Potential Antimalarials Research Articles

STRUCTURE-BASED DRUG DESIGN METHOD: MOLECULAR DOCKING STUDY AND PHARMACOPHORE MODELLING OF APIGENIN AS AN ANTIMALARIAL

Objective: Uses molecular docking and pharmacophore modeling methods to examine the antimalarial activity of apigenin (API) on distinct kinds and varieties of P. falciparum (Pf) receptors. Methods: Using Autodock 4.0.1 and ligandscout software, molecular docking was conducted on multiple types of Pf receptors, including lactate dehydrogenase (Oxidoreductase), Enoyl-acyl carrier-protein (Oxidoreductase), Triose-phosphate (Isomerase), and plasmepsin II (Hydroxylase). Results: The lowest free energy binding values found in two of the four investigations (API on an enoyl-acyl carrier and triose-phosphate receptors) suggested a potential effect. These values were-8.06 kcal/mol and-8.76 kcal/mol, respectively. The API had lower values of the inhibitory constant on the lactate dehydrogenase, enoyl-acyl carrier-protein, Triose-phosphate, and plasmepsin II receptors (44.06 µM, 1.24 µM, 376.76 nM, and 57.04 µM, respectively). In terms of the essential elements of amino acid residue interaction, the API and the native ligand were identical (SER218 for 1LF3 receptor; LEU315, GLY110, and TYR111 for 1NWH receptor; VAL212, LYS12, ASN233, and GLY232 for 1O5X receptor; and ILE31, PRO250, and PRO246 for 1U4O receptor). According to the findings of the pharmacophore modeling, the functional groups of hydroxyl were the most important functional groups to interact with the important amino acid residues of the receptors. Conclusion: The API considerably displays competitive antimalarial potency in various Pf receptors.

Evaluation of Anti-plasmodial Activities of Aqueous Leaf Extracts of Ficus trichocarpa and Lasianthera africana on Chloroquine-sensitive Plasmodium berghei berghei (NK65) Infected Male Albino Mice

This study was designed to evaluate the antiplasmodial activities of aqueous leaf extracts of Ficus trichocarpa and Lasianthera africana on chloroquine-sensitive Plasmodium berghei berghei (NK65) infected male albino mice. P. berghei was obtained from National Institute for Medical Research, Lagos, Nigeria, and maintained in the laboratory by serial passage in mice. Chemo-suppressive, prophylactic, and curative procedures were used to appraise the antiplasmodial potentials of the extracts. A total of 305 albino mice were used for this study. Forty-five albino mice which were divided into 9 groups were used for the acute toxicity study of F. trichocarpa and L. africana. For chemo-suppressive and prophylactic assessment, 180 albino mice were divided into 2 sets of 90 rats grouped into 6 of five albino mice each respectively, while 70 mice were used for the curative assessment. The remaining 10 infected mice served as donor mice. The infected mice were orally treated daily with 5 mg kg‾1 chloroquine 500, 1000, 1500, and 2000 mg kg‾1 bodyweight of F. trichocarpa and L. africana respectively, and a combined extract of F. trichocarpa and L. africana in a 1:1 ratio. The In vivo antiplasmodial effect of L. africana extract against P. berghei infection showed a significant (p˂0.05) dose-dependent schizonticidal activity for the prophylactic test. The percentage suppression of the malarial parasite by F. trichocarpa and L. africana after a 4-day treatment followed a dose-dependent manner and were significantly (p˂0.05) higher than the percentage suppression of groups treated with the combined extracts. Results of the prophylactic study showed that the percentage suppression of the parasite by the aqueous leaf extract of L. africana at each administered dosage was above 30%. It was, therefore, concluded that the leaf extracts of F. trichocarpa and L. africana possess antimalarial potencies when administered individually than as a combined regime and this property could be exploited for antimalarial therapy.

Preclinical evaluation of antimalarial activity of CPF-1 formulation as an alternative choice for the treatment of malaria

BackgroundKheaw Hom remedy is a traditional Thai medicine used to treat fever. Some plants used in the Kheaw Hom remedy show promising in vitro antimalarial activity. This study prepared novel formulations of plants from the Kheaw Hom remedy and evaluated their antimalarial and toxicological activities.MethodsSeven new formulations were prepared by combining at least three herbs of six selected plants from the Kheaw Hom remedy, namely Mammea siamensis Kosterm., Mesua ferrea L., Dracaena loureiroi Gagnep., Pogostemon cablin (Blanco) Benth., Kaempferia galanga L, and Eupatorium stoechadosmum Hance. In vitro antimalarial activities of each formulation’s aqueous and ethanolic extracts were evaluated using the parasite lactate dehydrogenase (pLDH) assay. Cytotoxicity in Vero and HepG2 cells was assessed using the MTT assay. An extract with good antimalarial potency and selectivity index (SI) was selected for in vivo antimalarial activity using Peter’s 4-day suppressive test and acute oral toxicity test in mice. In addition, bioactive compounds were identified using Gas chromatography-mass spectrometry (GC-MS) analysis.ResultsAmong the seven new formulations, ethanolic extracts of CPF-1 (Formulation 1) showed the highest activity with an IC50 value of 1.32 ± 0.66 µg/ml, followed by ethanolic extracts of Formulation 4 and Formulation 6 with an IC50 value of 1.52 ± 0.28 µg/ml and 2.48 ± 0.34 µg/ml, respectively. The highest SI values were obtained for the ethanolic extract of CPF-1 that was selected to confirm its in vivo antimalarial activity and toxicity. The results demonstrated a significant dose-dependent reduction in parasitemia. Maximum suppressive effect of the extract (72.01%) was observed at the highest dose administered (600 mg/kg). No significant toxicity was observed after the administration of 2000 mg/kg. Using GC-MS analysis, the most abundant compound in the ethanolic extract of CPF-1 was ethyl p-methoxycinnamate (14.32%), followed by 2-propenoic acid, 3-phenyl-, ethyl ester, (E)- (2.50%), and pentadecane (1.85%).ConclusionThe ethanolic extract of CPF-1 showed promising in vitro and in vivo antimalarial efficacy, with no toxic effects at a dose of 2000 mg/kg, suggesting that the ethanolic extract of CPF-1 may serves as a new herbal formulation for the treatment of malaria. Additional research is required for safety and clinical pharmacology studies.

Current developments on the antimalarial, antileishmanial, and antitrypanosomal potential and mechanisms of action of Terminalia spp.

Current developments on the antimalarial, antileishmanial, and antitrypanosomal potential and mechanisms of action of Terminalia spp.

Evaluation and Prediction of Anti-Malarial Activity by UbiquinolCytochrome-C Reductase Inhibition of Active Constituents of Ipomoea Carnea with Marketed Drug Atovaquone

Background: In 2017, 219 million cases of malaria across worldwide were estimated by World Health Organization and there were 435 thousands deaths were expected. African countries have the most number of cases and deaths due to malaria (~90%). Atovaquone is marketed drug used in the treatment of malaria. It shows inhibition of the Ubiquinol-cytochrome-c reductase activity in intra erythrocytes parasitic ETC pathway. Bush Morning Glory also known as Ipomoea carnea is a herbal medicinal plant which is used from ancient times to treat various diseases. There are various reported pharmacological activities of Ipomea carnea against various disorders. In this study using in silico drug discovery tools, the anti malarial potential is evaluated and compared with Atovaquone. Method: Anti malarial activity of active chemical constituents of Ipomoea carnea was studied with the help of In-silico passonline predication tool and molecular Protein-Ligand docking tool “swissdock”. Result: The data of anti-malarial activity and Molecular Protein-Ligand docking of chemical constituents of Ipomoea carnea was compared with Atovaquone data. It was observed that chemical constituents of Ipomoea carnea have more Pa value than Atovaquone for anti malarial activity. It was also observed that Stearic acid, Linoleic acid and Hexadecanoic acid binds to Ubiquinol-cytochrome-c reductase with high affinity and low binding affinity energy. Conclusion: It was also observed that Stearic acid, Linoleic acid and Hexadecanoic acid binds to Ubiquinol-cytochrome-c reductase with high affinity and low binding affinity energy. Therefore, these compounds of Ipomoea carnea have potential anti-malarial activity

Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against Plasmodium falciparum.

The spread of artemisinin (ART)-resistant Plasmodium falciparum threatens the control of malaria. Mutations in the propeller domains of P. falciparum Kelch13 (k13) are strongly associated with ART resistance. Ferredoxin (Fd), a component of the ferredoxin/NADP+ reductase (Fd/FNR) redox system, is essential for isoprenoid precursor synthesis in the plasmodial apicoplast, which is important for K13-dependent hemoglobin trafficking and ART activation. Therefore, Fd is an antimalarial drug target and fd mutations may modulate ART sensitivity. We hypothesized that loss of Fd/FNR function enhances the effect of k13 mutation on ART resistance. In this study, methoxyamino chalcone (C3), an antimalarial compound that has been reported to inhibit the interaction of recombinant Fd and FNR proteins, was used as a chemical inhibitor of the Fd/FNR redox system. We investigated the inhibitory effects of dihydroartemisinin (DHA), C3, and iron chelators including deferiprone (DFP), 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and deferiprone-resveratrol hybrid (DFP-RVT) against wild-type (WT), k13 mutant, fd mutant, and k13 fd double mutant P. falciparum parasites. Furthermore, we investigated the pharmacological interaction of C3 with DHA, in which the iron chelators were used as reference ART antagonists. C3 showed antimalarial potency similar to that of the iron chelators. As expected, combining DHA with C3 or iron chelators exhibited a moderately antagonistic effect. No differences were observed among the mutant parasites with respect to their sensitivity to C3, iron chelators, or the interactions of these compounds with DHA. The data suggest that inhibitors of the Fd/FNR redox system should be avoided as ART partner drugs in ART combination therapy for treating malaria.

Nutrient Limitation Mimics Artemisinin Tolerance in Malaria.

Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the rich media used for in vitro culture contains supraphysiological nutrient concentrations, pathogens encounter a relatively restrictive environment in vivo. We assessed the effect of nutrient limitation on the protozoan parasite that causes malaria and demonstrated that short-term growth under physiologically relevant mild nutrient stress (or "metabolic priming") triggers increased tolerance of a potent antimalarial drug. We observed beneficial effects using both short-term survival assays and longer-term proliferation studies, where metabolic priming increases parasite survival to a level previously defined as resistant (>1% survival). We performed these assessments by either decreasing single nutrients that have distinct roles in metabolism or using a media formulation that simulates the human plasma environment. We determined that priming-induced tolerance was restricted to parasites that had newly invaded the host red blood cell, but the effect was not dependent on genetic background. The molecular mechanisms of this intrinsic effect mimic aspects of genetic tolerance, including translational repression and protein export. This finding suggests that regardless of the impact on survival rates, environmental stress could stimulate changes that ultimately directly contribute to drug tolerance. Because metabolic stress is likely to occur more frequently in vivo compared to the stable in vitro environment, priming-induced drug tolerance has ramifications for how in vitro results translate to in vivo studies. Improving our understanding of how pathogens adjust their metabolism to impact survival of current and future drugs is an important avenue of research to slow the evolution of resistance. IMPORTANCE There is a dire need for effective treatments against microbial pathogens. Yet, the continuing emergence of drug resistance necessitates a deeper knowledge of how pathogens respond to treatments. We have long appreciated the contribution of genetic evolution to drug resistance, but transient metabolic changes that arise in response to environmental factors are less recognized. Here, we demonstrate that short-term growth of malaria parasites in a nutrient-limiting environment triggers cellular changes that lead to better survival of drug treatment. We found that these strategies are similar to those employed by drug-tolerant parasites, which suggests that starvation "primes" parasites to survive and potentially evolve resistance. Since the environment of the human host is relatively nutrient restrictive compared to growth conditions in standard laboratory culture, this discovery highlights the important connections among nutrient levels, protective cellular pathways, and resistance evolution.

Antimalarial potential, LC–MS secondary metabolite profiling and computational studies of Zingiber officinale

Malaria is among the top-ranked parasitic diseases that pose a threat to the existence of the human race. This study evaluated the antimalarial effect of the rhizome of Zingiber officinale in infected mice, performed secondary metabolite profiling and detailed computational antimalarial evaluation through molecular docking, molecular dynamics (MD) simulation and density functional theory methods. The antimalarial potential of Z. officinale was performed using the in vivo chemosuppressive model; secondary metabolite profiling was carried out using liquid chromatography–mass spectrometry (LC–MS). Molecular docking was performed with Autodock Vina while the MD simulation was performed with Schrodinger desmond suite for 100 ns and DFT calculations with B3LYP (6-31G) basis set. The extract showed 64% parasitaemia suppression, with a dose-dependent increase in activity up to 200 mg/kg. The chemical profiling of the extract tentatively identified eight phytochemicals. The molecular docking studies with plasmepsin II and Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) identified gingerenone A as the hit molecule, and MMGBSA values corroborate the binding energies obtained. The electronic parameters of gingerenone A revealed its significant antimalarial potential. The antimalarial activity elicited by the extract of Z. officinale and the bioactive chemical constituent supports its usage in ethnomedicine. Communicated by Ramaswamy H. Sarma

Cuscuta reflexa Possess Potent Inhibitory Activity Against Human Malaria Parasite: An In Vitro and In Vivo Study

Drug resistance to practicallyallantimalarialdrugs in use necessitate the development of new chemotherapeutics against malaria. In this aspect, traditionally used plants with folklore reputation are the pillar for drug discovery. Cuscuta reflexa being traditionally used in the treatment of malaria in Odisha, India we aimed to experimentally validate its antimalarial potential. Different solvent extracts of C. reflexa or column fractions from a promising solvent extract were evaluated for in vitro anti-plasmodial activity against Plasmodium falciparum strain Pf3D7. Potent fractions were further evaluated for inhibition of parasite growth against different drug resistant strains. Safety of these fractions was determined by in vitro cyto-toxicity, and therapeutic effectiveness was evaluated by suppression of parasitemia and improvement in survival of experimental mice. Besides, their immunomodulatory effect was investigated in Pf-antigen stimulated RAW cells. GCMS fingerprints of active fractions was determined. Column separation of methanol extract which showed the highest in vitro antiplasmodial activity (IC50 = 14.48μg/ml) resulted in eleven fractions, three of which (F2, F3, and F4) had anti-plasmodial IC50 ranging from ≤ 10 to 2.2μg/ml against various P. falciparum strains with no demonstration of in vitro cytotoxicity. F4 displayed the highest in vivo parasite suppression, and had a mean survival time similar to artesunate (19.3 vs. 20.6days). These fractions significantly modulated expression of inflammatory cytokines in Pf-antigen stimulated RAW cells. The findings of the study confirm the antimalarial potential of C. reflexa. Exploration of phyto-molecules in GCMS fingerprints of active fractions is warranted for possible identification of lead anti-malarial phyto-drugs.

Incorporation of Trifluoromethyltriazoline in the Side Chain of 4-Aminoquinolines: Synthesis and Evaluation as Antiplasmodial Agents.

Reported herein is the identification of a novel class of 4-aminoquinoline-trifluormethyltriazoline compounds as possible antiplasmodial agents. The compounds were accessed through a silver-catalyzed three-component reaction of trifluorodiazoethane with in situ generated Schiff base from corresponding quinolinylamine and aldehydes. While attempting to incorporate a sulfonyl moiety, the triazoline formed underwent spontaneous oxidative aromatization to afford triazole derivatives. All synthesized compounds were tested for their antimalarial potential in vitro and in vivo. Out of 32 compounds, four showed the most promising antimalarial activity with IC50 values ranging from 4 to 20 nM against Pf3D7 (chloroquine-sensitive) and from 120 to 450 nM against PfK1 (chloroquine-resistant) strains. One of these compounds was also found to be effective in animal studies; it showed a 99.9 % decrease in parasitic load on day 7 post-infection along with a 40 % cure rate and longest host life span.

Artesunate targets cellular metabolism to regulate the Th17/Treg cell balance.

Metabolic reprogramming is one of the important mechanisms of cell differentiation, and different cells have different preferences for energy sources. During the differentiation of naive CD4 + T cells into Th17 and Treg cells, these cells show specific energy metabolism characteristics. Th17 cells depend on enhanced glycolysis, fatty acid synthesis, and glutaminolysis. In contrast, Treg cells are dependent on oxidative phosphorylation, fatty acid oxidation, and amino acid depletion. As a potent antimalarial drug, artesunate has been shown to modulate the Th17/Treg imbalance and regulate cell metabolism. Relevant literatures on ART, cellular metabolism, glycolysis, lipid metabolism, amino acid metabolism, CD4 + T cells, Th17 cells, and Treg cells published from January 1, 2010 to now were searched in PubMed database. In this review, we will highlight recent advances in which artesunate can restore the Th17/Treg imbalance in disease states by altering T-cell metabolism to influence differentiation and lineage selection. Data from the current study show that few studies have focused on the effect of ART on cellular metabolism. ART can affect the metabolic characteristics of T cells (glycolysis, lipid metabolism, and amino acid metabolism) and interfere with their differentiation lineage, thereby regulating the balance of Th17/Treg and alleviating the symptoms of the disease.

In silico screening of phytochemicals from Dissotis rotundifolia against Plasmodium falciparum Dihydrofolate Reductase

BackgroundMalaria remains a major health concern in developing countries with high morbidity and mortality, especially in pregnant women and infants. A major obstacle to the treatment of malaria is a low effectiveness and an increase resistance of the parasite to antimalarial drugs. As a result, there is an ongoing demand for new and potent antimalarial drugs. Medicinal plants remain a potential source for the development of new antimalarial drugs. Amongst them is Dissotis rotundifolia is an ethnomedical important plant used in West Africa to treat malaria. PurposeThis study aimed at identifying new potential antifolates by virtually screening phytochemicals characterized from the whole plant methanolic extract of D. rotundifolia against Plasmodium falciparum Dihydrofolate Reductase (PfDHFR). MethodsLC-ESI-Q-TOF-MS analysis was employed to identify the phytochemicals present in the whole plant methanolic extract of D. rotundifolia. These phytochemicals were docked against the catalytic site of PfDHFR. The docking protocol was evaluated using the Area Under the Curve (AUC) of a Receiver Operating Characteristic (ROC) curve. The binding mechanisms and the drug-likeness of the phytochemicals were characterized. A 100 ns Molecular Dynamics (MD) simulation and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculations were utilized to analyze the stability, the energy decomposition per residue and the binding free energy of the potential leads. ResultsTwenty nine phytochemicals were characterized and docked against PfDHFR. Dimethylmatairesinol, flavodic acid, sakuranetin, and sesartemin were identified as potential leads with binding affinities of -8.4, -8.9, -8.6, and -8.9 kcal/mol respectively, greater than a stringent threshold of -8.0 kcal/mol. The potential leads also interacted hydrophobically with critical residue Phe58. A novel critical residue, Leu46 was identified to be crucial in the catalytic activity of PfDHFR. The potential leads were also predicted to be anti-protozoal with a probability of active (Pa) value ranging from 0.319 to 0.537. ConclusionThis study elucidates the potential inhibition of PfDHFR by dimethylmatairesinol, flavodic acid, sakuranetin and sesartemin present in D. rotundifolia. These compounds are druglike, do not violate Lipinski's rule of five, have a high binding affinity to PfDHFR, and interact with crucial residues involved in the catalytic activity PfDHFR. Dimethylmatairesinol, flavodic acid, sakuranetin and sesartemin could therefore be further investigated and developed as new antifolate drugs for malaria.

Bioprospecting the Biological Effects of Cultivating Pleurotus ostreatus Mushrooms from Selected Agro-Wastes and Maize Flour Supplements

Pleurotus mushrooms are valuable food supplements with health and environmental restorative potential. In this paper, we sought to evaluate the biological activities and profile the bioactive compounds found in Pleurotus ostreatus cultivated from agro-waste supplemented with maize flour. We investigated carbon to nitrogen (C/N), antimicrobial, antioxidant, and antimalarial potential for the varying supplementation during mushroom cultivation. GCMS was utilized for screening bioactive compounds found in P. ostreatus. Changes in supplementation directly correlate with changes in compound profiling. Nonetheless, some compounds were found to be common amongst the tested mushrooms, including pentadecanoic acid; 9,12-octadecadienoic acid, methyl ester; pentadecanoic acid, methyl ester; octadecanoic acid; and diisooctyl phthalate. The highest antimicrobial potential against Gram-positive Staphylococcus aureus was observed when maize flour supplements were increased to 12% and 18%. Our data demonstrated that the observed antioxidant (DPPH, ABTS, and reducing power) and antimicrobial activity could emanate from various supplementation conditions. Furthermore, supplementation has an impact on the mushroom yield and phytochemical profiles of the produced mushroom.

Investigations on the Antimalarial Properties of Cleistopholis patens (Annonaceae) Leaf Methanol Extract and Its Partitioned Fractions in Mice

Aim: The methanol extract and partitioned fractions of Cleistopholis patens leaf were evaluated for antiplasmodial activities with a view to establishing its antimalarial potential and identifying the most active partitioned fraction.
 Methods: The leaf was collected, authenticated, air-dried and powdered. The extract, prepared by maceration in methanol was tested (0-800 mg/kg) against P. berghei berghei in mice using Peter’s four-day test. Normal saline and Chloroquine (10 mg/kg) were negative and positive control respectively. Percentage parasitemia, percentage chemosuppression, effective doses, survival times and percentage survivors were the parameters used for the assessment. The extract was thereafter suspended in water and successively partitioned into n-hexane, dichloromethane and ethyl acetate and the resulting fractions and the aqueous phase were similarly tested at doses 10-80 mg/kg.
 Results: The methanol extract which was comparable (P=.06) in activity to chloroquine gave 1.05±0.09 percentage parasitemia, 77.45±4.39 percentage chemosuppression at 40 mg/kg and an ED50 and ED90 of 255.83±3.60 and 471.35±15.05 mg/kg. The most active n-hexane fraction elicited a percentage chemosuppression of 82%, 0.87 percentage parasitaemia at 80 mg/kg, moderately high percentage survivor and relatively low ED50 and ED90 of 28.87±5.29 and 56.30±8.44 mg/kg.
 Conclusion: The methanol extract of C. patens leaf is active against P. berghei berghei and the antimalarial compounds is likely to be concentrated in the n-hexane fraction.

Assessment of Solid-State Behaviour and in vitro Release of Artemether from Liquisolid Compact Using Mesoporous Material as an Excipient

Abstract: Background: Artemether is a potent antimalarial drug used in the first-line treatment of multi-drug-resistant malaria. It belongs to BCS II, exist in different polymorphic forms, and exhibits incomplete absorption and low oral bioavailability owing to poor dissolution. Aim: The present study evaluates the effect of different mesoporous materials in the liquisolid compact for the augmentation of dissolution of the drug, and polymorphic stability. Materials and Methods: In the liquisolid compact Tween 80 was used as a non-volatile solvent for the dispersion of the drug, microcrystalline cellulose as carrier, and Syloid244FP and SyloidXDP as coating materials at different coating and carrier ratios. Eight such formulations were prepared. The formulated liquisolid compact was evaluated for precompression parameters, followed by direct compression process. The tablets thus prepared were assessed for hardness, friability, wetting time, in-vitro dissolution, and stability studies. Physico-chemical characterization was done to study drug excipient interaction, thermal behaviour, and surface characteristics. Results and Discussion: The study revealed that an increasing quantity of mesoporous material exhibited a better release profile compared to the pure drug. Good compressibility and tablet ability were observed at a carrier and coating materials ratio of 1:5. Compatibility between the drug and excipients was established from the FTIR study. Noteworthy findings of PXRD and DSC suggested the presence of artemether in metastable β form in the formulations. Short-term stability of the formulations was established. Conclusion: Hence, the approach of liquisolid compact using mesoporous silicas at a suitable excipient ratio could be an optimistic approach for the enhancement of dissolution and stability of artemether. Keywords: Artemether, Liquisolid compact, Solid-state behaviour, Dissolution, Mesoporous silica.

Identification of new oxospiro chromane quinoline-carboxylate antimalarials that arrest parasite growth at ring stage

Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting Plasmodium proteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates 9(a–o) and carboxylic acids 10(a–b) for the inhibition of Plasmodium N-Myristoyltransferases (NMTs) using computational biology tools followed by chemical synthesis and functional analysis. The designed compounds exhibited a glide score of −9.241 to −6.960 kcal/mol for PvNMT and −7.538 kcal/mol for PfNMT model proteins. Development of the synthesized compounds was established via NMR, HRMS and single crystal X-ray diffraction study. The synthesized compounds were evaluated for their in vitro antimalarial efficacy against CQ-sensitive Pf3D7 and CQ-resistant PfINDO lines followed by cell toxicity evaluation. In silico results highlighted the compound ethyl 6-methyl-4-(naphthalen-2-yloxy)quinoline-3-carboxylate (9a) as a promising inhibitor with a glide score of −9.084 kcal/mol for PvNMT and −6.975 kcal/mol for PfNMT with IC50 values of 6.58 µM for Pf3D7 line. Furthermore, compounds 9n and 9o exhibited excellent anti-plasmodial activity (Pf3D7 IC50 = 3.96, 6.71 µM, and PfINDO IC50 = 6.38, 2.8 µM, respectively). The conformational stability of 9a with the active site of the target protein was analyzed through MD simulation and was found concordance with in vitro results. Thus, our study provides scaffolds for the development of potent antimalarials targeting both Plasmodium vivax and Plasmodium falciparum. Communicated by Ramaswamy H. Sarma

Therapeutic Potency of Mono- and Diprenylated Acetophenones: A Case Study of In-Vivo Antimalarial Evaluation

AbstractMalaria remains a febrile infection of public health concern in many countries especially tropical countries in Africa and certain countries in Southern and North America such as Brazil, Costa Rica, Mexico, Dominican Republic, Colombia, and Ecuador. Hence this has made research into this area paramount. Acetophenones are active fragments in many compounds with promising antimalarial activity, such as chalcones. The aim of the present study was to investigate antimalarial activity of 3,5-diprenyl acetophenone (I) and 5-diprenyl acetophenone (II) in in vivo. In this study, compounds I and II were synthesized using an aromatic substitution reaction. The in-vivo antimalarial potential of compounds I and II was analyzed in Plasmodium berghei-infected mice. Our data showed that compound I (25, 50, and 100 mg/kg) had promising antimalarial activity, with parasitemia inhibited rate being 68.03, 65.16, and 69.75%, respectively. Compound II dose-dependently inhibited parasitemia levels, it demonstrated an infinitesimally higher activity (72.12%) when compared with compound I (69.75%) at 100 mg/kg dose. The two compounds passed the rule of three, Lipinski's rule of five, predicted plausible pharmacokinetic profile (ADME), and apparent safety profile, and demonstrated drug-like fragments. The study provided guidance in exploring novel antimalarial compounds based on the scaffolds of prenylated acetophenones.

Curry Fish Extract's Antimalarial Potency in N-hexane and Ethyl Acetate Solvents using In vitro approach

The increase in malaria morbidity and mortality due to artemisinin derivative resistance was a global problem. Marine biota, curry fish or Sticophus hermanni was known to have bioactive components that are antibacterial and antifungal. The purpose of the study was to observe phytochemical tests and antimalarial activity of golden sea cucumber, curry fish using two types of solvents with different polarities using In vtro studies. The study was a true experimental study withIn vtro protocols, which included: (P1), control negative; (P2) P. falciparum medium with n-hexane extract of curry fish; (P3) P.falciparum medium with ethyl acetate extract of curry fish. The parameters were as follows: phytochemical assay, growth %, inhibitory rate, and IC50. The phytochemical analysis found various bioactive components in the ethyl acetate extract, including flavonoids, alkaloids, steroids, and tannins, whereas the n-hexane extract includes fewer active components, including flavonoids, alkaloids, steroids, and tannins. The extract's antimalarial action is demonstrated by a decrease in parasite growth, a rise in the inhibitory rate with increasing extract dose, and IC50 less than 5 µg/ml when administered with ethyl acetate and n-hexane. Both solvents in curry fish extract displayed high antimalarial activity; however, n-hexane had a lower IC50 than ethyl acetate.

7-N-Substituted-3-oxadiazole Quinolones with Potent Antimalarial Activity Target the Cytochrome bc1 Complex.

The development of new antimalarials is required because of the threat of resistance to current antimalarial therapies. To discover new antimalarial chemotypes, we screened the Janssen Jumpstarter library against the P. falciparum asexual parasite and identified the 7-N-substituted-3-oxadiazole quinolone hit class. We established the structure-activity relationship and optimized the antimalarial potency. The optimized analog WJM228 (17) showed robust metabolic stability in vitro, although the aqueous solubility was limited. Forward genetic resistance studies uncovered that WJM228 targets the Qo site of cytochrome b (cyt b), an important component of the mitochondrial electron transport chain (ETC) that is essential for pyrimidine biosynthesis and an established antimalarial target. Profiling against drug-resistant parasites confirmed that WJM228 confers resistance to the Qo site but not Qi site mutations, and in a biosensor assay, it was shown to impact the ETC via inhibition of cyt b. Consistent with other cyt b targeted antimalarials, WJM228 prevented pre-erythrocytic parasite and male gamete development and reduced asexual parasitemia in a P. berghei mouse model of malaria. Correcting the limited aqueous solubility and the high susceptibility to cyt b Qo site resistant parasites found in the clinic will be major obstacles in the future development of the 3-oxadiazole quinolone antimalarial class.

Bisbenzylisoquinolines from Cissampelos pareira L. as antimalarial agents: Molecular docking, pharmacokinetics analysis, and molecular dynamic simulation studies

Malaria is a major global health issue due to the emergence of resistance to most of the available antimalarial drugs. There is an urgent need to discover new antimalarials to tackle the resistance issue. The present study aims to explore the antimalarial potential of chemical constituents reported from Cissampelos pareira L., a medicinal plant traditionally known for treating malaria. Phytochemically, benzylisoquinolines and bisbenzylisoquinolines are the major classes of alkaloids reported from this plant. In silico molecular docking revealed prominent interactions of bisbenzylisoquinolines such as hayatinine and curine with Pfdihydrofolate reductase (−6.983 Kcal/mol and −6.237 Kcal/mol), PfcGMP-dependent protein kinase (−6.652 Kcal/mol and −7.158 Kcal/mol), and Pfprolyl-tRNA synthetase (−7.569 Kcal/mol and −7.122 Kcal/mol). The binding affinity of hayatinine and curine with identified antimalarial targets was further evaluated using MD-simulation analysis. Among the identified antimalarial targets, the RMSD, RMSF, the radius of gyration, and PCA indicated the formation of stable complexes of hayatinine and curine with Pfprolyl-tRNA synthetase. The outcomes of in silico investigation putatively suggested that bisbenzylisoquinolines may act on the translation of the Plasmodium parasite to exhibit antimalarial potency.