Role of seasonal importation and genetic drift on selection for drug-resistant genotypes of Plasmodium falciparum in high-transmission settings.

Historically Plasmodium falciparum has followed a pattern of drug resistance first appearing in low-transmission settings before spreading to high-transmission settings. Several features of low-transmission regions are hypothesized as explanations: higher chance of symptoms and treatment seeking, better treatment access, less within-host competition among clones and lower rates of recombination. Here, we test whether importation of drug-resistant parasites is more likely to lead to successful emergence and establishment in low-transmission or high-transmission periods of the same epidemiological setting, using a spatial, individual-based stochastic model of malaria and drug-resistance evolution calibrated for Burkina Faso. Upon controlling for the timing of importation of drug-resistant genotypes and examination of key model variables, we found that drug-resistant genotypes imported during the low-transmission season were (i) more susceptible to stochastic extinction due to the action of genetic drift, and (ii) more likely to lead to establishment of drug resistance when parasites are able to survive early stochastic loss due to drift. This implies that rare importation events are more likely to lead to establishment if they occur during a high-transmission season, but that constant importation (e.g. neighbouring countries with high levels of resistance) may produce a greater risk during low-transmission periods.

In Silico Screening and Molecular Dynamics Simulation of Potential Anti-Malarial Agents from Zingiberaceae as Potential Plasmodium falciparum Lactate Dehydrogenase (PfLDH) Enzyme Inhibitors.

Malaria continues to be a major public health issue in a number of countries, particularly in tropical regions-the emergence of drug-resistant Plasmodium falciparum encourages new drug discovery research. The key to Plasmodium falciparum survival is energy production up to 100 times greater than other parasites, primarily via the PfLDH. This study targets PfLDH with natural bioactive compounds from the Zingiberaceae family through molecular docking and molecular dynamic studies. Sulcanal, quercetin, shogosulfonic acid C, galanal A and naringenin are the Top 5 compounds with a lower binding energy value than chloroquine, which was used as a control in this study. By binding to NADH and substrate binding site residues, the majority of them are expected to inhibit pyruvate conversion to lactate and NAD+ regeneration. When compared to sulcanal and control drugs, the molecular dynamics (MD) simulation study indicated that quercetin may be the most stable molecule when interacting with PfLDH.

Role of Seasonal Importation and Random Genetic Drift on Selection for Drug-Resistant Genotypes of Plasmodium falciparum in High Transmission Settings.

Historically Plasmodium falciparum has followed a pattern of drug resistance first appearing in low transmission settings before spreading to high transmission settings. Several features of low-transmission regions are hypothesized as explanations: higher chance of symptoms and treatment seeking, better treatment access, less within-host competition among clones, and lower rates of recombination. Here, we test whether importation of drug-resistant parasites is more likely to lead to successful emergence and establishment in low-transmission or high-transmission periods of the same epidemiological setting, using a spatial, individual-based stochastic model of malaria and drug-resistance evolution calibrated for Burkina Faso. Upon controlling for the timing of importation of drug-resistant genotypes and examination of key model variables, we found that drug-resistant genotypes imported during the low transmission season were, (1) more susceptible to stochastic extinction due to the action of random genetic drift, and (2) more likely to lead to establishment of drug resistance when parasites are able to survive early stochastic loss due to drift. This implies that rare importation events are more likely to lead to establishment if they occur during a high-transmission season, but that constant importation (e.g., neighboring countries with high levels of resistance) may produce a greater risk during low-transmission periods.

Identification of covalent fragment inhibitors for Plasmodium falciparum UCHL3 with anti-malarial efficacy.

Malaria continues to be a major burden on global health, responsible for 619,000 deaths in 2021. The causative agent of malaria is the eukaryotic parasite Plasmodium. Resistance to artemisinin-based combination therapies (ACTs), the current first-line treatment for malaria, has emerged in Asia, South America, and more recently Africa, where >90% of all malaria-related deaths occur. This has necessitated the identification and investigation of novel parasite proteins and pathways as antimalarial targets, including components of the ubiquitin proteasome system. Here, we investigate Plasmodium falciparum deubiquitinase ubiquitin C-terminal hydrolase L3 (PfUCHL3) as one such target. We carried out a high-throughput screen with covalent fragments and identified seven scaffolds that selectively inhibit the plasmodial UCHL3, but not human UCHL3 or the closely related human UCHL1. After assessing toxicity in human cells, we identified four promising hits and demonstrated their efficacy against asexual P. falciparum blood stages and P. berghei sporozoite stages.

An updated review on distribution, biosynthesis and pharmacological effects of artemisinin: A wonder drug.

Plant-based drugs have been used for centuries for treating different ailments. Malaria, one of the prevalent threats in many parts of the world, is treated mainly by artemisinin-based drugs derived from plants of genus Artemisia. However, the distribution of artemisinin is restricted to a few species of the genus; besides, its yield depends on ontogeny and the plant's geographical location. Here, we review the studies focusing on biosynthesis and distributional pattern of artemisinin production in species of the genus Artemisia. We also discussed various agronomic and in vitro methods and molecular approaches to increase the yield of artemisinin. We have summarized different mechanisms of artemisinin involved in its anti-malarial, anti-cancer, anti-inflammatory and anti-viral activities (like against Covid-19). Overall the current review provides a synopsis of a global view of the distribution of artemisinin, its biosynthesis, and pharmacological potential in treating various diseases like malaria, cancer, and coronavirus, which may provoke future research efforts in drug development. Nevertheless, long-term trials and molecular approaches, like CRISPR-Cas, are required for in-depth research.

Bioactivity assays and phytochemical analysis upon Alcea glabrata; focusing on xanthine oxidase inhibitory and antimalarial properties.

Alcea glabrata from the family Malvaceae, was selected for evaluating its xanthine oxidase inhibitory, anti-malarial, and antioxidant activities. In addition, some phytochemical analysis upon different extracts of A. glabrata were performed. Aerial parts of the collected A. glabrata plant material were dried and solvent extracted via soxhlet apparatus using different solvents. Various chromatographic techniques were used for extra fractionation of the achieved extracts. Xanthine oxidase (XO) inhibitory, antimalarial and antioxidant activity assays upon different A. glabrata extracts and fractions were carried out and reported in terms of IC50s. Total phenolic and flavonoid contents of the A. glabrata methanol extract (MeOH) were determined using the 2,2-Di Phenyl-1-Picryl Hydrazyl (DPPH) assay, aluminum chloride colorimetric, and Folin-Ciocalteu reagents, respectively. In addition, A. glabrata essential oil was obtained through hydrodistillation by a Clevenger apparatus. Analysis and identification of essential oil compounds were carried out through gas chromatography mass spectrometry (GC-MS) analysis. MeOH extract showed the highest XO inhibitory activity with the IC50 of 0.37 ± 0.12 mg/mL antioxidant activity with the RC50 of 0.24 ± 0.06 mg/mL. While, chloroform extract revealed the strongest antimalarial activity with the IC50 of 0.4 ± 0.05 mg/mL. The total flavonoid and phenolic contents of the A. glabrata methanol extract were 39.8 mg quercetin equivalent and 6.1 g gallic acid equivalent per 100 g of dry plant material, respectively. GC-MS analysis showed that the monoterpenes were prevailing in A. glabrata essential oil where the major constituents: octacosane (30.7%), eugenol (12.3%), and anethole (12.0%). Concerning the results of this study, A. glabrata extracts and its ingredients could be considered as a novel promising herbal medicine in the design and also treatment of new drugs for the relief of gout and malaria diseases.

Challenges Based on Antiplasmodial and Antiviral Activities of 7-Chloro-4-aminoquinoline Derivatives.

We report the structural functionalization of the terminal amino group of N1 -(7-chloroquinolin-4-yl) butane-1,4-diamine, leading to a series of 7-chloro-4-aminoquinoline derivatives, and their evaluation as potent anti-malarial and anti-viral agents. Some compounds exhibited promising anti-malarial effects against the Plasmodium falciparum 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant) strains. In addition, these compounds were assayed in vitro against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compound 5 h, bearing an N-mesityl thiourea group, displayed pronounced anti-infectious effects against malaria, IAV, and SARS-CoV-2. These results provide new insights into drug discovery for the prevention or treatment of malaria and virus co-infection.

Quercetin nano phytosome: as a novel anti-leishmania and anti-malarial natural product.

Leishmaniasis is a vector-borne disease that affects several populations worldwide with the clinical manifestations in skin, mucous membranes, and internal organs and there are not any effective and available vaccines and conventional treatments are highly toxic. Quercetin is a kind of flavonoid with different biological effects including free radical scavenging and anti-microbial activity and this study is aimed to assess the anti-leishmania and anti-malarial effects of quercetin loaded phytosome and quercetin alone. In this experimental study, the in vitro activity of above drugs were measured using microscopically examinations and for evaluation the anti-leishmanial efficacy, the size of lesions were measured. Moreover the cytotoxicity of the treatments was evaluated on WI38 and J774 cell lines. Our results indicated that quercetin loaded phytosome and quercetin alone have acceptable anti-parasitic activity mostly at concentration of 400 µg/ml on both P. falciparium and L. major. The results of cytotoxicity revealed that the mentioned drugs have no effects on human cell lines and also have no hemolytic activity. The drug of choice for the treatment of leishmaniasis, in addition to killing the parasite, should not have a toxic effect on human cells and our results indicated that quercetin can be a valuable candidate for treatment of different kinds of leishmaniasis.

Plasmodium relictum MSP-1 capture antigen-based ELISA for detection of avian malaria antibodies in African penguins (Spheniscus demersus).

Avian malaria, caused by Plasmodium spp. and transmitted by mosquitos, is a leading cause of mortality of captive penguins. Antimalarial drugs are currently used to control infections in penguins. However, the effectiveness of treatment reduces significantly by the time the clinical signs appear, while early and unnecessary treatment interferes with development of protective immunity. Therefore, for suppressing parasitemia without affecting the development of immunity in captive penguins, antimalaria drugs need to be administered at the right time, which requires reliable diagnostic tools that can determine the levels of circulating antimalaria antibodies. In the present study, we have developed an enzyme-linked immunosorbent assay (ELISA) diagnostic assay based on the merozoite surface protein 1 (MSP-1) of P. relictum isolate SGS1 to specifically detect and relatively quantify antimalaria antibodies in penguins. We expressed and purified a truncated P. relictum isolate SGS1 MSP-1 and optimized its biotinylation and subsequent conjugation to streptavidin alkaline phosphatase for signal generation in ELISA. We tested the assay by analyzing sera obtained from penguins at the Baltimore Zoo, from Spring through Fall, and found that levels of detectable antibodies against MSP-1 varied seasonally for individual penguins, consistent with the expected seasonal variations in avian malaria prevalence. Corroboratively, we analyzed the sensitivity of the assay by titrating positive sera and found that the signal intensity generated was serum concentration-dependent, thus validating the ability of the assay to detect and relatively quantify the levels of antimalaria antibodies in penguin sera.

Factors influencing severity of recurrent malaria in a conflict-affected state of South Sudan: an unmatched case-control study.

BACKGROUND: The burden of malaria remains the highest in sub-Saharan Africa and South Sudan is not an exception. The country has borne the brunt of years of chronic warfare and remains endemic of malaria, with increasing mortality and morbidity. Limited data still exists on factors influencing the recurrence of severe malaria, especially in emergency contexts such as South Sudan, affected by various conflicts and humanitarian situations. This study therefore aimed to investigate factors influencing severity of occurrence malaria in selected primary healthcare centres in South Sudan. This would assist and guide in malaria prevention, treatment, and eradication efforts. METHODS: We conducted an unmatched case-control study using routinely collected clinic data for individuals aged 1 year and above who received a diagnosis of severe malaria at 3 primary healthcare centres (PHCC); Malual Bab PHCC, Matangai PHCC and Malek PHCC between September 15, 2019 to December 15, 2019 in South Sudan. Patient characteristics were analyzed using simple descriptive statistics. Inferential statistics were also conducted to identify the associated factors influencing recurrence of severe malaria. All analyses were conducted using R Version 3.6.2. RESULTS: A total of 289 recurrent malaria cases were included in this study. More than half of the participants were female. Overall, the prevalence of severe recurrent malaria was 66.1% (191) while 74.4% (215) did not complete malaria treatment. Among those who did not complete malaria treatment, 76.7% (165) had severe recurrent malaria, while among those who completed malaria treatment 35.1% (26) had severe recurrent malaria (p < 0.001). There is a significant association between marital status (OR 0.33, 95% CI 0.19-0.56, p < 0.001), employment status (OR 0.35, 95% CI 0.14-0.87, p = 0.024), the use of preventive measures (OR 3.82, 95% CI 1.81-8.43, p < 0.001) and nutrition status (OR 0.22, 95% CI 0.13-0.37, p < 0.001). When adjusted for employment, marital status, nutritional and prevention measures in turns using Mantel-Haenszel test of association, this effect remained statistically significant. CONCLUSIONS: Our study showed that there is a high prevalence of severe recurrent malaria in South Sudan and that a significant relationship exists between severe recurrent malaria and antimalarial treatment dosage completion influenced by certain personal and social factors such as marital status, employment status, the use of preventive measures and nutrition status. Findings from our study would be useful for effective response to control and prevent malaria in endemic areas of South Sudan.

Liver Enzymes and Lipid Profile of Malaria Patients Before and After Antimalarial Drug Treatment at Dembia Primary Hospital and Teda Health Center, Northwest, Ethiopia.

Background: Infection with malaria in humans involves liver cell destruction, which alters the levels of liver enzymes and lipid profiles. A number of studies have been conducted to address the impact of malaria on liver enzymes and lipid profiles but no studies were addressed after antimalarial treatment in Ethiopia. This study is intended to fill this gap. Methods: An observational cohort study was conducted at Dembia Primary Hospital and Teda Health Center, from June to August 2020. Eighty eight malaria infected study participants were recruited using random sampling techniques. Socio-demographic data, capillary and venous blood samples were collected. Assessment of liver enzymes and lipid profiles was done using Beckman Coulter DC-700 clinical chemistry analyzer. Data were entered using Epi-data and exported to SPSS version 20 for analysis. One way ANOVA, independent t-test, and paired t-test were used to compare the mean liver enzymes and lipid profile. p-value<0.05 was considered statistically significant. Results: Before anti-malaria treatment, among 88 study participants, elevated AST (87.5%), ALT (12.5%), ALP (43.2%), and TG (17.2%) and lower HDL (87.5%) and normal LDL and TC were observed. After treatment, 100% AST, ALT, HDL, and LDL and 92% ALP, 94.3% TC, and 86.4% TG levels were in the normal range. The mean level of AST and ALT increased while HDL decreased from low to higher density parasitaemia. Mean level of AST was significantly lower while ALT did not alter. HDL, LDL, and TC level were increased but statistically were insignificant (P>0.05). Conclusion: Malaria could be responsible for increased liver enzymes and certain lipids while decreasing some lipid profiles. After anti-malaria treatment, these parameters were reversed to normal from 86.4% to 100%. Hence, prompt treatment is important to improve liver enzymes and lipid profile impairment during malaria infection.

Deciphering the Role of Protein Phosphatases in Apicomplexa: The Future of Innovative Therapeutics?

Parasites belonging to the Apicomplexa phylum still represent a major public health and world-wide socioeconomic burden that is greatly amplified by the spread of resistances against known therapeutic drugs. Therefore, it is essential to provide the scientific and medical communities with innovative strategies specifically targeting these organisms. In this review, we present an overview of the diversity of the phosphatome as well as the variety of functions that phosphatases display throughout the Apicomplexan parasites' life cycles. We also discuss how this diversity could be used for the design of innovative and specific new drugs/therapeutic strategies.

Anti-malarial plants in Ethiopia and their activities on drug-resistant malaria.

In Ethiopia, the impacts of malaria continue to cause a many number of morbidity and mortality that accounts to most-outpatient observations. Ethiopia recently designed to attain nationwide malaria control by 2030 by beginning sub-national elimination in districts with low malaria transmission. However, the rise of drug-resistant parasites, especially Plasmodium falciparum hinder the malaria-containment strategies. Plasmodium falciparum and Plasmodium vivax are dispersed all over Ethiopia, and account for 60% and 40% of malaria cases, respectively. The aim of this report was to overview the phytochemical constituents, diversity, and effect of some compound extracts on drug-resistant plasmodium species. Many plant species, a total 200 identified by 82 studies, are used in traditional malaria treatments throughout the country. Allium sativum, Croton macrostachyus, and Carica papaya were the more frequently used medicinal plant species. There are so many phytochemical constituents found in medicinal plants used to treat malaria. Alkaloids, flavonoids, phenolics, terpenoids, and glycosides are the most-reported for their effective activity on drug-resistant malaria.

Can Antimalarial Phytochemicals be a Possible Cure for COVID-19? Molecular Docking Studies of Some Phytochemicals to SARS-CoV-2 3C-like Protease.

OBJECTIVE: To evaluate the efficacy of reported anti-malarial phytochemicals as lead compounds for possible drug development against COVID-19. METHODS: An in silico approach was used in this study to determine through molecular docking the binding affinities and site of binding of these phytochemicals to the 3C-like protease of COVID-19 which is considered as the main protease of the virus. RESULTS: A number of anti-malarial phytochemicals like apigenin-7-O-glucoside, decurvisine, luteolin- 7-O-glucoside, sargabolide J, and shizukaols A, B, F, and G showed predicted high binding energies with ΔG values of -8.0 kcal/mol or higher. Shizukaols F and B demonstrated the best binding energies of -9.5 and -9.8, respectively. The acridone alkaloid 5-hydroxynoracronycine also gave a predicted high binding energy of -7.9 kcal/mol. CONCLUSION: This is for the first time that decursivine and several shizukaols were reported as potential anti-viral agents. These compounds merit further studies to determine whether they can be effective drug candidates against COVID-19.

Practices of anti-malaria pharmaceuticals inventory control system and associated challenges in public health facilities of Oromiya special zone, Amhara region, Ethiopia.

BACKGROUND: Anti-malaria pharmaceuticals inventory control system helps to maintain an appropriate stock level using logistics management information system records and reports. Antimalaria pharmaceuticals are highly influenced by seasonality and demand variation. Thus, to compensate the seasonality, resupply quantities should be adjusted by multiplying the historical consumption with the Look-ahead seasonality indexes (LSI) to minimize stock-outs during the peak transmission season and overstocks (possible expiries) during off-peak seasons The purpose of this study was to assess anti-malaria pharmaceuticals inventory control practice and associated challenges in public health facilities of the Oromiya special zone, Amhara region, Ethiopia. METHODOLOGY: Facility-based cross-sectional study design employing both quantitative and qualitative methods, explanatory sequential mixed method, of data collection and analysis was used in all public health facilities in the Oromia special zone from September 1 to September 30, 2019. The study was conducted in 27 health centers and 2 hospitals, the dispensing units managing anti-malaria pharmaceuticals and data was collected using observation checklists The quantitative data were analyzed by Statistical package for social sciences using linear regression. Purposive sampling was used to select key informants and 12 in-depth interviews were conducted by the principal investigator. Thematic analysis was performed using Nvivo 11 plus and interpretation by narrative strategies. RESULTS: The quantitative finding in this study revealed that none of the health facilities surveyed calculated months of stock and multiplied the historical consumption with look ahead seasonal indices (LSI) to forecast the upcoming year consumptions.. Average months of stock of anti-malaria pharmaceuticals were 5.32 months with the annual wastage rate of 11.32%. The point and periodic availability of anti-malaria pharmaceuticals was 72.38 and 77.03% respectively. The number of stocks out days within the previous 6 months was 41.34 days. The study also reported bin card usage (ß = - 3.5, p = 0.04) and availability of daily dispensing register (ß = - 2.7, p = 0.005) had statistically significant effect on anti-malaria pharmaceuticals inventory control practice. The perceived challenges attributed to the poor anti-malaria pharmaceuticals inventory control practice were lack of integrated pharmaceutical logistics system training, management support, inadequate and near expiry supply from pharmaceuticals supply agency, job dissatisfaction, and staff turnover. CONCLUSION: Inventory control practices for anti-malaria pharmaceuticals was poor as indicated by maximum stock level and none of the health facilities calculated months of stock and the previous consumption was not multiplied by look ahead seasonal indices to compensate the seasonal and demand variation. Efforts should be under-taken by concerned bodies to improve inventory control practice; such as training and regular follow up have to be provided to the health professionals managing anti-malaria pharmaceuticals.

Ten-Year Molecular Surveillance of Drug-Resistant Plasmodium spp. Isolated From the China-Myanmar Border.

Antimalarial drug resistance has emerged as a major threat to global malaria control efforts, particularly in the Greater Mekong Subregion (GMS). In this study, we analyzed the polymorphism and prevalence of molecular markers associated with resistance to first-line antimalarial drugs, such as artemisinin, chloroquine, and pyrimethamine, using blood samples collected from malaria patients in the China-Myanmar border region of the GMS from 2008 to 2017, including 225 cases of Plasmodium falciparum and 194 cases of Plasmodium vivax. In artemisinin resistance, only the C580Y mutation with low frequency was detected in pfk13, and no highly frequent stable mutation was found in pvk12. In chloroquine resistance, the frequency of K76T mutation in pfcrt was always high, and the frequency of double mutations in pvmdr1 of P. vivax has been steadily increasing every year. In pyrimidine resistance, pfdhfr and pvdhfr had relatively more complex mutant types associated with drug resistance sites, and the overall mutation rate was still high. Therefore, artemisinin-based combination therapies are still suitable for use as the first choice of antimalarial strategy in the China-Myanmar border region in the future.

Therapeutic and Industrial Applications of Curdlan With Overview on Its Recent Patents.

Curdlan is an exopolysaccharide, which is composed of glucose linked with ß-(1,3)-glycosidic bond and is produced by bacteria, such as Alcaligenes spp., Agrobacterium spp., Paenibacillus spp., Rhizobium spp., Saccharomyces cerevisiae, Candida spp., and fungal sources like Aureobasidium pullulan, Poria cocos, etc. Curdlan has been utilized in the food and pharmaceutical industries for its prebiotic, viscosifying, and water-holding properties for decades. Recently, the usefulness of curdlan has been further explored by the pharmaceutical industry for its potential therapeutic applications. Curdlan has exhibited immunoregulatory and antitumor activity in preclinical settings. It was observed that curdlan can prevent the proliferation of malarial merozoites in vivo; therefore, it may be considered as a promising therapy for the treatment of end-stage malaria. In addition, curdlan has demonstrated potent antiviral effects against human immunodeficiency virus (HIV) and Aedes aegypti virus. It has been suggested that the virucidal properties of curdlans should be extended further for other deadly viruses, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2/COVID-19). The prebiotic property of curdlan would confer beneficial effects on the host by promoting the growth of healthy microbiota in the gut and consequently help to reduce gastrointestinal disorders. Therefore, curdlan can be employed in the manufacture of prebiotics for the management of various gastrointestinal dysbiosis problems. Studies on the mechanism of action of curdlan-induced suppression in microbial and tumor cells at the cellular and molecular levels would not only enhance our understanding regarding the therapeutic effectiveness of curdlan but also help in the discovery of new drugs and dietary supplements. The primary focus of this review is to highlight the therapeutic interventions of curdlan as an anticancer, anti-malaria, antiviral, and antibacterial agent in humans. In addition, our review provides the latest information about the chemistry and biosynthesis of curdlan and its applications for making novel dairy products, functional foods, and nutraceuticals and also details about the recent patents of curdlan and its derivatives.

In vitro antiplasmodial activity of Phyllanthus amarus against Plasmodium falciparum and evaluation of its acute toxicity effect in mouse model.

BACKGROUND: The emergence of widespread resistance of Plasmodium species to most antimalarial drugs has led to a more vigorous and concerted research on traditional medicinal plants for the treatment of malaria. OBJECTIVE OF STUDY: The study was aimed to investigate the in vitro antiplasmodial activity of crude ethanolic and aqueous extracts of Phyllanthus amarus against clinical isolates of Plasmodium falciparum in Northwestern Nigeria. MATERIALS AND METHODS: The plant was extracted using two solvents, water and ethanol, where a high yield was obtained from the aqueous extracts (11.9%) as compared to the ethanolic extract (9.64%). The extracts were evaluated in vitro at concentrations of 6.25, 12.5, 25, 50, and 100 µg/ml, and the level of potency in each case was expressed as the concentration of the extract that exhibited a 50% reduction of the parasites relative to control (100%) parasitemia. Artemether-lumefantrine was used as a positive standard in the assay. RESULTS: All extracts showed a significant reduction in parasite growth relative to control (P ≤ 0.05). Ethanolic extract exhibited a higher antiplasmodial activity of 76.8%, half-maximal inhibitory concentration (IC50) of 5.80 µg/ml, and aqueous extract had an activity of 75.3%, IC50 of 7.94 µg/ml. Both extracts exhibited very active antiplasmodial activity. Oral acute toxicity test in the doses of 500, 1000, and 1500 mg/kg showed no sign of toxicity on albino mice after 48 h. CONCLUSION: Although there was an increase in appetite after 24 and 48 h, the findings from this study show that P. amarus possesses a promising antimalarial activity which can be exploited for malaria therapy and justifies the traditional use of the plant in malaria treatment.

Organoboron Compounds: Effective Antibacterial and Antiparasitic Agents.

The unique electron deficiency and coordination property of boron led to a wide range of applications in chemistry, energy research, materials science and the life sciences. The use of boron-containing compounds as pharmaceutical agents has a long history, and recent developments have produced encouraging strides. Boron agents have been used for both radiotherapy and chemotherapy. In radiotherapy, boron neutron capture therapy (BNCT) has been investigated to treat various types of tumors, such as glioblastoma multiforme (GBM) of brain, head and neck tumors, etc. Boron agents playing essential roles in such treatments and other well-established areas have been discussed elsewhere. Organoboron compounds used to treat various diseases besides tumor treatments through BNCT technology have also marked an important milestone. Following the clinical introduction of bortezomib as an anti-cancer agent, benzoxaborole drugs, tavaborole and crisaborole, have been approved for clinical use in the treatments of onychomycosis and atopic dermatitis. Some heterocyclic organoboron compounds represent potentially promising candidates for anti-infective drugs. This review highlights the clinical applications and perspectives of organoboron compounds with the natural boron atoms in disease treatments without neutron irradiation. The main topic focuses on the therapeutic applications of organoboron compounds in the diseases of tuberculosis and antifungal activity, malaria, neglected tropical diseases and cryptosporidiosis and toxoplasmosis.

Inhibition of Plasmodium falciparum Lysyl-tRNA Synthetase via a Piperidine-Ring Scaffold Inspired Cladosporin Analogues.

Plasmodium falciparum lysyl-tRNA synthetase (PfKRS) represents a promising therapeutic anti-malarial target. Cladosporin was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with X-ray crystallography reveal compounds that are moderate in potency. Co-crystals of Cla-B and Cla-C with PfKRS reveal key atomic configurations that allow drug binding to and inhibition of the enzyme. Collectively these piperidine ring scaffold inhibitors lay a framework for further structural editing and functional modifications of the cladosporin scaffold to obtain a potent lead.