Antimalarial Activity Research Articles

Oleuropein activates autophagy to circumvent anti-plasmodial defense

Antimalarial drug resistance and unavailability of effective vaccine warrant for newer drugs and drug targets. Hence, anti-inflammatory activity of phyto-compound (oleuropein; OLP) was determined in antigen (LPS)-stimulated human THP-1 macrophages (macrophage model of inflammation; MMI). Reduction in the inflammation was controlled by the PI3K-Akt1 signaling to establish the "immune-homeostasis." Also, OLP treatment influenced the cell death/autophagy axis leading to the modulated inflammation for extended cell survival. The findings with MII prompted us to detect the antimalarial activity of OLP in the wild type (3D7), D10-expressing GFP-Atg18 parasite, and chloroquine-resistant (Dd2) parasite. OLP did not show the parasite inhibition in the routine invitro culture of P.falciparum whereas OLP increased the antimalarial activity of artesunate. The molecular docking of autophagy-related proteins, investigations with MMI, and parasite inhibition assays indicated that the host activated the autophagy to survive OLP pressure. The challenge model of P.berghei infection showed to induce autophagy for circumventing anti-plasmodial defenses.

Comparative Studies on the Antimalarial and Antioxidant Activities of Extracts and Silver Nanoparticles from Spermacoce verticillata

Comparative Studies on the Antimalarial and Antioxidant Activities of Extracts and Silver Nanoparticles from Spermacoce verticillata

New antimalarial iromycin analogs produced by Streptomyces sp. RBL-0292.

Two new antimalarial compounds, named prenylpyridones A (1) and B (2), were discovered from the actinomycete cultured material of Streptomyces sp. RBL-0292 isolated from the soil on Hamahiga Island in Okinawa prefecture. The structures of 1 and 2 were elucidated as new iromycin analogs having α-pyridone ring by MS and NMR analyses. Compounds 1 and 2 showed moderate in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 80.7 to 106.7 µM.

Role of Pineapple and its Bioactive Compound Bromelain in COVID 19

Background:: Ananas comosus (L.) Merr., which is commonly known as pineapple, is a well-studied plant for its medicinal properties. In terms of commercial importance, it ranks third among tropical fruits. It has been used for its antidiabetic, antimalarial, anticancer, abortifacient, antioxidant, and antidiarrhoeal activities. The review aimed to study the effects of pineapples and their bioactive compounds on the SARS-CoV-2 virus. Methods:: Research methods comprise significant studies on the treatment of COVID-19 utilizing pineapple and its bioactive compounds. To carry out the e-literature review, articles were downloaded from online search engines, including Elsevier, PubMed, and Google Scholar, using pineapple, bioactive compounds, bromelain, clinical trial, and COVID-19. Results:: The literature showed that pineapple and its bioactive compounds showed antiviral effects in COVID-19 patients by inhibiting the proinflammatory cytokines and affecting various signaling molecules, including NF-κB, proinflammatory cytokines, and cyclooxygenase-2. They modulate apoptotic protein levels and also cause a reduction of ACE-2 and TMPRSS2 expression. Conclusion:: For the development of phytomedicine that adheres to all safety regulations, pineapple, and its bioactive compounds can serve as lead molecules for clinical studies in SARS-CoV-2 infection treatment and therapy.

Advances on cyclopeptides of plants

Cyclopeptides isolated from a variety of plants are a class of cyclic nitrogen-containing compounds, and they are primarily formed by peptide bonds between amino acids, generally containing 2 to 37 L-configuration encoded or non-encoded amino acid residues. Cyclopeptides have significant values in scientific research as natural small-molecule metabolites produced by plants. The available studies have revealed that such natural products are ubiquitous in plants, which mainly include cyclic dipeptides, cyclic tetrapeptides, cyclic pentapeptides, cyclic hexapeptides, cyclic heptapeptides, cyclic octapeptides, cyclic nonapeptides, and cyclic decapeptides. Among them, cyclic dipeptides, cyclic hexapeptides, and cyclic octapeptides are the major active compounds. It has been reported that plant cyclopeptides have novel and unique chemical structures. They possess diverse pharmacological activities, such as antineoplastic, antimicrobial, antimalarial, anti-inflammatory, and antiviral activities. This paper summarizes the research achievements of plant cyclopeptides since 2006, aiming to provide theoretical reference for the research and application of plant cyclopeptides in medicine, health, and agriculture fields.

THE EFFECT OF PANDAN WANGI ROOTS ETHANOL EXTRACT (Pandanus amaryllifolius Roxb.) ON THE DEGREE OF PLASMODIUM BERGHEI PARASITEMIA IN VIVO

Malaria is an disease caused by Plasmodium genus and transmitted by female Anopheles mosquitoes via bites. The occurrence of antimalarial drug resistance in various places, such as Chloroquine and Artemisinin Combination Therapy, be a challenge for researchers to find new herbal and effective alternative antimalarial drugs. Pandan Wangi roots (Pandanus amaryllifolius Roxb.) contain compounds with antimalarial properties. This study aims to determine the effect of Pandan Wangi roots ethanol extract at doses of 1, 100, and 1,000 mg/kgBW (Body Weight on the degree of Plasmodium berghei parasitemia in vivo. This study employs an experimental in vivo method using the Post-Test Only Controlled Group Design. Sample of 24 mice were divided into one negative control group and three treatment groups. The data analysis technique employed is One Way ANOVA and Post Hoc Test. In this study, the mean degree of parasitemia in negative control group was 32.60%, treatment group with dose of 1 mg/kgBW was 22.27%, treatment group with dose of 100 mg/kgBW was 18.49%, and treatment group with dose of 1,000 mg/kgBW was 14.88%. The One Way ANOVA analysis resulted in p-value of 0.001, which is < 0.05, indicating a significant difference in the average degree of parasitemia among the three treatment groups. Thus, the effect of Pandan Wangi roots ethanol extract has antimalarial activity. Administration dose of 1,000 mg/kgBW proved to be the most effective in suppressing the growth of Plasmodium berghei parasitemia.
 Keywords : Pandanus amaryllifolius Roxb., Antimalarial, Plasmodium berghei, Degree of Parasitemia

Phytochemical profiling of Striga asiatica; characterisation and anti-microbial assessment of the isolates

One undescribed compound, striasinol (1), and twelve previously described compounds were isolated from the aerial parts of Striga asiatica. Structure elucidation of isolated compounds was achieved by the interpretation of 1D and 2D NMR and HRESIMS data. The absolute configuration (1S,5S) of 1 was ascertained based on GIAO NMR calculations, DP4+ probability analysis, and a comparison of the experimental and calculated specific rotation values. The isolated compounds were evaluated for their antimalarial action, and none was found to be effective against the chloroquine-sensitive (D6) or chloroquine-resistant (W2) strains of Plasmodium falciparum. The isolates were found non-toxic to the Vero cell line as well. Subsequent testing of these metabolites for antimicrobial activities against various bacterial and fungal strains (up to 20 µg/mL), revealed that compounds 6 (chryseriol) and 7 (apigenin) showed a reasonable activity towards methicillin-resistant Staphylococcus aureus ATCC 1708 (MRSA), with IC50 values of 5.81 and 3.60 μg/mL, respectively.

Production of Kinanthraquinone D with Antimalarial Activity by Heterologous Gene Expression and Biotransformation in Streptomyces lividans TK23.

Two new compounds, kinanthraquinone C (1) and kinanthraquinone D (2), were isolated along with two known compounds, kinanthraquinone (3) and kinanthraquinone B (4), produced by the heterologous expression of the kiq biosynthetic gene cluster and its pathway-specific regulator, kiqA, in Streptomyces lividans TK23. The chemical structures of compounds 1 and 2 were determined using mass spectrometry and nuclear magnetic resonance analyses. To examine a biosynthetic pathway of compounds 1 and 2, incubation experiments were conducted using S. lividans TK23 to supply the compounds 3 and 4. These experiments indicated that compounds 3 and 4 were converted to compounds 2 and 1, respectively, by the endogenous enzymes of S. lividans TK23. Compounds 2, 3, and 4 had antimalarial activities at half-maximal inhibitory concentration values of 0.91, 1.2, and 15 μM, respectively, without cytotoxicity up to 30 μM.

Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR mice.

Antimalarial drugs are an urgently need and crucial tool in the campaign against malaria, which can threaten public health. In this study, we examined the cytotoxicity of the 9 antimalarial compounds chemically synthesized using SKM13-2HCl. Except for SKM13-2HCl, the 5 newly synthesized compounds had a 50% cytotoxic concentration (CC50) > 100 µM, indicating that they would be less cytotoxic than SKM13-2HCl. Among the 5 compounds, only SAM13-2HCl outperformed SKM13-2HCl for antimalarial activity, showing a 3- and 1.3-fold greater selective index (SI) (CC50/IC50) than SKM13-2HCl in vitro against both chloroquine-sensitive (3D7) and chloroquine -resistant (K1) Plasmodium falciparum strains, respectively. Thus, the presence of morpholine amide may help to effectively suppress human-infectious P. falciparum parasites. However, the antimalarial activity of SAM13-2HCl was inferior to that of the SKM13-2HCl template compound in the P. berghei NK65-infected mouse model, possibly because SAM13-2HCl had a lower polarity and less efficient pharmacokinetics than SKM13-2HCl. SAM13-2HCl was more toxic in the rodent model. Consequently, SAM13-2HCl containing morpholine was selected from screening a combination of pharmacologically significant structures as being the most effective in vitro against human-infectious P. falciparum but was less efficient in vivo in a P. berghei-infected animal model when compared with SKM13-2HCl. Therefore, SAM13-2HCl containing morpholine could be considered a promising compound to treat chloroquine-resistant P. falciparum infections, although further optimization is crucial to maintain antimalarial activity while reducing toxicity in animals.

Brusatol's anticancer activity and its molecular mechanism: a research update.

Brusatol (BT) is a quassinoid compound extracted from Brucea javanica that is a traditional Chinese herbal medicine. Brusatol possesses biological and medical activity, including antitumor, antileukemia, anti-inflammatory, antitrypanosomal, antimalarial, and antitobacco mosaic virus activity. To summarize and discuss the antitumor effects of BT and its mechanisms of actions, we compiled this review by combining the extensive relevant literature and our previous studies. We searched and retrieved the papers that reported the pharmacological effects of BT and the mechanism of BT antitumor activity from PubMed until July 2023. Numerous studies have shown that BT is a unique nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor that acts on various signaling pathways and has good antitumor properties. Brusatol shows great potential in cancer therapy by inhibiting cell proliferation, blocking the cell cycle, promoting tumor cell differentiation, accelerating tumor cell apoptosis, inducing autophagy, suppressing angiogenesis, inhibiting tumor invasion and metastasis, and reversing multidrug resistance. This review summarizes recent updates on the antitumor activity and molecular mechanisms of BT and provides references for future development and clinical translation of BT and its derivatives as antitumor drugs.

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis

BackgroundMalaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive.MethodsWe first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays.ResultsThe results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-α were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects.ConclusionsIn conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel.5LH6oqsCtKBdVDis1L_PeKVideo

Evaluation of the antimalarial and CD4+ T-cell modulatory effects of leaf methanol extract of Phyllanthus muellerianus (Kuntze) Exell (Phyllanthaceae) in Plasmodium berghei-infected mice

Ethnopharmacological relevancePhyllanthus muellerianus (Kunze) Exell, a member of the Phyllanthaceae family, is a medicinal plant widely distributed in Africa. Decoctions from the leaves are used in Nigeria to treat fevers, convulsions, some neurological disorders and malaria. Aim of the studyThis study is to evaluate the anti-malarial properties of methanol extract of Phyllanthus muellerianus (MEPM) leaves and its ethyl acetate fraction using a murine malaria model infected with Plasmodium berghei. Additionally, we seek to investigate the potential modulatory effects of this extract and fraction on CD4+ T-cell populations in the context of malaria infection. Materials and methodsThe anti-malarial effects of the leaf methanol extract of Phyllanthus muellerianus (MEPM) were screened using three established in vivo models of anti-plasmodial screening namely the curative, suppressive and prophylactic models. The methanol extract (MEPM) was afterwards fractionated into hexane (HFPM), ethyl acetate (EAFPM), and methanol (MFPM) fractions. In the pilot anti-malarial screening of the fractions, EAFPM exhibited the best antiparasitic activity. Subsequently, EAFPM was screened for anti-malarial activity using the three models above. The effects of the MEPM and EAFPM on haematological indices (Hb and PCV) of the inoculated animals were further screened and the mean survival time (MST) of the animals was monitored. CD4+ T cells of various groups were counted before and after treatment using a flow cytometer. The EAFPM was further subjected to HPLC analysis for identification of its major compounds. ResultsThe EAFPM (100 and 200 mg/kg) elicited 88% and 93% cure respectively in the curative model, while artesunate (5 mg/kg,- the positive control) gave 87% protection. The MEPM and EAFPM also gave significant suppression of parasitemia in the suppressive model. The treated groups survived beyond 28 days as against 11 days by the control group (infected but not treated). The treated groups also prevented anaemia seen in the negative control. The EAFPM group significantly modulated the CD4+ T cell.Compounds identified were Gallocatechin, Quercetin -3-O-gallate, Ellagic acid, and Methylellagic acid rhamnoside). ConclusionThe study established that the leaf of Phyllanthus muellerianus possesses antimalarial activity, thus lending support to its use in the folkloric treatment of malaria.

Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum.

Malaria continues to pose a serious global health threat, and artemisinin remains the core drug for global malaria control. However, the situation of malaria resistance has become increasingly severe due to the emergence and spread of artemisinin resistance. In recent years, significant progress has been made in understanding the mechanism of action (MoA) of artemisinin. Prior research on the MoA of artemisinin mainly focused on covalently bound targets that are alkylated by artemisinin-free radicals. However, less attention has been given to the reversible noncovalent binding targets, and there is a paucity of information regarding artemisinin targets at different life cycle stages of the parasite. In this study, we identified the protein targets of artemisinin at different stages of the parasite's intraerythrocytic developmental cycle using a photoaffinity probe. Our findings demonstrate that artemisinin interacts with parasite proteins in vivo through both covalent and noncovalent modes. Extensive mechanistic studies were then conducted by integrating target validation, phenotypic studies, and untargeted metabolomics. The results suggest that protein synthesis, glycolysis, and oxidative homeostasis are critically involved in the antimalarial activities of artemisinin. In summary, this study provides fresh insights into the mechanisms underlying artemisinin's antimalarial effects and its protein targets.

Comprehensive Investigation of Juniperus virginiana Essential Oil: GC/MS Analysis, Thermoanalytical Characterization, and Evaluation of Bioactive Potential

Due to the ever-increasing unregulated antibiotic use, there have been increased risks of antibiotic-resistant bacterial infections. Natural agents, their products, and derivatives have been used for centuries to cure a variety of ailments. In the present study, an attempt was made to explore the physiochemical properties of the CEO. GC-MS analysis was used to identify the volatile components present in the oil. Additionally, TGA and DSC analysis were carried out to understand the thermal properties of the oil. The oil was characterized by higher amounts of terpenoids. The essential oil has potent anticancer, cytotoxic, antimalarial, and anti-inflammatory activity. This study concludes that the Juniperus virginiana essential oil could be used as a therapeutic agent.
 Keywords: Anticancer, Antioxidant, Cedarwood, Cytotoxicity, Essential oil

Azithromycin disrupts apicoplast biogenesis in replicating and dormant liver stages of the relapsing malaria parasites Plasmodium vivax and Plasmodium cynomolgi

The control and elimination of malaria caused by Plasmodium vivax is hampered by the threat of relapsed infection resulting from the activation of dormant hepatic hypnozoites. Currently, only the 8-aminoquinolines, primaquine and tafenoquine, have been approved for the elimination of hypnozoites, although their use is hampered by potential toxicity. Therefore, an alternative radical curative drug that safely eliminates hypnozoites is a pressing need. This study assessed the potential hypnozoiticidal activity of the antibiotic azithromycin, which is thought to exert antimalarial activity by inhibiting prokaryote-like ribosomal translation within the apicoplast, an indispensable organelle. The results show that azithromycin inhibited apicoplast development during liver-stage schizogony in P. vivax and Plasmodium cynomolgi, leading to impaired parasite maturation. More importantly, this study found that azithromycin is likely to impair the hypnozoite's apicoplast, resulting in the loss of this organelle. Subsequently, using a recently developed long-term hepatocyte culture system, this study found that this loss likely induces a delay in the hypnozoite activation rate, and that those parasites that do proceed to schizogony display liver-stage arrest prior to differentiating into hepatic merozoites, thus potentially preventing relapse. Overall, this work provides evidence for the potential use of azithromycin for the radical cure of relapsing malaria, and identifies apicoplast functions as potential drug targets in quiescent hypnozoites.

Nicholas Reactions of Pentadiynyl–Co2(CO)6 Cations. Synthesis of Antimalarial Hinokiresinol Analogues

AbstractPenta-1,4-diyn-3-ol–Co2(CO)6 complexes undergo Lewis acid mediated Nicholas reactions with high selectivity at the C-3 site, to give skipped (1,4-)diyne complexes. The compatible nucleophiles have a wide range of reactivity. The methodology has been applied to the synthesis of both (E)- and (Z)-isomers of a hinokiresinol and nyasol analogue, the (E)-isomer of which is known to have elevated antiplasmodial and antimalarial activity.

N-Substituted Phenylhydrazones Kill the Ring Stage of Plasmodium falciparum.

Antimalarial resistance has hampered the effective treatment of malaria, a parasitic disease caused by Plasmodium species. As part of our campaign on phenotypic screening of phenylhydrazones, a library of six phenylhydrazones was reconstructed and evaluated for their in vitro antimalarial and in silico receptor binding and pharmacokinetic properties. The structures of the phenylhydrazone hybrids were largely confirmed using nuclear magnetic resonance techniques. We identified two compounds which exhibited significant antimalarial potential against the ring stage (trophozoite) of 3D7 chloroquine-sensitive (CS) strain and DD2 chloroquine-resistant (CR) strains of Plasmodium falciparum with monosubstituted analogs bearing meta or para electron-donating groups showing significant activity in the single-digit micromolar range. Structure activity relationship is presented showing that electron-donating groups on the substituent hydrophobic pharmacophore are required for antimalarial activity. Compounds PHN6 and PHN3 were found to be the most potent with pIC50s (calculated form in vitro IC50s) of 5.37 and 5.18 against 3D7 CS and DD2 CR strains, respectively. Our selected ligands (PHN3 and PHN6) performed better when compared to chloroquine regarding binding affinity and molecular stability with the regulatory proteins of Plasmodium falciparum, hence predicted to be largely responsible for their in vitro activity. Pharmacokinetic prediction demonstrated that the phenylhydrazones may not cross the blood-brain barrier and are not P-glycoprotein (P-gp) substrates, a good absorption of 62% to 69%, and classified as a category IV compound based on toxicity grading.

Biological Activities of Secondary Metabolites from the Edible-Medicinal Macrofungi.

Macrofungi are well-known as edible-medicinal mushrooms, which belong mostly to Basidiomycota, with a few from Ascomycota. In recent years, macrofungi have been recognized as a rich resource of structurally unique secondary metabolites, demonstrating a wide range of bioactivities, including anti-tumor, antioxidant, anti-inflammatory, antimicrobial, antimalarial, neuro-protective, hypoglycemic, and hypolipidemic activities. This review highlights over 270 natural products produced by 17 families of macrofungi covering 2017 to 2023, including their structures, bioactivities, and related molecular mechanisms.

Betulinic Acid for Glioblastoma Treatment: Reality, Challenges and Perspectives.

Betulinic acid is a naturally occurring compound that can be obtained through methanolic or ethanolic extraction from plant sources, as well as through chemical synthesis or microbial biotransformation. Betulinic acid has been investigated for its potential therapeutic properties, and exhibits anti-inflammatory, antiviral, antimalarial, and antioxidant activities. Notably, its ability to cross the blood-brain barrier addresses a significant challenge in treating neurological pathologies. This review aims to compile information about the impact of betulinic acid as an antitumor agent, particularly in the context of glioblastoma. Importantly, betulinic acid demonstrates selective antitumor activity against glioblastoma cells by inhibiting proliferation and inducing apoptosis, consistent with observations in other cancer types. Compelling evidence published highlights the acid's therapeutic action in suppressing the Akt/NFκB-p65 signaling cascade and enhancing the cytotoxic effects of the chemotherapeutic agent temozolomide. Interesting findings with betulinic acid also suggest a focus on researching the reduction of glioblastoma's invasiveness and aggressiveness profile. This involves modulation of extracellular matrix components, remodeling of the cytoskeleton, and secretion of proteolytic proteins. Drawing from a comprehensive review, we conclude that betulinic acid formulations as nanoparticles and/or ionic liquids are promising drug delivery approaches with the potential for translation into clinical applications for the treatment and management of glioblastoma.

Betulinic and ursolic acids from Nauclea latifolia roots mediate their antimalarial activities through docking with PfEMP-1 and PfPKG proteins

BackgroundChemotherapies target the PfEMP-1 and PfPKG proteins in Plasmodium falciparum, the parasite that causes malaria, in an effort to prevent the disease’s high fatality rate. This work identified the phytochemical components of Nauclea latifolia roots and docked the chemical compounds against target proteins, and examined the in vivo antiplasmodial effect of the roots on Plasmodium berghei-infected mice.MethodsStandard protocols were followed for the collection of the plant’s roots, cleaning, and drying of the roots, extraction and fraction preparation, assessment of the in vivo antiplasmodial activity, retrieval of the PfEMP-1 and PfPKG proteins, GCMS, ADME, and docking studies, chromatographic techniques were employed to separate the residual fraction’s components, and the Swis-ADME program made it possible to estimate the drug’s likeness and pharmacokinetic properties. The Auto Dock Vina 4.2 tool was utilized for molecular docking analysis.ResultsThe residual fraction showed the best therapeutic response when compared favorably to amodiaquine (80.5%) and artesunate (85.1%). It also considerably reduced the number of parasites, with the % growth inhibition of the parasite at 42.8% (D2) and 83.4% (D5). Following purification, 25 compounds were isolated and characterized with GCMS. Based on their low molecular weights, non-permeation of the blood–brain barrier, non-inhibition of metabolizing enzymes, and non-violation of Lipinski’s criteria, betulinic and ursolic acids were superior to chloroquine as the best phytochemicals. Hence, they are lead compounds.ConclusionIn addition to identifying the bioactive compounds, ADME, and docking data of the lead compounds as candidates for rational drug design processes as observed against Plasmodium falciparum target proteins (PfEMP-1 and PfPKG), which are implicated in the pathogenesis of malaria, the study has validated that the residual fraction of N. latifolia roots has the best antiplasmodial therapeutic index.