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.

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.

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.

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.

Artemisinin sensitizes tumor cells to NK cell-mediated cytolysis.

The antimalarial drug Artemisinin has been reported to possess direct anti-tumor effects on various types of tumor cells. However, its anti-tumor potential has not been fully revealed, and its effects on tumor susceptibility to immune surveillance by the host are still unknown. Natural killer (NK) cells are the first line in tumor surveillance by the host, and have been recognized as a promising target for tumor immunotherapy. Here, we reported that Artemisinin sensitized tumor cells to NK cell cytolysis. Both human K562 and Raji tumor cells, and mouse YAC-1 tumor cells were more susceptible to human or mouse NK cell cytolysis in vitro after Artemisinin pretreatment. Conjugation formation between tumor cells and NK cells was increased after pretreatment with Artemisinin. Such effects on tumor cells by Artemisinin might not be the results of tumor recognition by NK cells, since major ligands of NK cell surface receptors were not affected. Mechanistically, although Artemisinin didn't induce tumor cell apoptosis, Artemisinin enriched apoptosis-related gene sets in these tumor cells, which might predispose tumor cells to apoptosis upon NK cell cytolysis. Moreover, NK cell numbers, percentages, maturation and functions were preserved in the presence of Artemisinin in vitro, suggesting that Artemisinin displays detrimental effects only on tumor cells but not on immune cells. These data reveal a novel anti-tumor mechanism of Artemisinin and demonstrate that Artemisinin could be a promising drug candidate for cancer treatment.

Structure-activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines.

BACKGROUND: Malaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (PfGSK-3) was suggested as a new anti-malarial drug target. 4-Phenylthieno[2,3-b]pyridines were previously identified as selective PfGSK-3 inhibitors with antiplasmodial activity. The present study aims at identifying a molecular position on this scaffold for the attachment of side chains in order to improve solubility and antiplasmodial activity. Furthermore, the role of axial chirality in the compound class for antiplasmodial activity and PfGSK-3 inhibition was investigated. METHODS: 4-Phenylthieno[2,3-b]pyridines with substituents in 4-position of the phenyl ring were docked into the ATP binding site of PfGSK-3. The compounds were synthesized employing a Thorpe reaction as final step. The enantiomers of one congener were separated by chiral HPLC. All derivatives were tested for inhibition of asexual erythrocytic stages of transgenic NF54-luc Plasmodium falciparum. Selected compounds with promising antiplasmodial activity were further evaluated for inhibition of HEK293 cells as well as inhibition of isolated PfGSK-3 and HsGSK-3. The kinetic aqueous solubility was assessed by laser nephelometry. RESULTS: The para position at the 4-phenyl ring of the title compounds was identified as a suitable point for the attachment of side chains. While alkoxy substituents in this position led to decreased antiplasmodial activity, alkylamino groups retained antiparasitic potency. The most promising of these congeners (4h) was investigated in detail. This compound is a selective PfGSK-3 inhibitor (versus the human GSK-3 orthologue), and exhibits improved antiplasmodial activity in vitro as well as better solubility in aqueous media than its unsubstituted parent structure. The derivative 4b was separated into the atropisomers, and it was shown that the (+)-enantiomer acts as eutomer. CONCLUSIONS: The attachment of alkylamino side chains leads to the improvement of antiplasmodial activity and aqueous solubility of selective PfGSK-inhibitors belonging to the class of 4-phenylthieno[2,3-b]pyridines. These molecules show axial chirality, a feature of high impact for biological activity. The findings can be exploited for the development of improved selective PfGSK-3 inhibitors.

What Approaches are Most Effective at Addressing Micronutrient Deficiency in Children 0-5 Years? A Review of Systematic Reviews.

Introduction Even though micronutrient deficiency is still a major public health problem, it is still unclear which interventions are most effective in improving micronutrient status. This review therefore aims to summarize the evidence published in systematic reviews on intervention strategies that aim at improving micronutrient status in children under the age of five. Methods We searched the literature and included systematic reviews that reported on micronutrient status as a primary outcome for children of 0-5 years old, had a focus on low or middle income countries. Subsequently, papers were reviewed and selected by two authors. Results We included 4235 reviews in this systematic review. We found that (single or multiple) micronutrient deficiencies in pre-school children improved after providing (single or multiple) micronutrients. However home fortification did not always lead to significant increase in serum vitamin A, serum ferritin, hemoglobin or zinc. Commercial fortification did improve iron status. Cord clamping reduced the risk of anemia in infants up to 6 months and, in helminth endemic areas, anthelminthic treatment increased serum ferritin levels, hemoglobin and improved height for age z-scores. Anti-malaria treatment improved ferritin levels. Discussion Based on our results the clearest recommendations are: delayed cord clamping is an effective intervention for reducing anemia in early life. In helminth endemic areas iron status can be improved by anthelminthic treatment. Anti-malaria treatment can improve ferritin. In deficient populations, single iron, vitamin A and multimicronutrient supplementation can improve iron, vitamin A and multimicronutrient status respectively. While the impact of home-fortification on multimicronutrient status remains questionable, commercial iron fortification may improve iron status.

Anti-Infective and Anti-Cancer Properties of the Annona Species: Their Ethnomedicinal Uses, Alkaloid Diversity, and Pharmacological Activities.

Annona species have been a valuable source of anti-infective and anticancer agents. However, only limited evaluations of their alkaloids have been carried out. This review collates and evaluates the biological data from extracts and purified isolates for their anti-infective and anti-cancer activities. An isoquinoline backbone is a major structural alkaloid moiety of the Annona genus, and more than 83 alkaloids have been isolated from this genus alone. Crude extracts of Annona genus are reported with moderate activities against Plasmodium falciparum showing larvicidal activities. However, no pure compounds from the Annona genus were tested against the parasite. The methanol extract of Annona muricata showed apparent antimicrobial activities. The isolated alkaloids from this genus including liriodenine, anonaine, asimilobine showed sensitivity against Staphylococcus epidermidis. Other alkaloids such as (+)-Xylopine and isocoreximine indicated significant anti-cancer activity against A549 and K-562 cell lines, respectively. This review revealed that the alkaloids from Annona genus are rich in structural diversity and pharmacological activities. Further exploration of this genus and their alkaloids has potential for developing novel anti-infective and anticancer drugs.

A systematic and prospectively validated approach for identifying synergistic drug combinations against malaria.

BACKGROUND: Nearly half of the world's population (3.2 billion people) were at risk of malaria in 2015, and resistance to current therapies is a major concern. While the standard of care includes drug combinations, there is a pressing need to identify new combinations that can bypass current resistance mechanisms. In the work presented here, a combined transcriptional drug repositioning/discovery and machine learning approach is proposed. METHODS: The integrated approach utilizes gene expression data from patient-derived samples, in combination with large-scale anti-malarial combination screening data, to predict synergistic compound combinations for three Plasmodium falciparum strains (3D7, DD2 and HB3). Both single compounds and combinations predicted to be active were prospectively tested in experiment. RESULTS: One of the predicted single agents, apicidin, was active with the AC50 values of 74.9, 84.1 and 74.9 nM in 3D7, DD2 and HB3 P. falciparum strains while its maximal safe plasma concentration in human is 547.6 ± 136.6 nM. Apicidin at the safe dose of 500 nM kills on average 97% of the parasite. The synergy prediction algorithm exhibited overall precision and recall of 83.5 and 65.1% for mild-to-strong, 48.8 and 75.5% for moderate-to-strong and 12.0 and 62.7% for strong synergies. Some of the prospectively predicted combinations, such as tacrolimus-hydroxyzine and raloxifene-thioridazine, exhibited significant synergy across the three P. falciparum strains included in the study. CONCLUSIONS: Systematic approaches can play an important role in accelerating discovering novel combinational therapies for malaria as it enables selecting novel synergistic compound pairs in a more informed and cost-effective manner.

Decline in malaria incidence in a typical county of China: Role of climate variance and anti-malaria intervention measures.

Malaria is an important vector-borne disease which is widespread in tropical and subtropical areas worldwide as well as in south China. Previous research has separately focused on the association between malaria incidence and meteorological variables or between malaria incidence and anti-malaria intervention measures in China, especially in Yunnan Province. Therefore, a typical county, Tengchong County, in Yunnan Province with high malaria incidence was selected as the study area to investigate the integrated influence of climate variance and anti-malaria intervention measures. Malaria incidence and meteorological variables were analyzed with a 2-month lag. The variables include average monthly temperature, minimum temperature, maximum temperature, cumulative precipitation, wind speed, maximum wind speed, relative humidity and minimum relative humidity. First, the principal component analysis was introduced to investigate the relationship between malaria incidence and meteorological variables; classification and regression trees were used to clarify contributions of key meteorological variables to malaria incidence afterwards. Second, based on existing anti-malaria intervention measures and above results, the integrated impact of climate variance and anti-malaria interventions on interannual trends of malaria incidence was analyzed. High malaria incidence occurred under one of the two meteorological conditions: 1) high minimum temperature combined with high minimum relative humidity or both precipitation and minimum relative humidity above middle level; 2) middle minimum temperature combined with both precipitation and minimum relative humidity below middle levels. Moreover, the steep interannual decline of malaria incidence in Tengchong was determined by slight climate variance and persistent anti-malaria intervention measures during malaria epidemics, predominantly by the latter. These findings will provide evidence data for developing malaria surveillance strategies in China.

Antimalarial Activity of Plant Metabolites.

Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum. As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

Elimination of Plasmodium falciparum malaria in Tajikistan.

Malaria was eliminated in Tajikistan by the beginning of the 1960s. However, sporadic introduced cases of malaria occurred subsequently probably as a result of transmission from infected mosquito Anopheles flying over river the Punj from the border areas of Afghanistan. During the 1970s and 1980s local outbreaks of malaria were reported in the southern districts bordering Afghanistan. The malaria situation dramatically changed during the 1990s following armed conflict and civil unrest in the newly independent Tajikistan, which paralyzed health services including the malaria control activities and a large-scale malaria epidemic occurred with more than 400,000 malaria cases. The malaria epidemic was contained by 1999 as a result of considerable financial input from the Government and the international community. Although Plasmodium falciparum constituted only about 5% of total malaria cases, reduction of its incidence was slower than that of Plasmodium vivax. To prevent increase in P. falciparum malaria both in terms of incidence and territory, a P. falciparum elimination programme in the Republic was launched in 200, jointly supported by the Government and the Global Fund for control of AIDS, tuberculosis and malaria. The main activities included the use of pyrethroids for the IRS with determined periodicity, deployment of mosquito nets, impregnated with insecticides, use of larvivorous fishes as a biological larvicide, implementation of small-scale environmental management, and use of personal protection methods by population under malaria risk. The malaria surveillance system was strengthened by the use of ACD, PCD, RCD and selective use of mass blood surveys. All detected cases were timely epidemiologically investigated and treated based on the results of laboratory diagnosis. As a result, by 2009, P. falciparum malaria was eliminated from all of Tajikistan, one year ahead of the originally targeted date. Elimination of P. falciparum also contributed towards speedy reduction of P. vivax incidence in Tajikistan.

Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages.

BACKGROUND: Malaria is a widespread infectious disease that threatens a large proportion of the population in tropical and subtropical areas. Given the emerging resistance against the current standard anti-malaria chemotherapeutics, the development of alternative drugs is urgently needed. New anti-malarials representing chemotypes unrelated to currently used drugs have an increased potential for displaying novel mechanisms of action and thus exhibit low risk of cross-resistance against established drugs. RESULTS: Phenotypic screening of a small library (32 kinase-inhibitor analogs) against Plasmodium falciparum NF54-luc asexual erythrocytic stage parasites identified a diarylthioether structurally unrelated to registered drugs. Hit expansion led to a series in which the most potent congener displayed nanomolar antiparasitic activity (IC50 = 39 nM, 3D7 strain). Structure-activity relationship analysis revealed a thieno[2,3-d]pyrimidine on one side of the thioether linkage as a prerequisite for antiplasmodial activity. Within the series, the oxazole derivative KuWei173 showed high potency (IC50 = 75 nM; 3D7 strain), good solubility in aqueous solvents (1.33 mM), and >100-fold selectivity toward human cell lines. Rescue experiments identified inhibition of the plasmodial coenzyme A synthesis as a possible mode of action for this compound class. CONCLUSIONS: The class of antiplasmodial bishetarylthioethers reported here has been shown to interfere with plasmodial coenzyme A synthesis, a mechanism of action not yet exploited for registered anti-malarial drugs. The oxazole congener KuWei173 displays double-digit nanomolar antiplasmodial activity, selectivity against human cell lines, high drug likeness, and thus represents a promising chemical starting point for further drug development.

Interrogating the Tailoring Steps of Pactamycin Biosynthesis and Accessing New Pactamycin Analogues.

Pactamycin is a bacteria-derived aminocyclitol antibiotic with a wide-range of biological activity. Its chemical structure and potent biological activities have made it an interesting lead compound for drug discovery and development. Despite its unusual chemical structure, many aspects of its formation in nature remain elusive. Using a combination of genetic inactivation and metabolic analysis, we investigated the tailoring processes of pactamycin biosynthesis in Streptomyces pactum. The results provide insights into the sequence of events during the tailoring steps of pactamycin biosynthesis and explain the unusual production of various pactamycin analogues by S. pactum mutants. We also identified two new pactamycin analogues that have better selectivity indexes than pactamycin against malarial parasites.

The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles.

Malaria remains one of the most important infectious diseases in the world, being a significant public health problem associated with poverty and it is one of the main obstacles to the economy of an endemic country. Among the several complications, the effects of malaria seem to target the skeletal muscle system, leading to symptoms, such as muscle aches, muscle contractures, muscle fatigue, muscle pain, and muscle weakness. Malaria cause also parasitic coronary artery occlusion. This article reviews the current knowledge regarding the effect of malaria disease and the anti-malarial drugs on skeletal and cardiac muscles. Research articles and case report publications that addressed aspects that are important for understanding the involvement of malaria parasites and anti-malarial therapies affecting skeletal and cardiac muscles were analysed and their findings summarized. Sequestration of red blood cells, increased levels of serum creatine kinase and reduced muscle content of essential contractile proteins are some of the potential biomarkers of the damage levels of skeletal and cardiac muscles. These biomarkers might be useful for prevention of complications and determining the effectiveness of interventions designed to protect cardiac and skeletal muscles from malaria-induced damage.

Toxicity associated with repeated administration of artemether-lumefantrine in rats.

Chemotherapy remains an important approach in the fight against malaria. Artemether-lumefantrine combination is widely in use due to its effectiveness against Plasmodium falciparum. Misuse in the form of multiple repeated doses of this anti-malaria drug is rampant in Nigeria. This study was designed to assess the hepatotoxic and clastogenic potential of extreme misuse of artemether-lumefantrine in rats. Graded doses of artemether-lumefantrine (1-5 mg/kg body weight) were administered by oral gavage for 6 weeks, twice daily, for 3 consecutive days per week. Artemether-lumefantrine, at all doses, did not have significant effects on the body and relative liver weight of treated group compared to the negative control group. The mean γ-glutamyltransferase, alanine, and aspartate aminotransaminase activity in groups of artemether-lumefantrine treated rats were significantly higher (p < 0.05) than that of the negative control group indicating that repeated administration of artemether-lumefantrine may be hepatotoxic. Findings from histological analyses of liver cross-section support the enzyme pattern of hepatoxicity. In addition, the drug, at all experimental doses, significantly induced (p < 0.05) formation of micronucleated polychromatic erythrocytes in the bone marrow cells of the treated rats compared with the negative control indicating clastogenic potential of the drug when misused.

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.

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.