Potential Antimalarials Research Articles

The antiplasmodial activity of the carboxylic acid metabolite of piperaquine and its pharmacokinetic profiles in healthy volunteers.

The long-acting antimalarial drug piperaquine can be metabolized into the carboxylic acid metabolite (PQM). However, the clinical relevance of PQM remains unclear. The pharmacodynamics/pharmacokinetics of PQM were studied. The antimalarial activity of PQM was studied in vitro (Plasmodium strains Pf3D7 and PfDd2) and in vivo (murine Plasmodium yoelii). The toxicity of PQM was evaluated in mice, in terms of the general measures of animal well-being, serum biochemical examination and ECG monitoring. The pharmacokinetic profiles of piperaquine and its metabolite PQM were investigated in healthy subjects after recommended oral doses of piperaquine. PQM showed no relevant in vitro antimalarial activity (IC50 > 1.0 μM) with no significant toxicity. After recommended oral administration of piperaquine to healthy subjects, the maximum concentration of PQM was less than 30.0 nM, and it did not accumulate after repeated dosing. With a low antimalarial potency, PQM should not contribute to the efficacy of piperaquine with clinically acceptable doses.

Antimalarial and Antileishmanial Flavonoids from Calendula officinalis Flowers

Calendula officinalis L. (Asteraceae), commonly known as English or pot marigold, is an herbaceous plant with edible flowers. In this study, UPLC-ESI-MS/MS analysis was used for tentative identification of compounds in marigold flower methanol extract (MFE). In addition, RP-HPLC-DAD analysis was used to quantify the flavonoids hesperidin and rutin in MFE. The antileishmanial potentials of the crude extract and compounds were evaluated against Leishmania major promastigotes and amastigotes. Further, in vivo 4-day antimalarial testing of the extract and compounds was carried out at doses of 25 mg kg−1 per day using mice infected with ANKA strain of Plasmodium berghei, following standard procedure. Molecular docking studies were carried out to assess the binding mode of flavonoids against the vital targets of L. major, including pteridine reductase 1 and farnesyl diphosphate synthase enzymes. The in silico antimalarial potentials of flavonoids were evaluated against wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase and phosphoethanolamine methyltransferase enzymes. Twenty compounds were tentatively identified by UPLC-ESI-MS/MS analysis of MFE, of which, seven flavonoids, six saponins, three phenolic acids, three fatty acids, and a triterpene glycoside were identified. MFE phytochemical analysis revealed that hesperidin content was 36.17 mg g−1 extract, that is, 9.9-fold their content of rutin (3.65 mg g−1 extract). The method was validated to ensure reproducibility of the results. The tested samples exhibited antileishmanial potentials against L. major promastigotes, with IC50 values of 98.62, 118.86, and 104.74 ng µL−1 for hesperidin, rutin, and MFE, respectively. Likewise, hesperidin showed inhibitory potentials against L. major amastigote with an IC50 value of 108.44 ± 11.2 µM, as compared to miltefosine. The mean survival time, parasitemia, and suppression percentages showed similar results for the three samples against ANKA strain of P. berghei. The docking studies showed good binding affinities of rutin and hesperidin with numerous H-bonding and van der Waals interactions. Marigold flowers are nutraceuticals, presenting important sources of bioactive flavonoids with potential against neglected tropical diseases.

Drug repurposing approach for identifying Pfmrk inhibitors as potential antimalarial agents: An in silico analysis

Malaria represents a major global health concern, primarily due to the emergence of resistance against most currently available antimalarial drugs. This pressing issue necessitates the discovery of novel antimalarial agents to combat the escalating resistance. A cyclin-dependent kinase (CDK)-like protein, Pfmrk, found in Plasmodium falciparum, plays a crucial role in regulating cell proliferation and exhibits a 36.28% sequence homology with its human counterpart hCDK7. Pfmrk forms a complex with plasmodial cyclin (Pfcyc-1) and stimulates kinase activity. Pfcyc-1 from P. falciparum, with the highest sequence homology to human cyclin (cyclin H), binds and activates Pfmrk in a cyclin-dependent manner. This discovery provides the first indication that cyclin subunits may regulate both human and plasmodial CDKs in a similar fashion. In this study, we conducted molecular docking and simulation analysis to investigate the interaction between Pfmrk and a selection of the FDA-approved drugs retrieved from the ZINC15 database. The top five drugs – Lurasidone, Vorapaxar, Donovex, Alvesco, and Orap – were screened based on their binding energies, with the best-docked scores ranging between −8 kcal/mol and −12 kcal/mol. Further, evaluation through molecular dynamics simulations for 100 nanoseconds revealed that Lurasidone exhibited the highest binding affinity (−105.90 ± 57.72 kJ/mol) followed by Donovex (−92.877 ± 17.872 kJ/mol). They exhibited stable interactions with the amino acid residues located in the active site of Pfmrk. The results of the in silico investigation indicate that Lurasidone and Donovex exhibit antimalarial potential and could serve as promising Pfmrk inhibitors. Further, development of new drugs based on these findings warrants subsequent in vitro studies.

Antimalarial activity of Toona ciliata MJ Roem aqueous methanolic leaf extract and its antioxidant and phytochemical properties.

Malaria is a global health issue causing substantial morbidity and mortality. Screening of various traditionally important medicinal plants is a key source for the discovery of new antimalarials. We evaluated the antimalarial and antioxidant activities, and performed detailed phytochemical analyses of Toona ciliata MJ Roem aqueous methanolic leaf extract (TcMLE). Invitro antiplasmodial studies in Plasmodium falciparum (Pf) 3D7 and PfCam3.IR539T strains were performed by [3H]-hypoxanthine uptake assays. Invitro cytotoxicity in HeLa and HEK293T cell lines was evaluated using MTT assays. Hemolysis assay was performed using RBCs. Phytochemical analysis by GC-MS and invitro antioxidant studies by DPPH and ABTS assays were performed. Invivo antimalarial studies in Pb-infected mice were carried out using Rane's test and Peters' 4-day test. TcMLE showed significant invitro antioxidant activity and had phytochemicals reported for antimalarial activity. Invitro studies showed prominent antiplasmodial activity against Pf3D7 strain (IC50 ∼22μg/ml) and PfCam3. IR539Tstrain (IC50 value ∼43μg/ml). Invitro cytotoxicity studies, invitro hemolytic assays, and invivo acute toxicity studies further suggested that TcMLE is nontoxic. Invivo antimalarial studies using Rane's test showed a significant decrease in parasitemia by ∼70% at 1200mg/kg doses and delayed the mortality of mice by ∼10-14 days. Peters' 4-day test also showed a similar pattern. The present study demonstrated the antimalarial potential of TcMLE. These findings deliver a platform for further studies to identify the active components of TcMLE and discover new antimalarials.

Evaluation of the artemisinin content of Artemisia annua L. grown in different Agro ecological zones of Cameroon

Artemisinin and its derivatives are potent antimalarials that have become essential components of Artemisinin Based Combination Therapies (ACTs) for malaria treatment. Production of artemisinin is less compared to its world demand and access to ACTs is still limited in worst hit countries. Secondary metabolite production in plants depends on a number of factors including agro ecology. This work sought to evaluate the growth characteristics and artemisinin content of Artemisia annua grown in four agro ecological zones of Cameroon. Experimental fields comprising of A annua were set up in the different agro-ecological zones, for growth and artemisinin assessments. Artemisinin detection and quantification was compared in leaves/flowers and stems of Artemisia annua from these agro-ecological zones, using High-Performance Liquid Chromatography. Soil provenance and other agro ecological factors significantly affected the growth parameters of A. annua as there were significant differences (p<0.05) in plant height, leaf area, number of branches, stem girth and number of leaves across the different study areas. There was significant variation (P<0.05) in the content of artemisinin from the plant in the different agro ecological zones. The mean levels of artemisinin in the samples was 0.34-0.80% in stem samples, and 0.18-0.61% for leaves/flowers. The highest artemisinin yield in leaf/flowers samples (0.61%) was recorded in samples from Bamenda, while that of stem samples (0.80%) was recorded in samples from Ngaoundere. The study confirms the effect of agro ecological factors on artemisinin content of A. annua in Cameroon and reveal that A. annua grown in most regions of the country contain commercially viable levels of artemisinin which can further be exploited for pharmaceutical purposes.

Antioxidant and Antimalarial Potential of Methanolic Extract from Leaves of Titi Tree (Alstonia sp)

Alstonia sp leaves extract has previously been reported as a potential antimalarial drug as traditional. This study aims to analyze the antimalarial activity and determine the antioxidant potential of titi tree leaves (Alstonia sp). The method used in this research is a modified method of "4 Days Suppressive Test" which was originally described by Peter with different doses (0.55 g/kg, 0.65 g/kg and 0.75 g/kg body weight) of methanol extract of leaves of Titi tree (Alstonia sp) was administered orally to albino mice. Antioxidants were analyzed using a spectrophotometer. The Leaves of Alstonia sp has antimalarial activity and contains potential antioxidant activity with an IC50 value of 70.12 ppm for leaves (strong category). The dose of 0.75 g has a better effect compared to the other effects because it lowers the level of parasitemia more strongly. So that the leaves of Alstonia sp. pressured to be developed as a nutraceutical.

Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites.

The use of artemisinin and its derivatives has helped reduce the burden of malaria caused by Plasmodium falciparum. However, artemisinin-resistant parasites are able, in the presence of artemisinins, to stop their cell cycles. This quiescent state can alter the activity of artemisinin partner drugs leading to a secondary drug resistance and thus threatens malaria eradication strategies. Drugs targeting epigenetic mechanisms (namely epidrugs) are emerging as potential antimalarial drugs. Here, we set out to evaluate a selection of various epidrugs for their activity against quiescent parasites, to explore the possibility of using these compounds to counter artemisinin resistance. The 32 chosen epidrugs were first screened for their antiplasmodial activity and selectivity. We then demonstrated, thanks to the specific Quiescent-stage Survival Assay, that four epidrugs targeting both histone methylation or deacetylation as well as DNA methylation decrease the ability of artemisinin-resistant parasites to recover after artemisinin exposure. In the quest for novel antiplasmodial drugs with new modes of action, these results reinforce the therapeutic potential of epidrugs as antiplasmodial drugs especially in the context of artemisinin resistance.

Assessment of anti-malarial potential of Allium Sativum against plasmodium vivax

Malaria is a vector-borne protozoal disease, caused by genus Plasmodium, where female anopheles’ mosquito works as a vector to transfer malarial parasite. The disease has been reported to be endemic in tropical and subtropical regions of the world. Since drug resistance of the Plasmodium species and economic burden of the disease are the major concerns associated with malaria. Thus, most of the world’s population is focusing on the utilization of medicinal plants as the natural treatment for several diseases including malaria. There is limited published data available regarding anti-malarial activity of Allium sativum against Plasmodium vivax. Therefore, this study was aimed to assess the in-vitro anti-malarial activity of Allium sativum methanolic extract. The methanolic extract of Allium sativum showed significant anti-plasmodial activity (80.57%) at 0.2 mg/ml highest tested dose after 24h. The phytochemical analysis showed the presence of Flavonoids, Vinyldithiins, Ajoenes, Alliin and Allicin in the Allium sativum methanolic extract. Among the phytochemicals, only Allicin at the highest tested dose (0.2mg/ml) showed the inhibition (59.75%) of P. vivax inhibition. Allium sativum methanolic extract exhibits anti-plasmodial activities in-vitro. However, further studies are required to assess the in-vivo anti-plasmodial activity of Allium sativum methanolic extract against plasmodium vivax in future.

Ultrastructural alterations due to sodium metavanadate treatment in the blood stages of Plasmodium yoelii yoelii

Malaria is a potentially mortal disease caused by parasites of the genus Plasmodium spp. It has a wide distribution in the world and unfortunately there are several factors that make its control difficult; among which the development of pharmacological resistance to the different drugs used to treat this disease stands out, which makes it necessary to design new compounds that have an antimalarial effect. Previous studies have shown that vanadium has a broad antiparasitic spectrum and is also safe for the host, so the objective of this research was to evaluate the antimalarial potential of sodium metavanadate (SM) and to analyze the ultrastructural changes in parasites exposed. The method consisted of inoculating CD-1 male mice with Plasmodium yoelii yoelii and administering a 10 mg/kg/day dose of SM orally for 4 days. On the fifth day, whole blood samples were obtained, processed for ultrastructural analysis, and the changes in the different parasite stages were compared against the control. Our results showed that SM decreased parasitemia compared to the group that did not receive treatment and modified the ultrastructure in all parasitic stages because it damaged the membranes, causing alterations mainly in the nucleus and in the mitochondria as well as the loss of cellular organization, which could affect the integrity of these parasites and decrease its viability.

Piezo1 activation accelerates osteoarthritis progression and the targeted therapy effect of artemisinin

IntroductionOsteoarthritis (OA) is a devastating whole-joint disease affecting a large population worldwide with no cure; its mechanism remains poorly defined. Abnormal mechanical stress is the main pathological factor of OA. ObjectivesTo investigate the effects of Piezo1 activation on OA development and progression and to explore Piezo1-targeting OA treatment. MethodsThe expression levels of Piezo1 were determined in human OA cartilage and experimental OA mice. Mice with genetic Piezo1 deletion in chondrocytes or intra-articular injection of the Piezo1 activator Yoda1 were utilized to determine the effects on DMM-induced OA progression. Effects of artemisinin (ART), a potent antimalarial drug, on Piezo1 activation, chondrocyte metabolism and OA lesions were determined. ResultsPiezo1 expression was elevated in articular chondrocytes in human OA and DMM-induced mouse OA cartilage. Piezo1 deletion in chondrocytes largely attenuates DMM-induced OA-like phenotypes. In contrast, intra-articular injection of Yoda1 aggravates the knee joint OA lesions in mice. PIEZO1 activation increases, while PIEZO1 siRNA knockdown decreases, expression of RUNX2 and catabolic enzymes MMP13 and ADAMTS5 in primary human articular chondrocytes in a PI3K-AKT dependent manner. We have provided strong evidence supporting that ART is a novel and potent inhibitor of Piezo1 activation in primary OA-HACs and all cell lines examined, including human endothelial HUVEC cells, ATDC5 chondrocyte-like cells and MLO-Y4 osteocytes-like cells. Results from in vitro experiments confirmed that ART decreases the Yoda1-induced increases in the levels of OA-related genes and p-PI3K and p-AKT proteins in OA-HACs and alleviates DMM-induced OA lesions in mice. ConclusionsWe establish a critical role of Piezo1 in promoting OA development and progression and define ART as a potential OA treatment.

Sheptide A: an antimalarial cyclic pentapeptide from a fungal strain in the Herpotrichiellaceae

As part of ongoing efforts to isolate biologically active fungal metabolites, a cyclic pentapeptide, sheptide A (1), was discovered from strain MSX53339 (Herpotrichiellaceae). The structure and sequence of 1 were determined primarily by analysis of 2D NMR and HRMS/MS data, while the absolute configuration was assigned using a modified version of Marfey’s method. In an in vitro assay for antimalarial potency, 1 displayed a pEC50 value of 5.75 ± 0.49 against malaria-causing Plasmodium falciparum. Compound 1 was also tested in a counter screen for general cytotoxicity against human hepatocellular carcinoma (HepG2), yielding a pCC50 value of 5.01 ± 0.45 and indicating a selectivity factor of ~6. This makes 1 the third known cyclic pentapeptide biosynthesized by fungi with antimalarial activity.

Comparative investigation on interaction between potent antimalarials and human serum albumin using multispectroscopic and computational approaches.

This study performed a comparative investigation to explore the interaction mechanisms between two potential antimalarial compounds, JMI 346 and JMI 105, and human serum albumin (HSA), a vital carrier protein responsible for maintaining important biological functions. Our aim was to assess the pharmacological efficiency of these compounds while comprehensively analyzing their impact on the dynamic behavior and overall stability of the protein. A comprehensive array of multispectroscopic techniques, including UV-Vis. spectroscopy, steady-state fluorescence analysis, synchronous fluorescence spectroscopy, three-dimensional fluorescence and circular dichroism spectroscopy, docking studies, and molecular dynamics simulations, were performed to probe the intricate details of the interaction between the compounds and HSA. Our results revealed that both JMI 346 and JMI 105 exhibited promising pharmacological effectiveness within the context of malaria therapy. However, JMI 346 was found to exhibit a significantly higher affinity and only minor altered impact on HSA, suggesting a more favorable interaction with the protein on the dynamic behavior and overall stability of the protein in comparison to JMI 105. Further studies can build on these results to optimize the drug-protein interaction and enable the development of more potent and targeted antimalarial treatments.

Conditional expression of NanoLuc luciferase through a multimodular system offers rapid detection of antimalarial drug activity

Conditional gene expression is a powerful tool to investigate putative vaccine and drug targets, especially in a haploid organism such as Plasmodium falciparum. Inducible systems based on regulation of either transcription, translation, protein or mRNA stability, among others, allow switching on an off the expression of any desired gene causing specific gain or loss of function phenotypes. However, those systems can be cumbersome involving the construction of large plasmids and generation of multiple transgenic parasite lines. In addition, the dynamic range of regulation achieved is not predictable for each individual gene and can be insufficient to generate detectable phenotypes when the genes of interest are silenced. Here, we combined up to three distinct inducible systems to regulate the expression of a single gene. Expression of the reporter NanoLuc luciferase was regulated over 40-fold, which correlates to the regulation achieved by each individual system multiplied by each other. We applied the conditionally expressed NanoLuc to evaluate the effect of fast-acting antimalarials such as chloroquine and artesunate as well as of slower-acting ones such as atovaquone. The conditionally expressed reporter allowed faster and more reliable detection of toxicity to the parasite, which correlated to the expected action of each compound. Bioluminescence achieved by the expression of this inducible highly sensitive reporter is therefore a promising tool to investigate the temporal effect of potential new antimalarials. This single plasmid combination system might also prove useful to achieve sufficient regulation of genes of interest to produce loss-of-function phenotypes.

Antimalarial activity test and GC-MS analysis of ethanol and ethyl acetate extract of snake plant (Sansevieria trifasciata Prain)

Snake plant or Mother-in-law's tongue (Sansevieria trifasciata Prain) is a plant possessing of many ethnobotanical uses one of which is for medicinal. Previous pharmacological studies showed that this plant has several properties such as healing lesions, anthelmenthic, antimicrobial and cytotoxic. This research was conducted to investigate phytocompounds constituents of ethanol and ethyl acetate of S. trifasciata and their antimalarial activity potential. The phytochemical constituents were analyzed using Gas Cromatography and Mass Spectroscopy (GCMS). The antiplasmodial properties of the extract against malaria parasites were determined by calculating the percentage of parasitaemia suppression which was then used as a variable in probit analysis to determine the IC50 value of the extract. There were 4 and 24 constituents of compounds detected using GC-MS in the ethanol and ethyl acetate extracts of the plant leaves respectively. Antiplasmodial assay of the extracts showed that ethyl acetate solvent gave stronger suppression against Plasmodium falciparum with an IC50 value of 21,29 µg/mL compared to ethanol solvent with an IC50 value of 21,29 µg/mL In conclusion plant leaf extract of Sansevieria trifasciata is potential to be developed as antimalarial ingredient.

Potentials of Terpenoids as Inhibitors of Multiple Plasmodium falciparum Protein Drug Targets.

The resistance of parasite to readily affordable antimalarial drugs, the high cost of currently potent drugs, and the resistance of vector mosquitoes to insecticides threaten the possibility of malaria eradication in malaria endemic areas. Due to the fact that quinine and artemisinin were isolated from plants sources, researchers have been encouraged to search for new antimalarials from medicinal plants. This is especially the case in Africa where a large percentage of the population depends on medicinal plant to treat malaria and other ailments. In this study, we evaluated previously characterized Plasmodium-cidal compounds obtained from the African flora to identify their likely biochemical targets, for an insight into their possible antimalarial chemotherapy. Molecular docking study was first conducted, after which remarkable compounds were submitted for molecular dynamic (MD) simulations studies. From a total of 38 Plasmodium-cidal compounds docked with confirmed Plasmodium falciparum protein drug targets [plasmepsin II (PMII), histo-aspartic protein (HAP) and falcipain-2 (FP)], two pentacyclic triterpene, cucurbitacin B and 3 beta-O-acetyl oleanolic acid showed high binding affinity relative to artesunate. This implies their capacity to inhibit the three selected P. falciparum target proteins, and consequently, antimalarial potential. From the MD simulations studies and binding free energy outcomes, results confirmed that the two compounds are stable in complex with the selected antimalarial targets; they also showed excellent binding affinities during the 100 ns simulation. These results showed that cucurbitacin B and 3 beta-O-acetyl oleanolic acid are potent antimalarials and should be considered for further studies.

Evaluation of in vitro antiplasmodial, antiproliferative activities, and in vivo oral acute toxicity of Spathodea campanulata flowers

Spathodea campanulata is used in traditional medicine to treat various ailments such as malaria, human immunodeficiency virus (HIV), cancer, fever and urethral inflammation. The aim of this study was to investigate the antiplasmodial, and antiproliferative activities of the extract and resulted fractions from S. campanulata flowers, as well as assessing the acute toxicity of its aqueous fraction. The in vitro cell-growth inhibition activities were assessed against Plasmodium falciparum strain 3D7 for antimalarial activity and three cancer cell lines: Hs683 (human oligodendroglioma), MCF7 (human breast carcinoma), and murine B16F10 (mouse melanoma) for antiproliferative activity while the in vivo acute oral toxicity was determined according to the modified organisation for Economic Co-operation and Development (OECD) guidelines 423 at a fixed dose on Female Wistar strain laboratory rats. The dichloromethane, ethyl acetate and hexane fractions at a concentration of 25 µg/mL each significantly reduced the viability of 3D7 Plasmodium cells with viability percentages of 19.0%, 14.1% and 31.9%, respectively, and IC50 of 28.1, 30.2 and 29.7 µg/mL, respectively. The ethyl acetate fraction showed a moderate antiproliferative activity on mouse melanoma with an I50 value of 54.6 µg/mL. Only the dichloromethane fraction was able to inhibit the 3 cell lines tested with IC50 values less than 15 µg/mL. An oral administration of the aqueous fraction did not induce an abnormal variation of the physiological parameters in female Wistar laboratory rats, at non-toxic doses up to 5000 mg/kg body weight for 14 days. These results confirm the use of this plant in traditional medicine for its antimalarial and anticancer potential.

Tackling the emerging Artemisinin-resistant malaria parasite by modulation of defensive oxido-reductive mechanism via nitrofurantoin repurposing

Oxidative stress-mediated cell death has remained the prime parasiticidal mechanism of front line antimalarial, artemisinin (ART). The emergence of resistant Plasmodium parasites characterized by oxidative stress management due to impaired activation of ART and enhanced reactive oxygen species (ROS) detoxification has decreased its clinical efficacy. This gap can be filled by development of alternative chemotherapeutic agents to combat resistance defense mechanism. Interestingly, repositioning of clinically approved drugs presents an emerging approach for expediting antimalarial drug development and circumventing resistance. Herein, we evaluated the antimalarial potential of nitrofurantoin (NTF), a clinically used antibacterial drug, against intra-erythrocytic stages of ART-sensitive (Pf3D7) and resistant (PfKelch13R539T) strains of P. falciparum, alone and in combination with ART. NTF exhibited growth inhibitory effect at submicro-molar concentration by arresting parasite growth at trophozoite stage. It also inhibited the survival of resistant parasites as revealed by ring survival assay. Concomitantly, in vitro combination assay revealed synergistic association of NTF with ART. NTF was found to enhance the reactive oxygen and nitrogen species, and induced mitochondrial membrane depolarization in parasite. Furthermore, we found that exposure of parasites to NTF disrupted redox balance by impeding Glutathione Reductase activity, which manifests in enhanced oxidative stress, inducing parasite death. In vivo administration of NTF, alone and in combination with ART, in P. berghei ANKA-infected mice blocked parasite multiplication and enhanced mean survival time. Overall, our results indicate NTF as a promising repurposable drug with therapeutic potential against ART-sensitive as well as resistant parasites.

Mangiferin is a new potential antimalarial and anticancer drug for targeting serine hydroxymethyltransferase

Mangiferin, a polyphenolic xanthone glycoside found in various botanical sources, including mango (Mangifera indica L.) leaves, can exhibit a variety of bioactivities. Although mangiferin has been reported to inhibit many targets, none of the studies have investigated the inhibition of serine hydroxymethyltransferase (SHMT), an attractive target for antimalarial and anticancer drugs. SHMT, one of the key enzymes in the deoxythymidylate synthesis cycle, catalyzes the reversible conversion of l-serine and (6S)-tetrahydrofolate (THF) into glycine and 5,10-methylene THF. Here, in vitro and in silico studies were used to probe how mangiferin isolated from mango leaves inhibits Plasmodium falciparum and human cytosolic SHMTs. The inhibition kinetics at pH 7.5 revealed that mangiferin is a competitive inhibitor against THF for enzymes from both organisms. Molecular docking and molecular dynamic (MD) simulations demonstrated the inhibitory effects of the deprotonated forms of mangiferin, specifically the C6–O- species and its resonance C9–O- species appearing at pH 7.5, combined with two docked poses, either a xanthone or glucose moiety, placed inside the THF-binding pocket. The MD analysis revealed that both C6–O- and its resonance-stabilized C9–O- species can favorably bind to SHMT in a similar fashion to THF, supporting the THF competitive inhibition of mangiferin. In addition, characterization of the proton dissociation equilibria of isolated mangiferin revealed that only three hydroxy groups of the xanthone moiety, C6–OH, C3–OH, and C7–OH, underwent varying degrees of deprotonation with pKa values of 6.38 ± 0.11, 8.21 ± 0.35, and 12.37 ± 0.30, respectively, while C1–OH remained protonated. Altogether, our findings demonstrate a new bioactivity of mangiferin and provide the basis for the future development of mangiferin as a potent antimalarial and anticancer drug.

Antimalarial Potential of Fraction 5 from Ethanolic Leaves Extract of Artocarpus Altilis

Background: Artocarpus altilis leaf extract (AAL.E) was separated by VLC, and six fractions were obtained. Fraction 5 (AAL.E.5) showed antimalarial activity with an IC50 value of 3.71 µg/mL. Objective: This study aimed to determine the antimalarial activity of AAL.E.5 subfractions against P. falciparum, the mechanism of action against Plasmodium Falciparum Malate quinone oxidoreductase (PfMQO), and the active substances. Methods: The AAL.E.5 was separated by open-column chromatography and eluted with chloroform-methanol gradient elution in order of increasing polarity. The antimalarial activity of all subfractions was assessed using a lactate dehydrogenase (LDH) assay against P. falciparum and the mechanism of action of the PfMQO enzyme. The profiles of the most active subfractions were analyzed using High-Performance Liquid Chromatography (HPLC). Results: The separation of fraction 5 (AAL.E.5) yielded 11 subfractions (AAL.E.5.1–AAL.E.5.11). Screening antimalarial activity at 10 μg/mL in this subfraction showed that only five subfractions (AAL.E.5.6-AAL. E.5.10) inhibited P. falciparum and two subfractions (AAL.E.5.6 and AAL.E.5.10) inhibited the PfMQO enzyme. Only subfraction 6 (AAL.E.5.6) inhibited both, with IC50 values of 6.609 µg/mL and 20.34 µg/mL. The thin layer chromatography profile of AAL.E.5.6 revealed reddish-orange spots, indicating the presence of flavonoid compounds, and was also presumed from the UV-visible to HPLC chromatogram for band I in the 300 – 400 nm range and band II in the 240–285 nm range. Conclusion: Subfraction 6 has antimalarial activity against P. falciparum and is thought to have a mechanism of action in PfMQO. Based on the TLC, HPLC, and UV-Vis spectra, subfraction 6 was assumed to be a flavonoid.

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 – 60%) to no activity (PCS: <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 ≤ PCS ≤ 98.77) in curative tests but weak chemoprophylaxis (PCP <30%). The efficacy tests showed that most of the investigated medicinal plants were more effective for prevention rather than for curative purposes.