg/mL) without cytotoxicity (GI50 > 400 μg/mL). Extracts of L. rotundifolia and S. marginatum exhibited moderate activities, with EC50 values ranging from 10-30 μg/mL. The A. gorgonum ethanolic extract showed activity toward early ring stages, and parasites treated with the T. senegalensis infusions progressed to the early trophozoite stage, although did not develop further to the late trophozoite or schizont stages. Antimalarial activities and the lack of cytotoxicity of the extracts are reported in the present study and support previous claims by traditional practitioners for the use of these plants against malaria while suggesting their ethnopharmacological usefulness as future antimalarials.

Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex.

In the fight against malaria, the key is early treatment with antimalarial chemotherapy, such as artemisinin-based combination treatments (ACTs). However, Plasmodium has acquired multidrug resistance, including the emergence of P. falciparum strains with resistance to ACT. The development of novel antimalarial molecules, that are capable of interfering in the asexual and sexual blood stages, is important to slow down the transmission in endemic areas. In this work, we studied the ability of the mettalo copper-cinchonine complex to interfere in the sexual and asexual stages of Plasmodium. The tested compound in the in vitro assay was a cinchonine derivative, named CinCu (Bis[Cinchoninium Tetrachlorocuprate(II)]trihydrate). Its biological functions were assessed by antiplasmodial activity in vitro against chloroquine-resistant P. falciparum W2 strain. The mice model of P. berghei ANKA infection was used to analyze the antimalarial activity of CinCu and chloroquine and their acute toxicity. The oocyst formation-blocking assay was performed by experimental infection of Anopheles aquasalis with P. vivax infected blood, which was treated with different concentrations of CinCu, cinchonine, and primaquine. We found that CinCu was able to suppress as high as 81.58% of parasitemia in vitro, being considered a molecule with high antiplasmodial activity and low toxicity. The in vivo analysis showed that CinCu suppressed parasitemia at 34% up to 87.19%, being a partially active molecule against the blood-stage forms of P. berghei ANKA, without inducing severe clinical signs in the treated groups. The transmission-blocking assay revealed that both cinchonine and primaquine were able to reduce the infection intensity of P. vivax in A. aquasalis, leading to a decrease in the number of oocysts recovered from the mosquitoes' midgut. Regarding the effect of CinCu, the copper-complex was not able to induce inhibition of P. vivax infection; however, it was able to induce an important reduction in the intensity of oocyst formation by about 2.4 times. It is plausible that the metallo-compound also be able to interfere with the differentiation of parasite stages and/or ookinete-secreted chitinase into the peritrophic matrix of mosquitoes, promoting a reduction in the number of oocysts formed. Taken together, the results suggest that this compound is promising as a prototype for the development of new antimalarial drugs. Furthermore, our study can draw a new pathway for repositioning already-known antimalarial drugs by editing their chemical structure to improve the antimalarial activity against the asexual and sexual stages of the parasite.

Secondary metabolites of the leaves of Tricalysia atherura N. Hallé (Rubiaceae) and their potential antiplasmodial activity

One monoterpene indole alkaloid, atheruramine (1) bearing an ether bridge linking, one hydrobenzoin derivative, tricalydioloside (2) and two ursane-type triterpenes, atherurosides (A and B) (3 and 4) were isolated from the leaves of Tricalysia atherura, together with eight known compounds. The structures of these new compounds were elucidated on the basis of the results of spectroscopic analysis, and the relative configurations of compounds 1–3 were established by NOE difference. Four of the metabolites were screened in vitro against both chloroquine (CQ)-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum; they were found to exhibit moderate activity against chloroquine-resistant (Dd2) (IC50 64.99–92.29 μg/mL). Meanwhile, crude extract possesses high antiplasmodial activity against both 3D7 and Dd2 strains of P. falciparum (IC50 4.39–7.54 μg/mL) and high selectivity indices values (SI > 10) and was found to be safe.

IN VIVO AND IN VITRO ANTIPLASMODIAL ACTIVITY OF EXTRACTS, FRACTIONS AND AN ISOLATED COMPOUND FROM SILK OF ZEA MAYS (CORN SILK)

This study has investigated antiplasmodial activity of extracts, fractions and an isolated compound from corn silk using both in vivo and in vitro assays. Also, safety studies were carried out on the extract. Pharmacologically, both aqueous and methanolic extracts demonstrated remarkable in vivo antiplasmodial activity of 78.9 ± 1.59 % and 77.3 ± 0.92 % reduction in parasitaemia respectively. The bioassay guided fractionation indicated that ethyl acetate fraction of the methanolic extract of corn silk exhibited highest antiplasmodial activity among the fractions investigated. Employing column chromatography and other chromatographic methods on the ethyl acetate fraction of the methanolic extract of corn silk led to isolation of norbergenin. Spectroscopic methods such as infrared, one-dimensional, two-dimensional nuclear magnetic resonance and others were used in characterization and identification of the compound. Antiplasmodial investigation of the compound using in vitro SYBR Green 1 fluorescent-based assay on the chloroquine-sensitive based plasmodial 3D7 strain showed that it possessed antiplasmodial activity of IC50 value of 15.31±2.10 μg/mL and could be linked to the bioactive compounds in ethyl acetate fraction. The results of this study have granted support to the local use of corn silk for the treatment of malaria. It is the first report of these pharmacological studies. It is also the first report of isolating norbergenin from corn silk.

Antiplasmodial activity of the ethanol extract of Dacryodes edulis leaf in Plasmodium berghei infected mice

Background: Malaria treatment in Africa is increasingly becoming difficult resulting from Plasmodium falciparum resistant to available antimalarial agents. Therefore, evaluating plants used in traditional medicines can lead to alternative treatment against malaria.Methods: This study evaluated the antiplasmodial activity of ethanol extract of Dacryodes edulis in chloroquine sensitive Plasmodium berghei NK65 strain in mice. The 4-day suppressive test, repository and curative effect against established rodent malaria infection models were assayed in this study. The oral acute toxicity test and phytochemical screening were also carried out on the ethanol leaf extract.Results: The ethanol leaf extract of Dacryodes edulis (D. edulis) at varying doses of 100 mg/kg, 200 mg/kg, 400 mg/kg significantly (p&lt;0.05) exhibited dose-dependent decrease in parasitaemia at suppressive, repository and curative studies. Chloroquine 10 mg/kg significantly (p&lt;0.05) decreased parasitaemia levels in the three models of malaria infections. The antiplasmodial activity of the leaf extract is comparable with the standard drug. The extract was found to be non-toxic acutely in mice.Conclusions: The findings show that D. edulis ethanol leaf extract demonstrated high antiplasmodial activity in a dose-dependent fashion. Thus, supporting claims of the plant traditional therapeutic importance for malaria treatment, and can be developed as an alternative therapy against the disease.

In vivo Chemosuppressive effects of Combinations of Three Nigerian Ethnomedicinal Antimalarial Plants

Aims: Appropriate ratios for combining some African ethnomedicinal plants with proven anti-plasmodial activity were determined with the aim of obtaining herbal remedies with higher efficacies.&#x0D; Place and Duration of the Study: Study was conducted in the Department of Pharmacognosy, Obafemi Awolowo University, Ile-Ife Nigeria.&#x0D; Study Design: Infusions of dried powders of three Nigerian ethnomedicinal plants, Eugenia uniflora leaf, Gongronema latifolium root and stem and Artocarpus altilis stem bark, were separately evaluated and in varied combination ratios for their anti-plasmodial activities&#x0D; Methodology: The infusions were separately prepared, concentrated in vacuo, freeze-dried and evaluated at 400mg/kg against Plasmodium berghei berghei parasites, using the Peter’s four-day chemosuppressive mice model. Normal saline and chloroquine (10mg/kg) were negative and positive controls, respectively. 2- and 3-combinations of the infusions were similarly tested.&#x0D; Results: Of the 2-plant combination ratios, 1:1, 1:3, 2:3 of EG and GA elicited percentage chemo suppressions which were comparable (P=.28; P=.07) to those of the single drugs. Only the EG ratios gave activities that were comparable (P=.28) to the positive control in addition to double survival times and high survivor values by EG 2:3 and GA 1:3. However, those of the EA group, gave relatively low values, barely above 20% with only the ratios 2:3 and 3:2 giving values which were significantly (P=.00) higher than negative control with double survival times. The 3-plant combination ratios, EGA 2:1:2 and 3:3:2 gave suppressions that were significantly (P=.00) higher than the negative control with others but comparable (P=.33) activities to those of the individual drugs. The other ratios with low suppression values were relatively inactive. But three ratios, EGA 3:1:2, 2:1:1, 1:1:1 elicited survival times doubled (204, 242 and 202 %) that of the negative control without commensurate high antiplasmodial activities.&#x0D; Conclusion: Ethnomedicinal antimalarial plants should not be combined without a data of previous scientific evaluations.

In vitro antiplasmodial activity of selected plants from the Colombian North Coast with low cytotoxicity.

Plants are an important option in the treatment of malaria, especially in endemic regions, and are a less expensive and more accessible alternative with a lower risk of toxicity. Colombia has a great diversity of plants, and evaluation of natural extracts could result in the discovery of new compounds for the development of antimalarial drugs. The purpose of this work was to evaluate the in vitro antiplasmodial activity and the cytotoxicity of plant extracts from the Colombian North Coast against Plasmodium falciparum. The antiplasmodial activity of 12 plant species from the Colombian North Coast that are used in traditional medicine was evaluated through in vitro cultures of P. falciparum, and the cytotoxicity of extracts of these species to human cells was determined. Plant extracts with high antiplasmodial activity were subjected to preliminary phytochemical screening. Extracts from five plants had promising antiplasmodial activity. Specifically, Bursera simaruba (Burseraceae) (bark), Guazuma ulmifolia Lam. (Malvaceae) (whole plant), Murraya exotica L. (Rutaceae) (leaves), Hippomane mancinella L. (Euphorbiaceae) (seeds), and Capparis odoratissima Jacq. (Capparaceae) (leaves). Extracts presented 50% inhibitory concentration values between 1 and 9 μg/ml. Compared to no extract, these active plant extracts did not show cytotoxic effects on mononuclear cells or hemolytic activity in healthy human erythrocytes. The results obtained from this in vitro study of antiplasmodial activity suggest that active plant extracts from the Colombian North Coast are promising for future bioassay-guided fractionation to allow the isolation of active compounds and to elucidate their mechanism of action against Plasmodium spp.

Hexane fraction of Globimetula braunii induces mitochondria-mediated apoptosis in Plasmodium berghei-infected mice

BackgroundApoptosis is a common pathology in malaria and most antimalarial drugs induce apoptosis during chemotherapy. Globimetula braunii is an African mistletoe used for the treatment of malaria but its effect on mitochondria-mediated apoptosis is not known. MethodsMalarial infection was induced by the intraperitoneal injection of NK 65 strain Plasmodium berghei-infected erythrocytes into mice which were treated with graded doses (100–400 mg/kg) of methanol extract (ME), and fractions of n-hexane, dichloromethane, ethylacetate and methanol (HF, DF, EF and MF) for 9 days after the confirmation of parasitemia. Artequine (10 mg/kg) was used as control drug. The fraction with the highest antiplasmodial activity was used (same dose) to treat mice infected with chloroquine-resistant (ANKA) strain for 5 consecutive days after the confirmation of parasitemia. P-alaxin (10 mg/kg) was used as control drug. On the last day of the treatment, liver mitochondria were isolated and mitochondrial Permeability Transition (mPT) pore opening, mitochondrial F0F1 ATPase (mATPase) activity, lipid peroxidation (mLPO) and liver deoxyribonucleic acid (DNA) fragmentation were assessed spectrophotometrically. Caspases 3 and 9 were determined by Enzyme-Linked Immunosorbent Assay (ELISA) technique. Cytochrome c, P53, Bcl-2-associated X protein (Bax), and B-cell lymphoma-2 (Bcl2) were determined via immunohistochemistry. Phytochemical constituents of the crude methanol extract of Globimetula braunii were determined via the Gas Chromatography-Mass Spectrometry (GC-MS) analysis ResultsThere was large amplitude mPT induction by malaria parasites, extract and fractions of Globimetula braunii. At 400 mg/kg, HF significantly (p < 0.01) downregulated mATPase activity, and mLPO in both (susceptible and resistant) models, caused DNA fragmentation (P < 0.0001), induced caspases activation, P53, bax and cytochrome c release but downregulated Bcl2 in both models. The GC-MS analysis of methanol extract of Globimetula braunii showed that α-amyrin is the most abundant phytochemical. ConclusionThe n-hexane fraction of Globimetula braunii induced mitochondrial-mediated apoptosis through the opening of the mitochondrial pore, fragmentation of genomic DNA, increase in the levels of P53, bax, caspase 3 and 9 activation and cytochrome c release with concomitant decrease in the level of Bcl2. α-Amyrin is a triterpene with apoptotic effects.

Mineral Fertilization Influences the Growth, Cryptolepine Yield, and Bioefficacy of Cryptolepis sanguinolenta (Lindl.) Schlt.

Cryptolepis sanguinolenta (Lindl.) Schlt., the main source of cryptolepine alkaloid, is intensively exploited in the wild to treat malaria and Lyme disease. In this study, the influence of four inorganic fertilizers (supplying N, P, K, or NPK) and four growth periods (3, 6, 9, and 12 months after transplanting) on the herb’s root biomass, cryptolepine content and yield, and biological activities were investigated in a pot and field trial. The results showed the application of N (in the form of Urea or NPK) increased root biomass yield, cryptolepine content, and cryptolepine yield compared to unfertilized plants. The 9-month-old plants recorded the maximum cryptolepine content (2.26 mg/100 mg dry root) and cryptolepine yield (304.08 mg/plant), indicating the perfect time to harvest the herb. Plant age at harvest had a more significant influence (50.6–55.7%) on cryptolepine production than fertilizer application (29.2–33.3%). Cryptolepine extracts from 9- to 12-month-old plants had the highest antiplasmodial activity (IC50 = 2.56–4.65 µg/mL) and drug selectivity index (2.15–3.91) against Plasmodium falciparum Dd2. These extracts were also cytotoxic to Jurkat leukaemia cell lines (CC50 < 62.56 µg/mL), indicating the possible use of cryptolepine for cancer management. Growing the herb in the field increased cryptolepine yield 2.5 times compared to growth in a pot, but this did not influence the antiplasmodial activity of the extract. Commercial cultivation of C. sanguinolenta for 9 months combined with N application could be a promising solution to the sustainable use of this threatened medicinal species.

In vitro antiplasmodial and in vivo toxicity potential of Mentha piperita and Ocimum gratissimum essential oils and their synergistic effect with conventional antimalarial drugs against Plasmodium falciparum

The study aimed to investigate the in vitro antiplasmodial and in vivo toxicity potential of essential oils from Mentha piperita and Ocimum gratissimum against Plasmodium falciparum, singly and in combination with antimalarial drugs. The essential oils (EOs) were obtained by steam distillation and phytochemical screening conducted using gas chromatography equipped with a flame ionization detector. Blood samples of malaria positive patients were cultured and P. falciparum identified microscopically. Micro-technique of schizont counting was used to determine the antiplasmodial baseline of the EOs and in combination with antimalarial drugs. Hematological and serum biochemical indices for in vivo toxicity assay using Wister rats were determined following WHO test procedures. Dose-response assay determined after 48 h for in vitro inhibition of maturation of trophozoites into schizonts showed that EO of M. piperita had a higher antiplasmodial activity of 6.62 ± 0.20, 10.74 ± 1.64 and 14.21 ± 0.45 µg values than O. gratissimum for IC30, IC50 and IC90, respectively against P. falciparum. When the EOs were combined with conventional antimalarial agents, M. piperita with Sulfadoxine/Pyrimethamine had the highest antiplasmodial activity with inhibitory concentration values of 1.92 ± 1.00, 4.07 ± 1.34 and 6.85 ± 0.75 ݜ‡g/mL for IC30, IC50 and IC90, respectively than O. gratissimum. In vivo hematological and biochemical studies after 14 days oral treatment showed no toxicity as a result of treatment with the oil extracts and these were significantly different (P

Antiplasmodial activity and cytotoxicity of plant extracts from the Asteraceae and Rubiaceae families

The increasing resistance of parasites to antimalarial drugs and the limited number of effective drugs are the greatest challenges in the treatment of malaria. It is necessary to search for an alternative medicine for use as a new, more effective antimalarial drug. Therefore, this study aimed to evaluate the in vitro antimalarial activity and cytotoxicity of extracts from plants belonging to the Asteraceae and Rubiaceae families. The phytoconstituents of one hundred ten ethanolic and aqueous extracts from different parts of twenty-three plant species were analyzed. Evaluation of their antimalarial activities against the chloroquine (CQ)-resistant Plasmodium falciparum (K1) strain was carried out using the lactate dehydrogenase (pLDH) assay, and their cytotoxicity in Vero cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric method. A total of 40.91% of the extracts were active antimalarial agents. Three extracts (2.73%) exhibited high antiplasmodial activity (IC50 < 10 μg/ml), twenty-four extracts (21.82%) were moderately active with IC50 values ranging from 10–50 μg/ml, and eighteen extracts (16.36%) were mildly active with IC50 values ranging from 50–100 μg/ml. The ethanolic leaf extract of Mussaenda erythrophylla (Dona Trining; Rubiaceae) exhibited the highest activity against P. falciparum, with an IC50 value of 3.73 μg/ml and a selectivity index (SI) of 30.74, followed by the ethanolic leaf extract of Mussaenda philippica Dona Luz x M. flava (Dona Marmalade; Rubiaceae) and the ethanolic leaf extract of Blumea balsamifera (Camphor Tree; Asteraceae), with IC50 values of 5.94 and 9.66 μg/ml and SI values of 25.36 and >20.70, respectively. GC–MS analysis of these three plant species revealed the presence of various compounds, such as squalene, oleic acid amide, β-sitosterol, quinic acid, phytol, oleamide, α-amyrin, sakuranin, quercetin and pillion. In conclusion, the ethanolic leaf extract of M. erythrophylla, the leaf extract of M. philippica Dona Luz x M. flava and the leaf extract of B. balsamifera had strong antimalarial properties with minimal toxicity, indicating that compounds from these plant species have the potential to be developed into new antiplasmodial agents.

Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-β-Carbolines.

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.

Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity.

The 2-phenoxybenzamide 1 from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of P. falciparum. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of P. falciparum. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D7.4 and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The tert-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against P. falciparum NF54 (PfNF54 IC50 = 0.2690 µM) and very low cytotoxicity (L-6 cells IC50 = 124.0 µM) resulting in an excellent selectivity index of 460. Compared to the lead structure 1 the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.

Antiplasmodial, antimalarial activities and toxicity of African medicinal plants: a systematic review of literature

BackgroundMalaria still constitutes a major public health menace, especially in tropical and subtropical countries. Close to half a million people mainly children in Africa, die every year from the disease. With the rising resistance to frontline drugs (artemisinin-based combinations), there is a need to accelerate the discovery and development of newer anti-malarial drugs. A systematic review was conducted to identify the African medicinal plants with significant antiplasmodial and/or anti-malarial activity, toxicity, as wells as assessing the variation in their activity between study designs (in vitro and in vivo).MethodsKey health-related databases including Google Scholar, PubMed, PubMed Central, and Science Direct were searched for relevant literature on the antiplasmodial and anti-malarial activities of African medicinal plants.ResultsIn total, 200 research articles were identified, a majority of which were studies conducted in Nigeria. The selected research articles constituted 722 independent experiments evaluating 502 plant species. Of the 722 studies, 81.9%, 12.4%, and 5.5% were in vitro, in vivo, and combined in vitro and in vivo, respectively. The most frequently investigated plant species were Azadirachta indica, Zanthoxylum chalybeum, Picrilima nitida, and Nauclea latifolia meanwhile Fabaceae, Euphorbiaceae, Annonaceae, Rubiaceae, Rutaceae, Meliaceae, and Lamiaceae were the most frequently investigated plant families. Overall, 248 (34.3%), 241 (33.4%), and 233 (32.3%) of the studies reported very good, good, and moderate activity, respectively. Alchornea cordifolia, Flueggea virosa, Cryptolepis sanguinolenta, Zanthoxylum chalybeum, and Maytenus senegalensis gave consistently very good activity across the different studies. In all, only 31 (4.3%) of studies involved pure compounds and these had significantly (p = 0.044) higher antiplasmodial activity relative to crude extracts. Out of the 198 plant species tested for toxicity, 52 (26.3%) demonstrated some degree of toxicity, with toxicity most frequently reported with Azadirachta indica and Vernonia amygdalina. These species were equally the most frequently inactive plants reported. The leaves were the most frequently reported toxic part of plants used. Furthermore, toxicity was observed to decrease with increasing antiplasmodial activity.ConclusionsAlthough there are many indigenous plants with considerable antiplasmodial and anti-malarial activity, the progress in the development of new anti-malarial drugs from African medicinal plants is still slothful, with only one clinical trial with Cochlospermum planchonii (Bixaceae) conducted to date. There is, therefore, the need to scale up anti-malarial drug discovery in the African region.

Ln vitro inhibition of beta-hematin formation and in vivo effects of Diospyros mespiliformis and Mondia whitei methanol extracts on chloroquine-susceptible Plasmodium berghei-induced malaria in mice.

Background and aimThis study was carried out to investigate antiplasmodial activities of Diospyros mespiliformis (DM) and Mondia whitei (MW) in Plasmodium berghei-infected mice.Materials and methodsAir-dried stem of DM and root of MW were soaked in methanol, decanted and concentrated to give extracts. Parts of these extracts were partitioned successively to give dichloromethane, ethylacetate and methanol fractions. Mice (18 ± 3 g) were infected with Plasmodium berghei-infected erythrocytes from a donor mouse and were treated with the extracts, while the drug control group received 10 mg/kg body weight of artesunate and the parasitized control received the vehicle (5% v/v DMSO). Percentage parasitemia and clearance were estimated from thin films of blood smear. Hematological parameters were determined using standard methods. Both extracts were also tested on in vitro inhibition of β-hematin formation.Results, discussion and conclusionResults showed that DM had the least percentage parasitemia (0.67%) and highest percentage parasite clearance (84.7%) while the MW had 0.89% percentage parasitemia and 79.7% clearance at the highest dose used after the seventh day relative to untreated control. The cell free antiplasmodial activity of the fractions and extracts of both DM and MW revealed that DM significantly inhibited β-hematin formation than MW. The packed cell volume, white blood cell count, Lymphocyte, Eosinophil, Monocyte and Neutrophil significantly increased in the treated groups compared with the control. The results showed that the DM had higher antiplasmodial activity.

In vitro antiplasmodial activity, cytotoxicity, and gas chromatography – flame ionization detector metabolites fingerprint of extracts and fractions from Tetrorchidium didymostemon

BackgroundTetrorchidium didymostemon is used as an antimalarial remedy in southern Nigeria. Objective(s)This study was aimed at providing scientific validation for the use of T. didymostemon in the treatment of malaria in Nigeria. Materials and methodsPlasmodium falciparum 3D7 (Pf3D7) strain was cultured and maintained in fresh O+ human erythrocytes. Standard methods were used to evaluate in vitro antiplasmodial activity, cytotoxic effect on Vero cell line, phytochemical screening, and antioxidant capacity. Gas Chromatography – Flame Ionization Detector (GC-FID) metabolite fingerprinting of the most potent fraction was carried out. ResultsThe methanol leaf extract had higher antiplasmodial activity (IC50Pf3D7 = 25 ± 0.21 μg/mL) in comparison with the stem bark extract (SBE) (IC50Pf3D7 = 50 ± 0.94 μg/mL). The n-hexane fraction of the leaf extract had the best antiplasmodial activity (IC50Pf3D7 = 3.92 ± 0.46 μg/mL) and selectivity index. This was followed by the dichloromethane (IC50Pf3D7 = 12.5 ± 1.32 μg/mL), ethyl acetate (IC50Pf3D7 = 35.0 ± 4.80 μg/mL), and hydromethanol fraction which was inactive (IC50Pf3D7 > 100 μg/mL). All extracts and fractions were not toxic on Vero cell line (CC50 > 1000 μg/mL). The n-hexane and dichloromethane fractions had the highest amount of phytochemicals. GC-FID analysis revealed high amounts of kaempferol, α-pinene, camphor, humulene, azulene, and β-caryophyllene in the n-hexane fraction. ConclusionThe results of our study validate the traditional use of T. didymostemon in the treatment of malaria in southern Nigeria. They also suggest that the phytoconstituent(s) responsible for the antiplasmodial activity of this plant may be more extractable in non-polar solvents.