Falciparum K1 Strain Research Articles

A novel peptide pair-based rapid fluorescent diagnostic system for malaria Plasmodium falciparum detection

Advanced diagnostic materials, such as aptamers, are required due to the scarcity of efficient diagnostic antibodies and the low sensitivity of rapid diagnostic kits at detecting the malaria parasite, Plasmodium falciparum. MethodsTwo peptides M2.9 [(KPTAEQTESPELQSAPEN) and M2.17 (KILFNVYSPLGCTCECWV)] were designed using simple epitope prediction tools and modified against the merozoite surface antigen 2 of P. falciparum (Pf.MSP2) by 3-dimensional modeling based on binding affinity. Based on five prediction tools for hydropathy, M2.17 was selected as an appropriate capture peptide. A peptide-based fluorescence-linked immunosorbent assay (FLISA) and a peptide pair-based fluorescent immunochromatographic test strip (FICT) were developed to detect P. falciparum 3D7 (drug-sensitive) and P. falciparum K1 (multi drugs-resistant) strains. ResultsBioinformatic analysis of two peptides demonstrated the potential binding affinity with the merozoite surface protein 2 of P. falciparum (Pf.MSP2) with a positive hydropathy value. The limit of detection (LOD) of FLISA was 10 parasites/μL and of a peptide pair-linked rapid FICT system was 5 and 200 parasites/μL for P. falciparum 3D7 and K1, respectively. Compared to commercial rapid detection systems (RDTs), a peptide pair-linked FICT system exhibited a 20-fold greater efficiency in detecting P. falciparum 3D7 and specifically discriminated another protozoan spp. ConclusionA peptide pair-linked rapid diagnostic strip could be an alternative to conventional RDTs for monitoring wild-type and drug-resistant malaria parasites.

Discovery of an anti-malarial compound, burnettiene A, with a multidrug-sensitive Saccharomyces cerevisiae screening system based on mitochondrial function inhibitory activity.

In this paper, we describe our discovery of burnettiene A (1) as an anti-malarial compound from the culture broth of Lecanicillium primulinum (Current name: Flavocillium primulinum) FKI-6715 strain utilizing our original multidrug-sensitive yeast system. This polyene-decalin polyketide natural product was originally isolated as an anti-fungal active compound from Aspergillus burnettii. However, the anti-fungal activity of 1 has been revealed in only one fungal species for and the mechanism of action of 1 remains unknown. After the validation of mitochondrial function inhibitory of 1, we envisioned a new anti-malarial drug discovery platform based on mitochondrial function inhibitory activity. We evaluated anti-malarial activity and 1 showed anti-malarial activity against Plasmodium falciparum FCR3 (chloroquine sensitive) and K1 strain (chloroquine resistant). Our study revealed the utility of our original screening system based on a multidrug-sensitive yeast and mitochondrial function inhibitory activity for the discovery of new anti-malarial drug candidates.

Evaluation of the antiplasmodial efficacy of synthetic 2,5-diphenyloxazole analogs of compounds naturally derived from Oxytropis lanata

The persistent prevalence and dissemination of drug-resistant malaria parasites continue to challenge the progress of malaria eradication efforts. As a result, there is an urgent need to search for and develop innovative therapies. In this study, we screened synthetic 2,5-diphenyloxazole analogs from Oxytropis lanata. Among 48 compounds, 14 potently inhibited the proliferation of P. falciparum strains 3D7 (chloroquine-sensitive) and K1 (multidrug-resistant) in vitro, exhibited IC50 values from 3.38 to 12.65 μM and 1.27–6.19 μM, respectively, and were toxic to human foreskin fibroblasts at 39.53–336.35 μM. Notably, Compounds 31 (2-(2′,3′-dimethoxyphenyl)-5-(2″-hydroxyphenyl)oxazole) and 32 (2-(2′,3′-dimethoxyphenyl)-5-(2″-benzyloxyphenyl)oxazole) exhibited the highest selectivity indices (SIs) against both P. falciparum strains (3D7/K1), with values > 40.20/>126.58 and > 41.27/> 59.06, respectively. In the IC50 speed and stage-specific assays, Compounds 31 and 32 showed slow action, along with distinct effects on the ring and trophozoite stages. Microscopy observations further revealed that both compounds impact the development and delay the progression of the trophozoite and schizont stages in P. falciparum 3D7, especially at concentrations 100 times their IC50 values. In a 72-h in vitro exposure experiment at their respective IC80 in P. falciparum 3D7, significant alterations in parasitemia levels were observed compared to the untreated group. In Compound 31-treated cultures, parasites shrank and were unable to reinvade red blood cells (RBCs) during an extended 144-h incubation period, even after compound removal from the culture. In vivo assessments were conducted on P. yoelii 17XNL-infected mice treated with Compounds 31 and 32 at 20 mg/kg administered once daily for ten days. The treated groups showed statistically significant lower peaks of parasitemia (Compound 31-treated: trial 1 12.7%, trial 2 15.8%; Compound 32-treated: trial 1 12.7%, trial 2 14.0%) compared to the untreated group (trial 1 21.7%, trial 2 28.3%). These results emphasize the potential of further developing 2,5-diphenyloxazoles as promising antimalarial agents.

Synthesis and pharmacological evaluation of fluoro/chloro-substituted acetyl and benzoyl esters of quinine as antimalarial agents

After establishment of the pharmacokinetic and toxicological profile of quinine derivatives using in silico approaches, this study reports the synthesis of new acetyl and benzoyl esters of quinine bearing one or more fluorine or chlorine atoms on the acetyl/benzoyl moiety. The antimalarial activity of these compounds on Plasmodium falciparum 3D7 and K1 strains as well as the antiprotozoal activity on Trypanosoma brucei brucei and Trypanosoma cruzi were evaluated. Lastly, the cytotoxicity on MRC-5SV2 cells was established. The fluoroacetyl ester compounds were found to be more active in vitro against Plasmodium falciparum 3D7 strain than the reference compound quinine. All synthesized quinine derivatives were non-cytotoxic for MRC-5SV2 cells (CC50 > 64 µM). These results confirm that the introduction of one or more fluorine atoms into acetyl and benzoyl esters of quinine can sometimes improve the biological activity.

Antiplasmodial Activity Evaluation of a Bestatin-Related Aminopeptidase Inhibitor, Phebestin.

The increasing burden and spread of resistant malaria parasites remains an immense burden to public health. These factors have driven the demand to search for a new therapeutic agent. From our screening, phebestin stood out with nanomolar efficacy against Plasmodium falciparum 3D7. Phebestin was initially identified as an aminopeptidase N inhibitor. Phebestin inhibited the in vitro multiplication of the P. falciparum 3D7 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains at IC50 values of 157.90 ± 6.26 nM and 268.17 ± 67.59 nM, respectively. Furthermore, phebestin exhibited no cytotoxic against human foreskin fibroblast cells at 2.5 mM. In the stage-specific assay, phebestin inhibited all parasite stages at 100 and 10-fold its IC50 concentration. Using 72-h in vitro exposure of phebestin at concentrations of 1 μM on P. falciparum 3D7 distorted the parasite morphology, showed dying signs, shrank, and prevented reinvasion of RBCs, even after the compound was washed from the culture. An in silico study found that phebestin binds to P. falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP), as observed for bestatin. In vivo evaluation using P. yoelii 17XNL-infected mice with administrations of 20 mg/kg phebestin, once daily for 7 days, resulted in significantly lower parasitemia peaks in the phebestin-treated group (19.53%) than in the untreated group (29.55%). At the same dose and treatment, P. berghei ANKA-infected mice showed reduced parasitemia levels and improved survival compared to untreated mice. These results indicate that phebestin is a promising candidate for development as a potential therapeutic agent against malaria.

Antimalarial efficacy and toxicological assessment of medicinal plant ingredients of Prabchompoothaweep remedy as a candidate for antimalarial drug development

BackgroundDrug resistance exists in almost all antimalarial drugs currently in use, leading to an urgent need to identify new antimalarial drugs. Medicinal plant use is an alternative approach to antimalarial chemotherapy. This study aimed to explore potent medicinal plants from Prabchompoothaweep remedy for antimalarial drug development.MethodsForty-eight crude extracts from Prabchompoothaweep remedy and its 23 plants ingredients were investigated in vitro for antimalarial properties using Plasmodium lactate dehydrogenase (pLDH) enzyme against Plasmodium falciparum K1 strain and toxicity effects were evaluated in Vero cells. The plant with promising antimalarial activity was further investigated using gas chromatography-mass spectrometry (GC-MS) to identify phytochemicals. Antimalarial activity in mice was evaluated using a four-day suppressive test against Plasmodium berghei ANKA at dose of 200, 400, and 600 mg/kg body weight, and acute toxicity was analyzed.ResultsOf the 48 crude extracts, 13 (27.08%) showed high antimalarial activity against the K1 strain of P. falciparum (IC50 < 10 μg/ml) and 9 extracts (18.75%) were moderately active (IC50 = 11–50 μg/ml). Additionally, the ethanolic extract of Prabchompoothaweep remedy showed moderate antimalarial activity against the K1 strain of P. falciparum (IC50 = 14.13 μg/ml). Based on in vitro antimalarial and toxicity results, antimalarial activity of the aqueous fruit extract of Terminalia arjuna (IC50 = 4.05 μg/ml and CC50 = 219.6 μg/ml) was further studied in mice. GC-MS analysis of T. arjuna extract identified 22 compounds. The most abundant compounds were pyrogallol, gallic acid, shikimic acid, oleamide, 5-hydroxymethylfurfural, 1,1-diethoxy-ethane, quinic acid, and furfural. Analysis of the four-day suppressive test indicated that T. arjuna extract at dose of 200, 400, and 600 mg/kg body weight significantly suppressed the Plasmodium parasites by 28.33, 45.77, and 67.95%, respectively. In the acute toxicity study, T. arjuna extract was non-toxic at 2000 mg/kg body weight.ConclusionsThe aqueous fruit extract of T. arjuna exerts antimalarial activity against Plasmodium parasites found in humans (P. falciparum K1) and mice (P. berghei ANKA). Acute toxicity studies showed that T. arjuna extract did not show any lethality or adverse effects up to a dose of 2000 mg/kg.

Exploring Potential Antimalarial Candidate from Medicinal Plants of Kheaw Hom Remedy.

The Kheaw Hom remedy is a traditional Thai medicine widely used to treat fevers. Some plant ingredients in this remedy have been investigated for their antimicrobial, antiviral, anti-inflammatory, and antioxidant activities. However, there have been no reports on the antimalarial activities of the medicinal plants in this remedy. Therefore, this study focuses on identifying potential antimalarial drug candidates from the medicinal plant ingredients of the Kheaw Hom remedy. Eighteen plants from the Kheaw Hom remedy were extracted using distilled water and ethanol. All extracts were investigated for their in vitro antimalarial activity and cytotoxicity. An extract that exhibited good in vitro antimalarial activity and low toxicity was selected for further investigation by using Peter's 4-day suppressive test and an acute oral toxicity evaluation in mice. Based on the in vitro antimalarial activity and cytotoxicity studies, the ethanolic extract of Globba malaccensis rhizomes showed promising antimalarial activity against the Plasmodium falciparum K1 strain (IC50 = 1.50 µg/mL) with less toxicity to Vero cells (CC50 of &gt;80 µg/mL). This extract exhibited a significant dose-dependent reduction in parasitemia in P. berghei-infected mice. The maximum suppressive effect of this extract (60.53%) was observed at the highest dose administered (600 mg/kg). In a single-dose acute toxicity test, the animals treated at 2000 mg/kg died within 48 h after extract administration. In conclusion, our study indicates that the ethanolic extract of G. malaccensis rhizomes exhibited in vitro and in vivo antimalarial activities, which could serve as a promising starting point for antimalarial drug.

Synthesis and in vitro SAR evaluation of natural vanillin-based chalcones tethered quinolines as antiplasmodial agents

A series of novel chalcone derivatives were synthesized and investigated against the chloroquine-sensitive P. falciparum 3D7 (Pf3D7) strain and chloroquine-resistant P. falciparum K1 strain to establish their structure-activity relationship. In this study, compound 7 was found most active as well as less cytotoxic (IC50 = 4.12 µM and 3.14 µM for Pf3D7 and PfK1 respectively; CC50 = 46.18 µM). Compound 7 was studied for effect on parasite growth and the microscopic examination showed excessive DNA damage in the trophozoite stage. The parasite recovery after drug removal was poor due to the dramatic genotoxic effect of compound 7. It suggested that 7-chloro quinoline and triazole linkage were crucial for antimalarial potential. Graphical abstract

Dual role of azo compounds in inhibiting Plasmodium falciparum adenosine deaminase and hemozoin biocrystallization

Protein-ligand (GOLD) docking of the NCI compounds into the ligand-binding site of Plasmodium falciparum adenosine deaminase (PfADA) identified three most active azo compounds containing 4-[(4-hydroxy-2-oxo-1H-quinolin-3-yl) moiety. These compounds showed IC50 of 3.7–15.4 μM against PfADA, as well as inhibited the growth of P. falciparum strains 3D7 (chloroquine (CQ)-sensitive) and K1 (CQ-resistant) with IC50 of 1.8–3.1 and 1.7–3.6 μM, respectively. The identified compounds have structures similar to the backbone structure (4-N-(7-chloroquinolin-4-yl)) in CQ, and NSC45545 could mimic CQ by inhibiting the bioformation of hemozoin in parasitic food vacuole. The amount of in situ hemozoin in the ring-stage parasite was determined using a combination of synchrotron transmission Fourier transform infrared microspectroscopy and Principal Component Analysis. Stretching of the C–O bond of hemozoin propionate group measured at 1220–1210 cm−1 in untreated intraerythrocytic P. falciparum strains 3D7 and K1 was disappeared following treatment with 1.85 and 1.74 μM NSC45545, similar to those treated with 0.02 and 0.13 μM CQ, respectively. These findings indicate a novel dual function of 4-[(4-hydroxy-2-oxo-1H-quinolin-3-yl) azo compounds in inhibiting both PfADA and in situ hemozoin biocrystallization. These lead compounds hold promise for further development of new antimalarial therapeutics that could delay the onset of parasitic drug resistance.

Antimalarial and Anticancer Activity Evaluation of Bridged Ozonides, Aminoperoxides, and Tetraoxanes.

Bridged aminoperoxides, for the first time, were investigated for the in vitro antimalarial activity against the chloroquine-resistant Plasmodium falciparum strain K1 and for their cytotoxic activities against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Aminoperoxides exhibit good cytotoxicity against lung A549 cancer cell line. Synthetic ozonides were shown to have high activity against the chloroquine-resistant P. falciparum. A cyclic voltammetry study of peroxides was performed, and most of the compounds did not show a direct correlation in oxidative capacity-activity. Peroxides were analyzed for ROS production to understand their mechanism of action. However, none of the compounds has an impact on ROS generation, suggesting that ozonides induce apoptosis in HepG2 cells through ROS-independent dysfunction pathway.

Antioxidant Activity, Total Phenolic and Flavonoid Content and LC–MS Profiling of Leaves Extracts of Alstonia angustiloba

Plants have a wide range of active compounds crucial in treating various diseases. Most people consume plants and herbals as an alternative medicine to improve their health and abilities. A. angustiloba extract showed antinematodal activity against Bursaphelenchus xylophilus, antitrypanosomal action against Trypanosoma brucei and anti-plasmodial activity against the chloroquine-resistant Plasmodium falciparum K1 strain. Moreover, it has demonstrated growth inhibitory properties towards several human cancer cell lines, such as MDA-MB-231, SKOV-3, HeLa, KB cells and A431. DPPH and ABTS assays were carried out to determine the antioxidant activity of the aqueous and 60% methanolic extract of A. angustiloba leaves. Moreover, total phenolic and flavonoid contents were quantified. The presence of potential active compounds was then screened using liquid chromatography coupled with a Q-TOF mass spectrometer (LC–MS) equipped with a dual electrospray ionisation (ESI) source. The EC50 values measured by DPPH for the 60% methanolic and aqueous extracts of A. angustiloba leaves were 80.38 and 94.11 µg/mL, respectively, and for the ABTS assays were 85.80 and 115.43 µg/mL, respectively. The 60% methanolic extract exhibited the highest value of total phenolic and total flavonoid (382.53 ± 15.00 mg GAE/g and 23.45 ± 1.04 mg QE/g), while the aqueous extract had the least value (301.17 ± 3.49 mg GAE/g and 9.73 ± 1.76 mg QE/g). The LC–MS analysis revealed the presence of 103 and 140 compounds in the aqueous and 60% methanolic extract, respectively. It consists of phenolic acids, flavonoids, alkaloids, amino acids, glycosides, alkaloids, etc. It can be concluded that the therapeutic action of this plant is derived from the presence of various active compounds; however, further research is necessary to determine its efficacy in treating diseases.

Inhibitory effects of anthracyclines on partially purified 5′–3′ DNA helicase of Plasmodium falciparum

BackgroundPlasmodium falciparum has been becoming resistant to the currently used anti-malarial drugs. Searching for new drug targets is urgently needed for anti-malarial development. DNA helicases separating double-stranded DNA into single-stranded DNA intermediates are essential in nearly all DNA metabolic transactions, thus they may act as a candidate for new drug targets against malarial parasites.MethodsIn this study, a P. falciparum 5′ to 3′ DNA helicase (PfDH-B) was partially purified from the crude extract of chloroquine- and pyrimethamine-resistant P. falciparum strain K1, by ammonium sulfate precipitation and three chromatographic procedures. DNA helicase activity of partially purified PfDH-B was examined by measuring its ability to unwind 32P-labelled partial duplex DNA. The directionality of PfDH-B was determined, and substrate preference was tested by using various substrates. Inhibitory effects of DNA intercalators such as anthracycline antibiotics on PfDH-B unwinding activity and parasite growth were investigated.ResultsThe native PfDH-B was partially purified with a specific activity of 4150 units/mg. The PfDH-B could unwind M13-17-mer, M13-31-mer with hanging tail at 3′ or 5′ end and a linear substrate with 3′ end hanging tail but not blunt-ended duplex DNA, and did not need a fork-like substrate. Anthracyclines including aclarubicin, daunorubicin, doxorubicin, and nogalamycin inhibited the unwinding activity of PfDH-B with an IC50 value of 4.0, 7.5, 3.6, and 3.1 µM, respectively. Nogalamycin was the most effective inhibitor on PfDH-B unwinding activity and parasite growth (IC50 = 0.1 ± 0.002 µM).ConclusionPartial purification and characterization of 5′–3′ DNA helicase of P. falciparum was successfully performed. The partially purified PfDH-B does not need a fork-like substrate structure found in P. falciparum 3′ to 5′ DNA helicase (PfDH-A). Interestingly, nogalamycin was the most potent anthracycline inhibitor for PfDH-B helicase activity and parasite growth in culture. Further studies are needed to search for more potent but less cytotoxic inhibitors targeting P. falciparum DNA helicase in the future.

Indole alkaloid ellipticine as efficient multitarget compound

First isolated from the tropical plant Oschrosia elliptica, indole alkaloid ellipticine provoked huge interest since it demonstrated antitumor activity was demonstrated along with limited toxic side effects and a complete lack of hematological toxicity. In this work, a five-step Cranwell and Saxton synthesis was used for obtaining ellipticine (Ell). Ellipticine hydrochloride salt (Ell×HCl) was also synthesized. Detailed in vitro studies of anticancer, antimalarial, and leishmanicidal activities were performed. Antiproliferation assay using DU145 cancer cell line treated with Ell showed a consistent reduction in cell proliferation and cell viability when treated with 5 μmol Ell. Anti-proliferation activity was more pronounced for the Ell×HCl solutions. Both the Ell and Ell×HCl revealed moderate activity in vitro against Leishmania amazonensis promastigotes, which is related to insufficient solubility of the drugs. IC50 values of Ell and Ell×HCl were determined in vitro against multidrug resistant Plasmodium falciparum strain K1. The Ell×HCl was shown to be almost three times more potent than the Ell in DMSO. Upon dilution with water, Ell solubility and activity drops down, while the activity and solubility of Ell×HCl is enhanced up to 10 times in 50:50 aqueous DMSO solutions

Synthesis, in-vitro biological evaluation, and molecular docking study of novel spiro-β-lactam-isatin hybrids

In our ongoing search for bioactive compounds, a class of novel spiro-β-lactam isatin hybrids has been synthesized through a [2 + 2] cycloaddition reaction from 1-allyl-3-(arylimino)indolin-2-one, ketenes and various aryloxy acetic acids. The formation of all cycloadducts was confirmed by FTIR, 1H NMR, 13C NMR, and mass spectroscopy as well as elemental analyses. The new β-lactams were subsequently evaluated for their biological activities demonstrating moderate to good activities against P. falciparum K1 strain. Among them, 4b and 4e lead to the best results with IC50 of 5.04 and 7.18 µM, respectively. The molecular docking simulation of 4b with P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site presented several important intermolecular interactions. All the synthesized β-lactams were also evaluated for their antimicrobial activities against both Gram-positive (S. aureus ATCC 25923) and Gram-negative bacteria (E. coli ATCC 28922, P. aeruginosa ATCC 27853) but unfortunately MICs up to 200 µg/mL were encountered in all cases.

Chemical Composition and Insecticidal, Antiplasmodial, and Anti-Leishmanial Activity of Capparis spinosa Essential Oil and Its Main Constituents.

Background This investigation was designed to evaluate the insecticidal, antiplasmodial, anti-leishmanial, and cytotoxic effects of Capparis spinosa essential oil (CSEO) and its main components, methyl isothiocyanate, hexadecanoic acid, and limonene. Methods Insecticidal activity of CSEO and its main components, methyl isothiocyanate, hexadecanoic acid, and limonene, was determined against Aedes aegypti 4th-instar larvae at 25 ± 2°C. Antiplasmodial and anti-leishmanial effects of CSEO and its main components were carried out against chloroquine-resistant Plasmodium falciparum K1 strain and Leishmania major amastigotes based on the Malstat method and the macrophage model, respectively. We also performed the cytotoxic activity of CZEO and its main components against J774A1 macrophage cells using the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. In addition, the plasma membrane permeability and caspase-3-like activity CSEO and its main components were evaluated against L. major. Results CSEO and its main components showed considerable (p < 0.001) larvicidal activity against Ae. aegypti larva. The 50% lethal concentration values for CSEO, methyl isothiocyanate, hexadecanoic acid, and limonene were 21.6, 30.9, 41.6, and 35.3 μg/mL, respectively. By antiplasmodial effects, the 50% inhibitory concentration (IC50) values for CSEO, methyl isothiocyanate, hexadecanoic acid, and limonene were 7.4, 14.5, 19.6, and 21.3 μg/mL, respectively, while these values for their anti-leishmanial effects were 9.1, 20.7, 23.3, and 18.6 μg/mL, respectively. The 50% cytotoxic concentration values for CSEO, methyl isothiocyanate, hexadecanoic acid, and limonene were 93.7, 216.2, 199.4, and 221.3 μg/mL, respectively. Different concentrations of CSEO and its main components significantly (p < 0.05) increased the plasma membrane permeability and caspase-3-like activity against L. major promastigote level as dose-dependent response. Conclusion Based on the obtained results, C. spinosa essential oil and its main components, methyl isothiocyanate, hexadecanoic acid, and limonene, displayed insecticidal, antiplasmodial, and anti-leishmanial activity against healthy 4th-instar larvae of A. aegypti, chloroquine-resistant P. falciparum K1 strain, and L. major amastigotes, respectively. However, further surveys are required to display the mechanisms of action mode of tested drugs and their efficacy in animal model and clinical settings.

Insecticidal, Antimalarial, and Antileishmanial Effects of Royal Jelly and Its Three Main Fatty Acids, trans-10-Hydroxy-2-decenoic Acid, 10-Hydroxydecanoic Acid, and Sebacic Acid.

Natural products and their derivatives as an inexpensive, accessible, and useful alternative medicine are broadly applied for the treatment of a wide range of diseases and infectious ones. The present study was designed to evaluate the insecticidal, antimalarial, antileishmanial, and cytotoxic effects of royal jelly and its three main fatty acids (trans-10-hydroxy-2-decenoic acid (10-H2DA), 10-hydroxydecanoic acid (10-HDAA), sebacic acid (1,10-decanedioic acid)). Insecticidal activity of RJ and 10-H2DA, 10-HDAA, and sebacic acid was performed against healthy 4th instar larvae at 25 ± 2°C. Antiplasmodial and antileishmanial effects of RJ and 10-H2DA, 10-HDAA, and sebacic acid were also performed against chloroquine-resistant Plasmodium falciparum K1-strain and Leishmania major amastigotes according to the Malstat method and macrophage model, respectively. In addition, the level of nitric oxide (NO) production in J774-A1 macrophages cells, plasma membrane permeability, and caspase-3-like activity and cytotoxicity effects of RJ and 10-H2DA, 10-HDAA, and sebacic acid against human embryonic kidney 293 (HEK239T cells) were evaluated. Considering the insecticidal activity, the results showed that the lethal concentration 50% value for RJ, 10-H2DA, 10-HDAA, and sebacic acid was 24.6, 31.4, 37.8, and 44.7 μg/mL μg/mL, respectively. RJ, 10-H2DA, 10-HDAA, and sebacic acid showed potent (P < 0.0001) antileishmanial effects with IC50 values ranging from 2.4 to 8.4 μg/mL. Various concentrations of RJ, 10-H2DA, 10-HDAA, and sebacic acid significantly (P < 0.05) increased the production of NO, plasma membrane permeability, and caspase-3-like activity level as a dose-dependent response. Considering the cytotoxicity, SIs > 10 of these compounds exhibited their specificity to parasites and safety against human HEK239T normal cells. The results of the present investigation revealed the promising insecticidal, antimalarial, and antileishmanial effects of RJ and its three main fatty acids (10-H2DA, 10-HDAA, and sebacic acid). However, more studies are required to confirm the mechanisms of action mode of these compounds as well as their efficacy in animal models and clinical settings.

Antimalarial properties and molecular docking analysis of compounds from Dioscorea bulbifera L. as new antimalarial agent candidates

BackgroundAt present, the emergence and spread of antimalarial drug resistance has become a significant problem worldwide. There has been a challenge in searching for natural products for the development of novel antimalarial drugs. Therefore, this study aims to evaluate compounds from Dioscorea bulbifera responsible for antimalarial properties and investigate potential interactions of the compounds with Plasmodium falciparum lactate dehydrogenase (PfLDH), an essential glycolytic enzyme in the parasite’s life cycle.MethodsAn in vitro study of antimalarial activity against chloroquine (CQ)-resistant Plasmodium falciparum (K1 strain) and CQ-sensitive P. falciparum (3D7 strain) was performed using the 3H-hypoxanthine uptake inhibition method. The cytotoxic effects of the pure compounds were tested against Vero cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The interactions of the compounds with the PfLDH active site were additionally investigated using a molecular docking method.ResultsQuercetin (6) exhibited the highest antimalarial activity against the P. falciparum K1 and 3D7 strains, with IC50 values of 28.47 and 50.99 μM, respectively. 2,4,3′,5′-Tetrahydroxybibenzyl (9), 3,5-dimethoxyquercetin (4) and quercetin-3-O-β-D-galactopyranoside (14) also possessed antimalarial effects against these two strains of P. falciparum. Most pure compounds were nontoxic against Vero cells at a concentration of 80 μg/ml, except for compound 9, which had a cytotoxic effect with a CC50 value of 16.71 μM. The molecular docking results indicated that 9 exhibited the best binding affinity to the PfLDH enzyme in terms of low binding energy (− 8.91 kcal/mol) and formed strong hydrogen bond interactions with GLY29, GLY32, THR97, GLY99, PHE100, THR101 and ASN140, amino acids as active sites. In addition, 6 also possessed remarkable binding affinity (− 8.53 kcal/mol) to PfLDH by interacting with GLY29, ILE31, ASP53, ILE54, THR97 and THR101.ConclusionQuercetin is a major active compound responsible for the antimalarial activity of D. bulbifera and is an inhibitor of PfLDH. These findings provide more evidence to support the traditional use of D. bulbifera for malaria treatment. Structural models of its interactions at the PfLDH active site are plausibly useful for the future design of antimalarial agents.

Diatretol, an α, α'-dioxo-diketopiperazine, is a potent in vitro and in vivo antimalarial.

A fungal metabolite, diatretol, has shown to be a promising antimalarial agent. Diatretol displayed potent in vitro antiparasitic activity against the Plasmodium falciparum K1 strain, with an IC50 value of 378 ng ml−1, as well as in vivo efficacy in a Plasmodium berghei-infected mice model, with ca. 50% inhibition at 30 mg/kg (p.o.).

In vitro anti-plasmodial activity of new synthetic derivatives of 1-(heteroaryl)-2- ((5-nitroheteroaryl)methylene) hydrazine

Objective: To evaluate new compounds synthesized by integrating quinoline, quinazoline, and acridine rings with the active moiety of (5-nitroheteroaryl) methylene hydrazine.Methods: A new series of compounds (1a, 1b, 2a, 2b, 3a, and 3b) were synthesized and evaluated for cytotoxicity against COS-7 cells using the MTT assay. In vitro anti-plasmodial activity of the compounds was measured against CQ-sensitive (3D7) and CQ-resistant (K1) Plasmodium (P.) falciparum strains. β-hematin assay was performed to assess the inhibitory effects of β-hematin formation for new compounds.Results: The synthetic compounds had anti-plasmodial activity against blood-stage of 3D7 [IC50=(0.328-5.483) μM] and K1 [IC50=(0.622-7.746) μM] strains of P. falciparum, with no cytotoxicity against COS-7 cells in effective doses. Compounds 1a, 1b, and 2b were the most effective derivatives against P. falciparum 3D7 and K1 strains. Based on the β-hematin assay, the inhibition of β-hematin formation is the main mechanism of the inhibitory effect of these compounds.Conclusions: The synthetic compounds could inhibit the erythrocytic stages of CQ-sensitive and resistant P. falciparum strains without toxicity towards mammalian cells. Compounds 1b, 2a, and 2b had comparable anti-plasmodial activity against both CQ-sensitive (3D7) and resistant (K1) P. falciparum strains. These compounds may be promising lead structures for the development of new anti-malarial drugs.

Antiplasmodial activity of Anthocleista djalonensis leaves extracts against clinical isolates of Plasmodium falciparum and multidrug resistant K1 strains

Information collected from nine (09) traditional healers in the Moronou village in the Department of Toumodi revealed that Anthocleista djanlonensis is regularly used by the population for primary health care in the processing of malaria. Evaluation of the In vitro antiplasmodial activity showed that the aqueous extracts inhibit growth of clinical isolates and chloroquinoresistant strains (K1) with IC50 of 8.29 µg/mL and 10.23 µg/mL while the ethanolic extracts had IC50 of 37.65 µg/mL and 46.07 µg/mL on the same strains respectively. Results of the In vitro antimalarial bioassay showed that aqueous extracts have promising antiplasmodial effects on clinical isolates and on Plasmodium falciparum multidrug resistant K1 strain (3 µg/mL &lt;IC50 &lt;15 µg/mL). Phytochemical screening revealed that the extracts contain mainly alkaloids, polyphenols, polyterpenes and flavonoids