Resistant Plasmodium Research Articles

Curcumin‐loaded nanomedicines as therapeutic strategy in malaria management

AbstractMalaria, a parasitic protozoan disease widespread in tropical climates, is transmitted by Plasmodium spp. Many people are affected by this significant public health disease, which has a high incidence of illness and mortality worldwide. Because drug‐resistant parasites are on the rise, there are not enough controls on mosquitoes, and there are not any malaria vaccinations. Malaria is particularly challenging in developing countries. Antimalarial drugs approved by Food and Drug Administration are the main options for combating and preventing malaria; also the control of transmission at the level of mosquitoes is important. Current antimalarial chemotherapeutic therapies have significant clinical flaws such as Plasmodium resistance, the drugs that call for the development of novel drug candidates. To combat malaria, nanotechnology may give a viable alternative that is both more effective and safer than current treatment options. Nanotechnology‐based curcumin formulations have proved to overcome the limitations of current therapies in terms of optimum therapeutic benefits, safety, and cost‐efficiency, which increases a patient's capacity to adhere to prescribed medicine. The limits of current malaria therapies and the need to employ nanotechnological curcumin to treat malaria were addressed and discussed in this paper.

Artemisinin resistance in P. falciparum: probing the interacting partners of Kelch13 protein in parasite

Artemisinin (ART) resistance in Plasmodium is threatening the artemisinin combination therapies-the first line of defence against malaria. ART resistance has been established to be mediated by the Plasmodium Kelch13 (PfK13) protein. For the crucial role of PfK13 in multiple pathways of the Plasmodium life cycle and ART resistance, it is imperative that we investigate its interacting partners. We recombinantly expressed PfK13-p (Bric a brac/Poxvirus and zinc finger and propeller domains), generating anti-PfK13-p antibodies to perform co-immunoprecipitation assays and probed PfK13 interacting partners. Surface plasmon resonance and pull-down assays were performed to establish physical interactions of representative proteins with PfK13-p. The co-immunoprecipitation assays identified 17 proteins with distinct functions in the parasite life cycle- protein folding, cellular metabolism, and protein binding and invasion. In addition to the overlap with previously identified proteins, our study identified 10 unique proteins. Fructose-biphosphate aldolase and heat shock protein 70 demonstrated strong biophysical interaction with PfK13-p, with KD values of 6.6 µM and 7.6 µM, respectively. Additionally, Plasmodium merozoite surface protein 1 formed a complex with PfK13-p, which is evident from the pull-down assay. This study adds to our knowledge of the PfK13 protein in mediating ART resistance by identifying new PfK13 interacting partners. Three representative proteins-fructose-biphosphate aldolase, heat shock protein 70, and merozoite surface protein 1-demonstrated clear evidence of biophysical interactions with PfK13-p. However, elucidation of the functional relevance of these physical interactions are crucial in context of PfK13 role in ART resistance.

Molecular insights into artemisinin resistance in Plasmodium falciparum: An updated review.

Malaria still poses a major burden on human health around the world, especially in endemic areas. Plasmodium resistance to several antimalarial drugs has been one of the major hindrances in control of malaria. Thus, the World Health Organization recommended artemisinin-based combination therapy (ACT) as a front-line treatment for malaria. The emergence of parasites resistant to artemisinin, along with resistant to ACT partner drugs, has led to ACT treatment failure. The artemisinin resistance is mostly related to the mutations in the propeller domain of the kelch13 (k13) gene that encodes protein Kelch13 (K13). The K13 protein has an important role in parasite reaction to oxidative stress. The most widely spread mutation in K13, with the highest degree of resistance, is a C580Y mutation. Other mutations, which are already identified as markers of artemisinin resistance, are R539T, I543T, and Y493H. The objective of this review is to provide current molecular insights into artemisinin resistance in Plasmodium falciparum. The trending use of artemisinin beyond its antimalarial effect is described. Immediate challenges and future research directions are discussed. Better understanding of the molecular mechanisms underlying artemisinin resistance will accelerate implementation of scientific findings to solve problems with malarial infection.

Malaria in 2022: clinical and therapeutic aspects

In 2022 as in 1884, the clinical presentation of uncomplicated malaria is unspecific: fever of variable intensity, continuous or rhythmic, chills, flu syndrome, headache, respiratory and digestive disorders. At any time, it can evolve into a severe form (ex-pernicious attack or cerebral malaria) or even lethal. By reading again Alphonse Laveran's book on malarial fevers, we realized to what extent the observations made at that time allowed for a methodical and orderly description of the clinical forms of malaria, very close to what we can still observe today. No symptom or sign is pathognomonic of the disease. Only the detection of plasmodia or "malaria microbes" by direct or immuno-chromatographic methods allows for diagnostic confirmation, which is a prerequisite for the implementation of a curative treatment.Serendipity, synthetic chemistry and traditional medicine are the three methods that led to the discovery and large-scale production of antimalarial drugs. Serendipity for quinine, synthetic chemistry for chloroquine, and research conducted around traditional Chinese medicine for artemisinin and its derivatives. The latter have marked a real revolution in the management of malaria, both in its uncomplicated and severe forms. However, as with other antimalarial drugs, its medium- and long-term efficacy is compromised by the emergence and spread of resistance in malaria parasites, particularly P. falciparum. The control and eradication of malaria therefore require continued research in both prevention and therapy.The disease so well described by Alphonse Laveran has not yet said its last word….

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

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

Toxins from Animal Venoms as a Potential Source of Antimalarials: A Comprehensive Review.

Malaria is an infectious disease caused by Plasmodium spp. and it is mainly transmitted to humans by female mosquitoes of the genus Anopheles. Malaria is an important global public health problem due to its high rates of morbidity and mortality. At present, drug therapies and vector control with insecticides are respectively the most commonly used methods for the treatment and control of malaria. However, several studies have shown the resistance of Plasmodium to drugs that are recommended for the treatment of malaria. In view of this, it is necessary to carry out studies to discover new antimalarial molecules as lead compounds for the development of new medicines. In this sense, in the last few decades, animal venoms have attracted attention as a potential source for new antimalarial molecules. Therefore, the aim of this review was to summarize animal venom toxins with antimalarial activity found in the literature. From this research, 50 isolated substances, 4 venom fractions and 7 venom extracts from animals such as anurans, spiders, scorpions, snakes, and bees were identified. These toxins act as inhibitors at different key points in the biological cycle of Plasmodium and may be important in the context of the resistance of Plasmodium to currently available antimalarial drugs.

In silico screening, synthesis, and antimalarial evaluation of PABA substituted 1,3,5-triazine derivatives as Pf-DHFR inhibitors

ObjectivesDrug resistance in malaria parasites necessitates the development of new antimalarial drugs with unique mechanisms of action. In the present research work, the PABA conjugated 1,3,5-triazine derivatives were designed as an antimalarial agent. MethodsIn this present work, a library of two hundred-seven compounds was prepared in twelve different series such as [4A (1-23), 4B(1-22), 4C(1-21), 4D(1-20), 4E(1-19), 4F(1-18), 4G(1-17), 4H(1-16), 4I(1-15), 4J(1-13), 4K(1-12) and 4L(1-11) ] respectively using different primary and secondary aliphatic and aromatic amines. Ten compounds were ultimately selected through in silico screening. They were synthesized by conventional and microwave-assisted methods followed by in vitro antimalarial evaluations performed in chloroquine-sensitive (3D7) and resistant (DD2) strains of P. falciparum. ResultsThe docking results showed that compound 4C(11) had good binding interaction with Phe116, Met55 (−464.70 kcal/mol) and Phe116, Ser111 (−432.60 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. Furthermore, in vitro, antimalarial activity results indicated that compound 4C(11) showed potent antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain of P. falciparum along with IC50 (14.90 μg mL−1) and (8.30 μg mL−1). ConclusionThese PABA-substituted 1,3,5-triazine compounds could be exploited to develop a new class of Pf-DHFR inhibitors as a lead candidate.

A review of malaria molecular markers for drug resistance in Plasmodium falciparum and Plasmodium vivax in China.

China has now achieved the elimination of malaria, but it still faces severe challenges in the post-elimination stage. China continues to be plagued by imported malaria cases, and preventing re-transmission of imported malaria is critical. The effectiveness of antimalarial drugs for malaria control largely depends on the study of drug resistance markers in vitro. Monitoring molecular markers of parasite-associated drug resistance can help predict and manage drug resistance. There is currently a lack of systematic reviews of molecular markers for indigenous and imported malaria in China. Therefore, this review summarizes the published articles related to molecular marker polymorphism of indigenous and imported malaria cases in China in the past two decades, to study the mutation frequency and distribution of crt, mdr1, dhps, dhfr and K13 gene resistance-related loci. This can provide a whole picture of molecular markers and the resistance mutations of imported cases in China, which has certain significance for drug resistance surveillance planning, safe and effective treatment, and preventing the recurrence of local transmission by imported malaria in China in the future.

Exploring the potential of antimalarial nanocarriers as a novel therapeutic approach

Malaria is a life-threatening parasitic disease that affects millions of people worldwide, especially in developing countries. Despite advances in conventional therapies, drug resistance in malaria parasites has become a significant concern. Hence, there is a need for a new therapeutic approach. To combat the disease effectively means eliminating vectors and discovering potent treatments. The nanotechnology research efforts in nanomedicine show promise by exploring the potential use of nanomaterials that can surmount these limitations occurring with antimalarial drugs, which include multidrug resistance or lack of specificity when targeting parasites directly. Utilizing nanomaterials would possess unique advantages over conventional chemotherapy systems by increasing the efficacy levels while reducing side effects significantly by delivering medications precisely within the diseased area. It also provides cheap yet safe measures against Malaria infections worldwide-ultimately improving treatment efficiency holistically without reinventing new methods therapeutically. This review is an effort to provide an overview of the various stages of malaria parasites, pathogenesis, and conventional therapies, as well as the treatment gap existing with available formulations. It explores different types of nanocarriers, such as liposomes, ethosomal cataplasm, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanocarriers, and metallic nanoparticles, which are frequently employed to boost the efficiency of antimalarial drugs to overcome the challenges and develop effective and safe therapies. The study also highlights the improved pharmacokinetics, enhanced drug bioavailability, and reduced toxicity associated with nanocarriers, making them a promising therapeutic approach for treating malaria.

CASE REPORT: PANCYTOPENIA IN SEVERE MALARIA WITH SUSPECTED HEMOPHAGOCYTIC SYNDROME AT ATAMBUA HOSPITAL

Background: Malaria is a parasitic infectious disease caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malaria. The signs of a malaria infection include fever, chills, anemia, and splenomegaly. In the Belu district, the incidence of malaria is still high. It’s about 10,6 per 1000 population. Objective: To describe a case of Malaria in one of patient in Indonesia.Methods: Case reportResults: A 61-year-old woman with Malaria with clinical manifestations as follow, fever, body aches, and chills felt since 3 days before hospital admissions. On the 4th day of treatment, plasmodium falciparum was found.Conclusion: A combination of anti-malarial medications (OAM) is used in the treatment of malaria with the goal of reducing plasmodium resistance to anti-malarial medications.

Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models.

The global spread of multi-drug resistant P. falciparum, P. vivax, and P. malariae strains and absence of long-term effective vaccine makes chemotherapy the mainstay of malaria control strategies in endemic settings. The Mossman's assay and the Organization for Economic Co-operation and Development (OECD), 2001 guideline 423, were used to determine the cytotoxicity and acute oral toxicity of a novel hybrid drug, artesunate-3-Chloro-4(4-chlorophenoxy) aniline (ATSA), in vitro and in vivo, respectively. A modified Desjardins method was used to screen for antiplasmodial activity using P. falciparum (3D7 and W2) strains in vitro. The Peter's 4-day suppressive tests (4DTs) was used to evaluate the in vivo antimalaria activity using P. berghei ANKA strain, lumefantrine resistant (LuR), and piperaquine resistant (PQR) P. berghei lines. In silico prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles was assayed using PreADMET online prediction tool. The reference drug in all experiments was artesunate (ATS). Statistical significance between ATSA's activities in treated and control mice was evaluated by one-way analysis of variance (ANOVA). Results show that inhibitory concentrations-50 (IC50) of ATSA is 11.47 ± 1.3 (3D7) and 1.45 ± 0.26 (W2) against 4.66 ± 0.93 (3D7) and 0.60 ± 0.15 (W2) ng/ml of ATS with a selective index of 2180.91(3D7) and a therapeutic index (TI) of > 71). No mortalities were observed in acute oral toxicity assays and mean weight differences for test and controls were statistically insignificant (P > 0.05). The in vivo activity of ATSA was above 40% with effective dosage-50 (ED50) of 4.211, 2.601, and 3.875mg/kg body weight against P. berghei ANKA, LuR, and PQR lines, respectively. The difference between treated and control mice was statistically significant (P < 0.05). ATSA has high intestinal absorption (HIA) > 95% and has medium human ether-a-go-go related gene (hERG) K+ channel inhibition risks. Preclinical and clinical studies on ATSA are recommended to evaluate its value in developing novel drugs for future management of multi-drug resistant malaria parasites.

A snapshot of the prevalence of dihydropteroate synthase-431V mutation and other sulfadoxine-pyrimethamine resistance markers in Plasmodium falciparum isolates in Nigeria

BackgroundMalaria is a major public health issue with substantial risks among vulnerable populations. Currently, the World Health Organization (WHO) recommends SP-IPTp in the second and third trimesters. However, the efficacy of SP-IPTp is threatened by the emergence of sulfadoxine-pyrimethamine resistant malaria parasites due to single nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. This study aimed to assess the current prevalence of Pfdhfr/Pfdhps mutations in P. falciparum isolates collected from individuals residing in Ile-Ife, Nigeria, and also present maps of the prevalence of Pfdhps 431V and 581G within Nigeria and surrounding countries.MethodsBetween October 2020 and April 2021, samples were collected as dried blood spots among 188 participants who showed malaria positivity with a histidine-rich-protein-based rapid diagnostic test (RDT). Nested PCR assays were used to confirm falciparum in the samples with RDT positivity, and to amplify fragments of the Pfdhfr/Pfdhps genes followed by targeted amplicon sequencing. Published data since 2007 on the prevalence of the Pfdhps genotypes in Nigeria and the neighbouring countries were used to produce maps to show the distribution of the mutant genotypes.ResultsOnly 74 and 61 samples were successfully amplified for the Pfdhfr and Pfdhps genes, respectively. At codons resulting in N51I, C59R, and S108N, Pfdhfr carried mutant alleles of 97.3% (72/74), 97.3% (72/74) and 98.6% (73/74), respectively. The Pfdhps gene carried mutations at codons resulting in amino acid changes at 431–436-437–540-581–613; I431V [45.9%, (28/61)], A581G [31.1% (19/61)] and A613S [49.2% (30/61)]. Constructed haplotypes were mainly the triple Pfdhfr mutant 51I-59R-108N (95.9%), and the most common haplotypes observed for the Pfdhps gene were the ISGKAA (32.8%), ISGKGS (8.2%), VAGKAA (14.8%), VAGKAS (9.8%) and VAGKGS (14.8%). In the context of the previously published data, a high prevalence of 431V/581G mutations was found in the study population. It seems quite evident that the Pfdhps 431V, 581G and 613S often co-occur as Pfdhps-VAGKGS haplotype.ConclusionThis study showed that the prevalence of VAGKGS haplotype seems to be increasing in prevalence. If this is similar in effect to the emergence of 581G in East Africa, the efficacy of SP-IPTp in the presence of these novel Pfdhps mutants should be re-assessed.

An in silico quest for next-generation antimalarial drugs by targeting Plasmodium falciparum hexose transporter protein: a multi-pronged approach

The emergence of artemisinin resistance by malaria parasites is a major challenge in the fight against malaria, thus posing serious threat to the public health across the world. To tackle this, antimalarial drugs with unconventional mechanisms are therefore urgently needed. It has been reported that selective starvation of Plasmodium falciparum by blocking the function of hexose transporter 1 (PfHT1) protein, the only known transporter for glucose uptake in P. falciparum, could provide an alternative approach to fight the drug resistant malaria parasites. In this study, three high affinity molecules (BBB_25784317, BBB_26580136 and BBB_26580144) that have shown the best docked conformation and least binding energy with PfHT1 were shortlisted. The docking energy of BBB_25784317, BBB_26580136 and BBB_26580144 with PfHT1 were −12.5, −12.1 and −12.0 kcal/mol, respectively. In the follow up simulation studies, the protein 3D structure maintains considerable stability in the presence of the compounds. It was also observed that the compounds produced a number of hydrophilic and hydrophobic interactions with the protein allosteric site residues. This demonstrates strong intermolecular interaction guided by close distance hydrogen bonds of compounds with Ser45, Asn48, Thr49, Asn52, Ser317, Asn318, Ile330 and Ser334. Revalidation of compounds binding affinity was conducted by more appropriate simulation based binding free energy techniques (MM-GB/PBSA and WaterSwap). Additionally, entropy assay was performed that further strengthen the predictions. In silico pharmacokinetics confirmed that the compounds would be suitable candidates for oral delivery due to their high gastrointestinal absorption and less toxic reaction. Overall, the predicted compounds are promising and could be further sought as antimalarial leads and subjected to thorough experimental investigations.Communicated by Ramaswamy H. Sarma

New Iron Twist to Chloroquine─Upgrading Antimalarials with Immunomodulatory and Antimicrobial Features.

Herein, upgraded chloroquine (CQ) derivatives capable of overcoming Plasmodium resistance and, at the same time, suppressing excessive immune response and risk of concurrent bacteremia were developed. Twelve new ferrocene-CQ hybrids tethered with a small azathia heterocycle (1,3-thiazolidin-4-one, 1,3-thiazinan-4-one, or 5-methyl-1,3-thiazolidin-4-one) were synthesized and fully characterized. All hybrids were evaluated for their in vitro antiplasmodial, antimicrobial, and immunomodulatory activities. Additional assays were performed on selected hybrids to gain insights into their mode of action. Although only hybrid 4a was more potent than the parent drug toward CQ-resistant Dd2 Plasmodium falciparum strain, several other hybrids (such as 6b, 6c, and 6d) manifested substantially improved antimicrobial and immunomodulatory properties. Interesting structure-activity relationship data were obtained, hinting at future research for the development of new multitarget chemotherapies for malaria and other infectious diseases complicated by drug resistance, bacterial co-infection, and immune-driven pathology issues.

Evolution of Plasmodium vivax and resistance patterns for infection based on Duffy genotype and phenotype.

The Duffy protein, a transmembrane molecule, acts as a receptor for various chemokines and facilitates binding between reticulocytes and the Plasmodium Duffy antigen binding protein. Duffy expression is associated with the Duffy chemokine receptor antigen genotype on chromosome 1 and exhibits variation across different geographic regions. Traditionally, the Duffy negative genotype and phenotype have been described to confer a certain level of protection against infection and symptom development. However, recent data suggest a shift in this behavior, with significantly higher prevalence observed in individuals with Duffy negative genotype or phenotype. Given that malaria is an endemic vector-borne disease in regions of Asia, Africa, and Latin America, posing a substantial global burden of disease and prioritizing public and global health, identifying evolutionary changes in infection and resistance patterns holds great importance for the design of strategies and reevaluation of conventional interventions. Hence, the aim of this review was to analyze the evolution of Plasmodium vivax and infection resistance patterns based on Duffy genotype and phenotype. The distribution of genotypes, phenotypes, and polymorphisms of P. vivax ligands and erythrocyte receptors varies geographically, notably resistance patterns of this microorganism in individuals with Duffy negative genotype and phenotype have significantly changed compared to studies conducted 30 years ago. The prevalence of vivax malaria in individuals with a Duffy negative status can reach up to 100%. Consequently, prioritizing research on this topic is essential for public health.

Naphthyl bearing 1,3,4-thiadiazoleacetamides targeting the parasitic folate pathway as anti-infectious agents: in silico, synthesis, and biological approach.

Malaria is still a complex and lethal parasitic infectious disease, despite the availability of effective antimalarial drugs. Resistance of malaria parasites to current treatments necessitates new antimalarials targeting P. falciparum proteins. The present study reported the design and synthesis of a series of a 2-(4-substituted piperazin-1-yl)-N-(5-((naphthalen-2-yloxy)methyl)-1,3,4-thiadiazol-2-yl)acetamide hybrids for the inhibition of Plasmodium falciparum dihydrofolate reductase (PfDHFR) using computational biology tools followed by chemical synthesis, structural characterization, and functional analysis. The synthesized compounds were evaluated for their in vitro antimalarial activity against CQ-sensitive PfNF54 and CQ-resistant PfW2 strain. Compounds T5 and T6 are the most active compounds having anti-plasmodial activity against PfNF54 with IC50 values of 0.94 and 3.46 μM respectively. Compound T8 is the most active against the PfW2 strain having an IC50 of 3.91 μM. Further, these active hybrids (T5, T6, and T8) were also evaluated for enzyme inhibition assay against PfDHFR. All the tested compounds were non-toxic against the Hek293 cell line with good selectivity indices. Hemolysis assay also showed non-toxicity of these compounds on normal uninfected human RBCs. In silico molecular docking studies were carried out in the binding pocket of both the wild-type and quadruple mutant Pf-DHFR-TS to gain further insights into probable modes of action of active compounds. ADME prediction and physiochemical properties support their drug-likeness. Additionally, they were screened for antileishmanial activity against L. donovani promastigotes to explore broader applications. Thus, this study provides molecular frameworks for developing potent antimalarials and antileishmanial agents.

Structure-based scoring of anthocyanins and molecular modeling of PfLDH, PfDHODH, and PfDHFR reveal novel potential P. falciparum inhibitors

Resistance of malaria parasites to antimalarial drugs is a huge public health concern. Partial resistance of Plasmodium falciparum to artemisinin has been reported in many malaria-endemic regions. Therefore, there is a need to develop new and potent treatments which possibly target multiple genes of the parasite simultaneously. This study aimed to identify compounds with potential inhibitory interaction with P. falciparum lactate dehydrogenase (PfLDH), dihydroorotate dehydrogenase (PfDHODH), and dihydrofolate reductase (PfDHFR). Anthocyanins, a class of flavonoids were engaged to elucidate their inhibitory potential on these targets. In silico screening was performed on the selected targets and phytoligands. Following that, an additional MM-GBSA technique was used to re-score the interactions and determine the binding free energy and spontaneity of the reactions. Five compounds with outstanding binding affinities were identified for each target. The compounds demonstrated excellent binding data in comparison to the co-crystallized ligand., yielding outstanding findings, delphinidin 3,5-O-diglucoside and cyanidin 3-O-diglucoside-5-O-glucoside with −15.253 and −13.430 docking score, respectively were the compounds with the highest score. Also, the induced fit docking result shows low standard deviations. Highest bindinf affinity was recorded in PfDHFR complexes (−80.76, −67.76, −69.21, −66.06, and −67.72 kcal/mol for delphinidin 3,5-O- glucosidel, cyaniding 3-O-diglucoside-5-O-glucoside, pelargonidin 3-O-rutinoside, cyanidin 3,5-O-diglucoside and cyaniding 3-O-(6″-caffeoyl-glucoside)). Additional pharmacokinetic testing anticipated moderate profiles. The findings in this study suggest that the reported compounds can be employed in combination therapy to develop good antimalarial drugs by targeting different genes of the parasite. Hence, further exploratory analyses are recommended to validate these findings.

Pharmacokinetic Profiling of Prepared Artemisinin-Loaded Poly(lactic co-glycolic acid) Nanoparticles in Mice Infected with Artemisinin-Sensitive and-Resistant Plasmodium berghei K173 Using by HPLC-MS/MS Assay

Low solubility and bio-availability of artmisinin (ART) limit the clinical efficacy and unfortunately, the resistance of Plasmodium to ART has been gradually reported in recent years. In order to improve its dissolvebility, we therefore prepared ART-loaded poly(lactic co-glycolic acid) (PLGA) nanoparticles and characterized them. Later, the pharmacokinetic differences between ART original materials and artemisinin-loaded nanoparticles in mice infected with ART-sensitive and-resistant Plasmodium berghei K173 were investigated by orally administrated (40 mg/kg) by using a successfully developed and validated LC-MS/MS detection method. ART-loaded nanoparticles exhibited a smooth and spherical shape with average diameters of 193.80±7.65 nm. In vitro release results showed that ART-loaded nanoparticles displayed a stable sustained release effect. Meanwhile, the pharmacokinetic properties of ART-loaded nanoparticles were significantly improved when compared with the crude materials both in two groups. The AUC(0−t) significantly increased 2.91 and 2.85 folds as well as 4.03, 3.61 folds higher half-life period (t1/2) and 2.76, 3.27 folds higher maximum retention time (MRT), respectively. CL, meanwhile, declined 3.33 and 3.33 folds. These results suggested that ART-loaded nanoparticles enhanced the retention of ART in vivo and contributed to its long-lasting antimalarial effect.

Antimalarial Efficacy and Safety of Senna occidentalis (L.) Link Root Extract in Plasmodium berghei-Infected BALB/c Mice.

Emergence of Plasmodium resistance to antimalarial drugs presents a major drawback in efforts to control malaria. To address this problem, there is an urgent and continuous need for the development of new and effective antimalarial agents. Senna occidentalis (L.) link extract has exhibited in vitro antiplasmodial activity in many pharmacological studies. To our knowledge, data on its in vivo antimalarial efficacy is still very limited. A recent study demonstrated that polar extracts from the plant roots inhibit Plasmodium berghei proliferation in a mouse model. This study further describes the efficacy and safety of a methanolic root extract of the plant as an antimalarial agent by demonstrating its effect on hematological, biochemical, and histological parameters of Plasmodium berghei-infected BALB/c mice. Rane's test, a curative approach, was used to evaluate the antimalarial efficacy of Senna occidentalis methanolic root extract in Plasmodium berghei-infected BALB/c mice. The effect of the extract on both hematological and biochemical parameters was evaluated using automated analyzers. Kidney, liver, lung, spleen, and brain tissues were harvested from euthanized mice and examined for changes in organ architecture. This study demonstrates that methanolic root extract of Senna occidentalis significantly inhibited Plasmodium berghei parasitemia in BALB/c mice (p < 0.01). Infected mice that were treated with the extract depicted a significantly low level of total leucocytes (p < 0.01), red blood cell distribution width (p < 0.01), and a significantly high hemoglobin concentration (p < 0.001) compared to the infected animals that were administered with the vehicle only. The infected animals that were treated with the extract exhibited a significantly low level of urea, creatinine, bilirubin, and alkaline phosphatase (p < 0.05), compared to the infected animals that were given the vehicle only. The level of sodium, potassium and chloride ions, lymphocytes, granulocytes, hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein, albumin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total platelets, mean platelet volume (MPV), and platelet distribution width of the infected animals treated with the extract was not significantly different from those of the infected animals that were given the vehicle only (p > 0.05). The extract alleviated organ pathological changes in the infected mice. The extract did not induce any remarkable adverse effect on the growth, hematological, and biochemical parameters of uninfected animals (p > 0.05). In addition, administration of the extract did not alter the gross appearance and histological architecture of the organs, implying that the extract was well tolerated in mice. Senna occidentalis methanolic root extract exhibited good antimalarial activity against Plasmodium berghei and may be safe in mice.

Heparin-Coated Dendronized Hyperbranched Polymers for Antimalarial Targeted Delivery.

The rampant evolution of resistance in Plasmodium to all existing antimalarial drugs calls for the development of improved therapeutic compounds and of adequate targeted delivery strategies for them. Loading antimalarials in nanocarriers specifically targeted to the parasite will contribute to the administration of lower overall doses, with reduced side effects for the patient, and of higher local amounts to parasitized cells for an increased lethality toward the pathogen. Here, we report the development of dendronized hyperbranched polymers (DHPs), with capacity for antimalarial loading, that are coated with heparin for their specific targeting to red blood cells parasitized by Plasmodium falciparum. The resulting DHP-heparin complexes exhibit the intrinsic antimalarial activity of heparin, with an IC50 of ca. 400 nM, added to its specific targeting to P. falciparum-infected (vs noninfected) erythrocytes. DHP-heparin nanocarriers represent a potentially interesting contribution to the limited family of structures described so far for the loading and targeted delivery of current and future antimalarial compounds.