Potential Antimalarials Research Articles

Eryptosis and Malaria: New Experimental Guidelines and Re-Evaluation of the Antimalarial Potential of Eryptosis Inducers.

Erythrocytes possess an unusual programmed cell death mechanism termed eryptosis, and several compounds have been previously claimed to induce eryptosis in vitro. Malaria parasites (genus Plasmodium) reside in erythrocytes during the pathogenic part of their life cycle, and the potential of several eryptosis inducers to act as antimalarials has been tested in recent years. However, the eryptosis-inducing capacity of these compounds varies significantly between eryptosis-focused studies and malaria investigations. Here, we investigated the reasons for these discrepancies, we developed a protocol to investigate eryptosis in malaria cultures and we re-evaluated the potential of eryptosis inducers as antimalarials. First, we showed that eryptosis read-out in vitro is dependent on culture conditions. Indeed, conditions that have consistently been used to study eryptosis do not support P. falciparum growth and prime erythrocytes for eryptosis. Next, we defined culture conditions that allow the detection of eryptosis while supporting P. falciparum survival. Finally, we selected six eryptosis-inducers based on their clinical use, molecular target and antimalarial activities, and re-evaluated their eryptosis inducing capacities and their potential as antimalarials. We demonstrate that none of these compounds affect the viability of naïve or P. falciparum-infected erythrocytes in vitro. Nevertheless, three of these compounds impair parasite development, although through a mechanism unrelated to eryptosis and yet to be elucidated. We conclude that careful consideration of experimental set up is key for the accurate assessment of the eryptosis-inducing potential of compounds and their evaluation as potential antimalarials.

Determination of Antimalarial Property, Chemical Constituents and Toxicity Level of Alstonia Boonei Aqueous Stem Bark Extract in Plasmodium Berghei Infected Mice

This study, which is part of a project on the antimalarial potential of different extracts of Alstonia boonei plant parts, was carried out to determine the antimalarial property, chemical constituents and toxicity level of Alstonia boonei aqueous stem bark extract in white albino mice infected with Plasmodium berghei. The extract exhibited substantial dose dependent antimalarial property as shown by the suppressive effect (41.48%, 52.67% and 69.82% for 100, 200 and 400 mgkg -1 body weights) prophylactic effect (48.69%, 54.37% and 62.63% for 100, 200 and 400 mgkg -1 body weights) and curative effect (52.63%, 63.55% and 68.82% for 100, 200 and 400 mgkg -1 body weights) in white albino mice infected with Plasmodium berghei. The results of the antimalarial tests were significantly different compared to the negative control at P < 0.05. Phytochemical screening of the extract revealed that the plant contains chemical constituents including tannins, flavonoids, steroids, phenols, alkaloids, saponins, glycosides and terpenoids. The toxicity test indicated that the extract is safe up to the lethal dose of 5000 mg/body weight. From the results, the extract possesses important chemical constituents which are safe and exhibit good antimalarial property. This calls for further study of the extract as a potential antimalarial drug target.

Antimalarial potential of quinones isolated from plants: an integrative review

Antimalarial treatment is often associated with the resistance developed by Plasmodium which generate ineffective drug treatment. Based on this, the search for therapeutic alternatives is necessary and urgent. This review intends to assess the antimalarial potential of quinones isolated from plants. The search for scientific articles was carried out on the CAPES Journal Portal (PPC), Virtual Health Library (VHL), PUBMED, NCBI and SCIELO, using the following descriptors: quinones and antimalarials. Inclusion criteria were adopted based on studies about quinones isolated from plants and tested against Plasmodium falciparum and Plasmodium berghei. The exclusion criteria were based mainly on articles that tested extracts, fractions and synthesis of quinones obtained from plants and other natural products. A total of 1344 publications were collected for screening (PPC = 5, VHL = 248, PUBMED = 525, NCBI = 462 and SCIELO = 94). From this total, 1280 articles were excluded, with only 64 articles selected for full reading. All benzoquinones were active against P. falciparum. Naphthoquinones were active, inactive and moderately active against the P. falciparum e P berghei. Anthraquinones and anthrones were active and moderately active against P. falciparum. The naphthoquinone 2-acetylnaphtho- [2,3b] -furan-4,9-dione was the most active of all the molecules tested against Plasmodium. Whereas lapachol was the most studied naphthoquinone and structural changes do not seem to contribute to the activity. In summary, quinones are promising as antimalarials, however, need in vivo studies.

Hybrid Compounds Containing a Ferrocene Scaffold as Potential Antimalarials

AbstractMalaria is an infectious disease, and it remains a serious health problem globally. The drugs developed for its treatment suffer from several shortcomings such as low water solubility, poor bioavailability, drug toxicity, and resistance. Molecular hybridization of different bioactive agents is a promising approach for developing hybrid compounds with improved therapeutic effects. Ferrocene, an organometallic, has been hybridized with several pharmacophores resulting in compounds with potent biological activities. In this research, a modified ferrocene scaffold was hybridized with selected pharmacophores. The synthesized compounds were characterized by Fourier‐Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance Spectroscopy (NMR), and Liquid Chromatography‐Mass Spectroscopy. The hybrid compounds were obtained in good yields (53–76 %). In vitro evaluation against NF54 (drug‐sensitive) strain of Plasmodium falciparum parasites revealed the compounds, 16 and 19 (hybrids containing artesunate scaffold), together with 18 and 21 (hybrids containing oleanolic acid scaffold), as promising antimalarial agents. These compounds displayed IC50 values of 116.73±3.18, 56.33±15.20, 78.22±21.05, and 58.22±15.20 nM, respectively. These findings revealed the potency of ferrocene as a precursor for the development of promising antimalarials.

Rapid ethnographic assessment for potential anti-malarial mass drug administration in an outbreak area of Santo Domingo, Dominican Republic

BackgroundIn the Dominican Republic, a recent outbreak of malaria in the capital, Santo Domingo, threatens efforts to eliminate the disease. Mass drug administration (MDA) has been proposed as one strategy to reduce transmission. The success of MDA is contingent upon high levels of acceptance among the target population. To inform the design of future MDA campaigns, this rapid ethnographic assessment examined malaria-related knowledge and attitudes toward malaria MDA among residents of a transmission focus in Santo Domingo.MethodsIn October 2019, a rapid ethnographic assessment was conducted in the Los Tres Brazos transmission focus, which had not previously received MDA. National malaria programme staff conducted 61 structured interviews with key informants, recorded observations, and held 72 informal conversations. Using a grounded theory approach, data were analysed during three workshop sessions with research team members.ResultsAmong those who had heard of malaria in the structured interviews (n = 39/61; 64%), understanding of the disease was largely based on personal experience from past outbreaks or through word-of-mouth. Community health workers (promotores) were trusted for health information and malaria diagnosis more so than professional clinicians. No participant (0%) was familiar with malaria MDA. After learning about MDA, almost all study participants (92%) said that they would participate, seeing it as a way to care for their community. Reasons for not participating in future MDA included not trusting drug administrators, feeling reluctant to take unprescribed medicine, and fear of missing work. Additional identified challenges to MDA included reaching specific demographic groups, disseminating effective MDA campaign messages, and managing misinformation and political influence.ConclusionResidents appear accepting of MDA despite a lack of prior familiarity. Successful MDA will depend on several factors: fostering relationships among community-based health workers, clinicians, community leaders, and others; developing clear health messages that use local terms and spreading them through a variety of media and social networks; and contextualizing MDA as part of a broader effort to promote community health.

Structure activity refinement of phenylsulfonyl piperazines as antimalarials that block erythrocytic invasion.

The emerging resistance to combination therapies comprised of artemisinin derivatives has driven a need to identify new antimalarials with novel mechanisms of action. Central to the survival and proliferation of the malaria parasite is the invasion of red blood cells by Plasmodium merozoites, providing an attractive target for novel therapeutics. A screen of the Medicines for Malaria Venture Pathogen Box employing transgenic P.falciparum parasites expressing the nanoluciferase bioluminescent reporter identified the phenylsulfonyl piperazine class as a specific inhibitor of erythrocyte invasion. Here, we describe the optimization and further characterization of the phenylsulfonyl piperazine class. During the optimization process we defined the functionality required for P.falciparum asexual stage activity and determined the alpha-carbonyl S-methyl isomer was important for antimalarial potency. The optimized compounds also possessed comparable activity against multidrug resistant strains of P.falciparum and displayed weak activity against sexual stage gametocytes. We determined that the optimized compounds blocked erythrocyte invasion consistent with the asexual activity observed and therefore the phenylsulfonyl piperazine analogues described could serve as useful tools for studying Plasmodium erythrocyte invasion.

Antimalarial Activity of Nigella sativa L. Seed Extracts and Selection of Resistance in Plasmodium berghei ANKA in a Mouse Model.

Background Chemotherapy plays a crucial role in malaria control. However, the main obstacle to treatment has been the rise of parasite resistance to most antimalarial drugs. Artemisinin-based combination therapies (ACTs) remain the most effective antimalarial medicines available today. However, malaria parasite tolerance to ACTs is now increasingly prevalent especially in Southeast Asia presenting the danger of the spread of ACTs resistance to other parts of the world. Consequently, this creates the need for alternative effective antimalarials. Therefore, this study sought out to determine antimalarial potential, safety, and resistance development of the extracts in a mouse model. Method Methanolic and ethyl acetate extracts were obtained by solvent extraction. The extracts were assayed for acute toxicity in vivo. Additionally, the two extracts were evaluated for antimalarial activity in vivo against Plasmodium berghei ANKA strain by the 4-day suppressive test at 500, 250, and 125 mg/kg/day. Packed cell volume was evaluated to determine anemia manifestation. Finally, continuous drug pressure experiment at 500 mg/kg and DNA amplification via PCR were conducted. The amplicons underwent through Sanger sequencing. Results There was no toxicity realized in the animals at 2000 mg/kg. Importantly, high parasitemia suppression of 75.52% and 75.30% using a dose of 500 mg/kg of methanolic and ethyl acetate extracts, respectively, was noted. The extracts were able to reverse packed cell volume reduction. Nigella sativa-resistant phenotype was selected as delayed parasite clearance. However, there was no change in the nucleotide sequences of PbMDR1 and PbCRT genes. Conclusion The results provide room for future exploitation of the plant as an antimalarial.

The Effect of Gastric pH on the Pharmacokinetics-pharmacodynamics of Naphthoquine in Rodents, as well as in Human Predicted Using a PBPK Model.

Fixed-dose combination of artemisinin and naphthoquine (NQ) is a new artemisinin- based combination therapy for the treatment of uncomplicated Plasmodium falciparum. NQ absorption has been reported to be affected by food in humans. The effect of gastric pH on NQ pharmacokinetics and antiplasmodial activity was investigated. The pharmacokinetic profiles of NQ were studied in healthy rodents after an oral dose of NQ with or without gastric pH modulators, i.e., pentagastrin (stimulator) and famotidine (suppressant). The effect of gastric pH on NQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. The effect of gastric pH on the antiplasmodial activity of NQ was evaluated in mice infected with Plasmodium yoelii. Neither pentagastrin nor famotidine affected NQ absorption (AUC0-t and Cmax) significantly (P > 0.05) in rodents. The predicted PK profiles of NQ in humans did not show an effect of gastric pH. Compared to pure NQ (ED90, 1.2 mg/kg), the combination with pentagastrin showed non-significantly (< 1.5-fold) higher antimalarial potency (ED90, 1.1 mg/kg). Correspondingly, the elevation of gastric pH (up to pH 5) by famotidine treatment resulted in a relatively weaker antimalarial potency for NQ (ED90, 1.4 mg/kg). Such a difference is within the acceptable range of variability in NQ pharmacokinetics and antiplasmodial activity. Although the food was found to significantly impact NQ pharmacokinetics, other factors except for gastric pH should account for the result, and the warning of careful use of NQ in patients with the acid-related disease is not expected to be clinically meaningful.

Balancing glucose and oxygen uptake rates to enable high amorpha-4,11-diene production in Escherichia coli via the methylerythritol phosphate pathway.

Amorpha-4,11-diene (AMD4,11) is a precursor to artemisinin, a potent antimalarial drug that is traditionally extracted from the shrubs of Artemisia annua. Despite significant prior efforts to produce artemisinin and its precursors through biotechnology, there remains a dire need for more efficient biosynthetic routes for its production. Here, we describe the optimization of key process conditions for an Escherichia coli strain producingAMD4,11 via the native methylerythritol phosphate (MEP) pathway. By studying the interplay between glucose uptake rates and oxygen demand, we were able to identify optimal conditions for increasing carbon flux through the MEP pathway by manipulating the availability of NADPH required for terpenoid production. Installation of an optimal qO2 /qglucose led to a 6.7-fold increase in product titers and a 6.5-fold increase in carbon yield.

Targeting malaria protein kinases.

Malaria is one of the most impacting public health problems in tropical and subtropical areas of the globe, with approximately 200 million cases worldwide annually. In the absence of an effective vaccine, rapid treatment is vital for effective malaria control. However, parasite resistance to currently available drugs underscores the urgent need for identifying new antimalarial therapies with new mechanisms of action. Among potential drug targets for developing new antimalarial candidates, protein kinases are attractive. These enzymes catalyze the phosphorylation of several proteins, thereby regulating a variety of cellular processes and playing crucial roles in the development of all stages of the malaria parasite life cycle. Moreover, the large phylogenetic distance between Plasmodium species and its human host is reflected in marked differences in structure and function of malaria protein kinases between the homologs of both species, indicating that selectivity can be attained. In this review, we describe the functions of the different types of Plasmodium kinases and highlight the main recent advances in the discovery of kinase inhibitors as potential new antimalarial drug candidates.

ATP2, The essential P4-ATPase of malaria parasites, catalyzes lipid-stimulated ATP hydrolysis in complex with a Cdc50 β-subunit

ABSTRACT Gene targeting approaches have demonstrated the essential role for the malaria parasite of membrane transport proteins involved in lipid transport and in the maintenance of membrane lipid asymmetry, representing emerging oportunites for therapeutical intervention. This is the case of ATP2, a Plasmodium-encoded 4 P-type ATPase (P4-ATPase or lipid flippase), whose activity is completely irreplaceable during the asexual stages of the parasite. Moreover, a recent chemogenomic study has situated ATP2 as the possible target of two antimalarial drug candidates. In eukaryotes, P4-ATPases assure the asymmetric phospholipid distribution in membranes by translocating phospholipids from the outer to the inner leaflet. In this work, we have used a recombinantly-produced P. chabaudi ATP2 (PcATP2), to gain insights into the function and structural organization of this essential transporter. Our work demonstrates that PcATP2 associates with two of the three Plasmodium-encoded Cdc50 proteins: PcCdc50B and PcCdc50A. Purified PcATP2/PcCdc50B complex displays ATPase activity in the presence of either phosphatidylserine or phosphatidylethanolamine. In addition, this activity is upregulated by phosphatidylinositol 4-phosphate. Overall, our work describes the first biochemical characterization of a Plasmodium lipid flippase, a first step towards the understanding of the essential physiological role of this transporter and towards its validation as a potential antimalarial drug target.

The Role of Hsp70s in the Development and Pathogenicity of Plasmodium falciparum.

The main agent of human malaria, the protozoa, Plasmodium falciparum is known to infect liver cells, subsequently invading the host erythrocyte, leading to the manifestation of clinical outcomes of the disease. As part of its survival in the human host, P. falciparum employs several heat shock protein (Hsp) families whose primary purpose is to ensure cytoprotection through their molecular chaperone role. The parasite expresses six Hsp70s that localise to various subcellular organelles of the parasite, with one, PfHsp70-x, being exported to the infected human erythrocyte. The role of these Hsp70s in the survival and pathogenicity of malaria has received immense research attention. Several studies have reported on their structure-function features, network partnerships, and elucidation of their potential substrates. Apart from their role in cytoprotection and pathogenicity, Hsp70s are implicated in antimalarial drug resistance. As such, they are deemed potential antimalarial drug candidates, especially suited for co-targeting in combination therapies. In addition, Hsp70 is implicated in host immune modulation. The current report highlights the various structure-function features of these proteins, their roles in the development of malaria, current and prospective efforts being employed towards targeting them in malaria intervention efforts.

Design, molecular docking, drug-likeness, and molecular dynamics studies of 1,2,4-trioxane derivatives as novel Plasmodium falciparum falcipain-2 (FP-2) inhibitors.

Despite significant progress made in drug discovery and development over the past few decades, malaria remains a life-threatening infectious disease across the globe. Because of the widespread emergence of drug-resistant strains of Plasmodium falciparum, the clinical utility of existing drug therapies including Artemisinin-based Combination Therapies (ACTs) in the treatment of malaria has been increasingly limited. It has become a serious health concern which, therefore, necessitates the development of novel drug molecules and/or alternative therapies to combat, particularly resistant P. falciparum. The objective of the present study was to develop 1,2,4-trioxane derivatives as novel antimalarial agents that would be effective against resistant P. falciparum. In our study, 15 new trioxane derivatives were designed by molecular modification of the 1,2,4-trioxane scaffold as possible antimalarial agents. Molecular modeling studies of trioxane derivatives were performed based on the CADD approach using Biovia Discovery Studio (DS) 2018 software. The protein-ligand docking study was performed against P. falciparum falcipain 2 (FP-2) using the simulation-based docking protocol LibDock by the flexible docking method. The assessment of drug-likeness, ADMET properties, and toxicity was also performed. Furthermore, the compounds CC3 and CC7, which showed the best binding affinity against the target P. falciparum FP-2, were investigated by molecular dynamics (MD) simulation studies followed by the calculation of MM-PBSA binding free energy of protein-ligand complexes using DS 2020. Results of the docking study showed that among the 15 compounds, three trioxane derivatives were found to possess promising binding affinity with LibDock scores ranging from 117.16 to 116.90. Drug-likeness, ADMET, and toxicity properties were found to be satisfactory for all the compounds. Among the 15 compounds, two compounds, namely CC3 and CC7, showed the highest binding affinity against FP-2 with LibDock score of 117.166 and 117.200, respectively. The Libdock score of the co-crystal inhibitor was 114.474. MD studies along with MM-PBSA calculations of binding energies further confirmed the antimalarial potential of the compounds CC3 and CC7, with the formation of well-defined and stable receptor-ligand interactions against the P. falciparum FP-2 enzyme. Additionally, the selectivity of trioxane hits identified as potential inhibitors of P. falciparum cysteine protease FP-2 was determined on human cysteine proteases such as cathepsins (Cat K and Cat L), which are host homologous. Finally, it was concluded that the newly designed 1,2,4-trioxane derivatives can be further studied for in vitro and in vivo antimalarial activities for their possible development as potent antimalarial agents effective against resistant P. falciparum.

Natural Product Inspired Synthesis of Tryptanthrin Analogues as Potential Antimalarial Agents

A new series of tryptanthrin analogues have been synthesized as potential antimalarial molecules. Synthesis of tryptanthrin aminoalkyl derivatives have been achieved via alkylation of oxime functionality of tryptanthrin derivatives by various alkyl amino pharmacophoric chains. 21-Membered small library of tryptanthrin aminoalkyl analogues were synthesized with variation in both parent natural alkaloid and in amino alkyl side chains. Synthesized compounds were fully characterized with 1H &amp; 13C NMR, IR spectroscopy. Further all the members were screened for their antimalarial potential against Plasmoum falciparum in both sensitive (3D7) and in resistant (k1) strains. Most of the screened compounds were exhibited potent antimalarial activity in both strains. Compounds (5m, 3c and 5l) having nitro group at the 8 position in tryptanthrin framework were most promising compounds in series (IC50 = 10 nm) with IC50 value as low as 10 nm comparable to chloroquine. These compounds were also tested for their toxic effect and found to be highly safe with very high value of SI index.

Ethnopharmacology and phytochemistry-based review on the antimalarial potential of Acacia pennata (L.) Willd.

A protozoan infection called malaria is caused by Plasmodium parasites. In 2018, it infected more than 228 million people and caused 405,000 fatalities. Worryingly, the present antimalarial drugs had developed drug resistance. Furthermore, they are associated with adverse effects and price issues. Amidst the gloomy scenario, drug discovery based on natural products had renewed the hope to overcome the burdens associated with the present antimalarial drugs. Auspiciously, medicinal plants had contributed significantly to the modern pharmacotherapy of malaria. Interestingly, Acacia pennata (L.) Willd. was also documented as a traditional antimalarial agent. However, there is still no scientific evidence regarding its antimalarial activity. Therefore, this article was aimed to study the phytochemical profile of A. pennata and explore their potential activity against malarial parasites. A. pennata contains different classes of bioactive compounds such as alkaloids, flavonoids, phenols, glycosides, terpenoids, phytosterols, and saponins whose antimalarial activities had been reported. Accordingly, the future scopes and challenges regarding the possible antimalarial activity for A. pennata are also discussed. To maximize the chances for finding a new antimalarial chemical entity from A. pennata, a schematic flow chart on the ethnopharmacology based drug discovery approach is also provided. Thus, this literary work may be used by researchers as a referential guide in the search for new antimalarial phytochemicals.

Antimalarials and Phytotoxins from Botryosphaeria dothidea Identified from a Seed of Diseased Torreya taxifolia.

The metabolic pathways in the apicoplast organelle of Plasmodium parasites are similar to those in plastids in plant cells and are suitable targets for malaria drug discovery. Some phytotoxins released by plant pathogenic fungi have been known to target metabolic pathways of the plastid; thus, they may also serve as potential antimalarial drug leads. An EtOAc extract of the broth of the endophyte Botryosphaeria dothidea isolated from a seed collected from a Torreya taxifolia plant with disease symptoms, showed in vitro antimalarial and phytotoxic activities. Bioactivity-guided fractionation of the extract afforded a mixture of two known isomeric phytotoxins, FRT-A and flavipucine (or their enantiomers, sapinopyridione and (-)-flavipucine), and two new unstable γ-lactam alkaloids dothilactaenes A and B. The isomeric mixture of phytotoxins displayed strong phytotoxicity against both a dicot and a monocot and moderate cytotoxicity against a panel of cell lines. Dothilactaene A showed no activity. Dothilactaene B was isolated from the active fraction, which showed moderate in vitro antiplasmodial activity with high selectivity index. In spite of this activity, its instability and various other biological activities shown by related compounds would preclude it from being a viable antimalarial lead.

Estudo químico e avaliação da atividade antimalárica dos galhos de Piranhea trifoliata

Este trabalho teve como objetivos realizar o estudo químico dos galhos de Piranhea trifoliata (Picrodendraceae) e avaliar o seu potencial antimalárico. Foram realizadas duas coletas no Estado do Pará. O material foi seco, moído e extraído com diclorometano (DCM), metanol (MeOH) e água (H2O). Os extratos DCM e MeOH foram submetidos à análise em cromatografia em camada delgada comparativa (CCDC), e apresentaram características principalmente de terpenos. Do estudo fitoquímico do extrato DCM da 2ª coleta, foi isolada: friedelan-3-ona e do extrato MeOH da 2ª coleta foi isolado: o triterpeno esqualeno, e mistura dos esteroides estigmasterol e β-sitosterol. Quanto à atividade antimalárica, os extratos e as fases dos extratos MeOH foram avaliados in vitro frente ao Plasmodium falciparum, e os extratos MeOH da 1ª e 2ª coletas foram considerados ativos (CI50 = 13,7 µg/mL; CI50 = 5,8 µg/mL, respectivamente). Este trabalho contribuiu para o conhecimento biológico e químico da espécie Piranhea trifoliata e da família Picrodendraceae, sendo este o primeiro relato de atividades biológicas para a espécie em estudo.

A novel class of fast-acting antimalarial agents: Substituted 15-membered azalides.

Background and PurposeEfficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low.Experimental ApproachFour compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum , cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model.Key ResultsNovel fast‐acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine‐resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin‐containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half‐lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti‐plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow‐acting azithromycin.Conclusion and ImplicationsThe hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy.

Metacytofilin has potent anti-malarial activity.

Metacytofilin (MCF) was isolated from the fungus Metarhizium sp. TA2759. Although MCF possesses anti-Toxoplasma activity, the effects of this compound against other parasites are unknown. Here, we evaluated the in vitro anti-malarial activity of MCF against the 3D7 strain and the chloroquine-resistant K1 strain of Plasmodium falciparum. The half maximal inhibitory concentrations (IC50) of MCF against the 3D7 and K-1 strains following culture for 48h were 666nM and 605nM, respectively. Artemisinin was more potent than MCF against both strains (3D7 IC50: 17.4nM; K-1 IC50: 18.3nM), while chloroquine was ineffective against the chloroquine-resistant strain (3D7 IC50: 39.1nM; K-1 IC50: 1.62μM). MCF affected the ring stage of the parasites, resulting in their death as shown by spots within red blood cells. MCF also inhibited parasite growth following culture for 72h (3D7 IC50, 285nM). Four optical isomers of cyclo[Leu-Phe]-diketopiperazine derivatives with modified methoxy and/or hydroxyl groups lost anti-malarial activity, suggesting that the spatial positions of the methoxy and hydroxyl groups in MCF play an important role in its anti-malarial effects. Together, these data suggest that MCF may represent a promising lead compound for treatment of drug-resistant malarial parasites.

Characterisation of plasmodial transketolases and identification of potential inhibitors: an in silico study

BackgroundPlasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme. Despite this, features contributing to such have not been exploited for anti-malarial drug design. Additionally, there are no anti-malarial drugs targeting PTKTs whereas the broad activity of these inhibitors against PTKTs from other Plasmodium spp. is yet to be reported. This study characterises different PTKTs [Plasmodium falciparum (PfTKT), Plasmodium vivax (PvTKT), Plasmodium ovale (PoTKT), Plasmodium malariae (PmTKT) and Plasmodium knowlesi (PkTKT) and the human homolog (HsTKT)] to identify key sequence and structural based differences as well as the identification of selective potential inhibitors against PTKTs.MethodsA sequence-based study was carried out using multiple sequence alignment, phylogenetic tree calculations and motif discovery analysis. Additionally, TKT models of PfTKT, PmTKT, PoTKT, PmTKT and PkTKT were modelled using the Saccharomyces cerevisiae TKT structure as template. Based on the modelled structures, molecular docking using 623 South African natural compounds was done. The stability, conformational changes and detailed interactions of selected compounds were accessed viz all-atom molecular dynamics (MD) simulations and binding free energy (BFE) calculations.ResultsSequence alignment, evolutionary and motif analyses revealed key differences between plasmodial and the human TKTs. High quality homodimeric three-dimensional PTKTs structures were constructed. Molecular docking results identified three compounds (SANC00107, SANC00411 and SANC00620) which selectively bind in the active site of all PTKTs with the lowest (better) binding affinity ≤ − 8.5 kcal/mol. MD simulations of ligand-bound systems showed stable fluctuations upon ligand binding. In all systems, ligands bind stably throughout the simulation and form crucial interactions with key active site residues. Simulations of selected compounds in complex with human TKT showed that ligands exited their binding sites at different time steps. BFE of protein–ligand complexes showed key residues involved in binding.ConclusionsThis study highlights significant differences between plasmodial and human TKTs and may provide valuable information for the development of novel anti-malarial inhibitors. Identified compounds may provide a starting point in the rational design of PTKT inhibitors and analogues based on these scaffolds.