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Ethnopharmacological Relevance: Andrographis paniculata (AP) ((Burm f.) Wall. ex Nees) is a medicinal plant, documented for its folkloric use in the treatment of malaria., Aim: This study was designed to determine the potency of extract and fractions of A. paniculata (AP) as a curative, both for susceptible and resistant malaria and to also determine the plant's mechanism of action. This study was also designed to determine whether AP extract and its most potent fraction will mitigate infection-mediated mitochondrial dysfunction, and to assess the phytochemical constituents of the most potent fraction., Materials and Methods: n-Hexane, dichloromethane, ethylacetate and methanol were used to partition the methanol extract of A. paniculata. Graded doses of these extract and fractions were used to treat mice infected with chloroquine-sensitive strain of P. berghei in a curative model. The most potent fraction was used to treat mice infected with resistant (ANKA strain) P. berghei. Inhibition of hemozoin formation, reversal of mitochondrial dysfunction and antiinflammatory potentials were determined. A combination of ultraperformance liquid chromatography-quadrupole time of flight-mass spectrometry and nuclear magnetic resonance spectroscopy were used for chemical analysis., Results: Microscopy revealed that the dichloromethane fraction decreased the parasite burden the most, and inhibition of the hemozoin formation is one of its mechanisms of action. The dichloromethane fraction reversed parasite-induced mitochondrial pore opening in the host, enzyme-dependent ATP hydrolysis and peroxidation of host mitochondrial membrane phospholipids as well as its antiinflammatory potentials. The UPLC-qTOF-MS report and NMR fingerprints of the dichloromethane fraction of A. paniculata yielded fourteen compounds of which sibiricinone C was identified from the plant for the first time., Conclusion: Fractions of A. paniculata possess antiplasmodial effects with the dichloromethane fraction having the highest potency. The potent effect of this fraction may be attributed to the phytochemicals present because it contains terpenes implicated with antimalarial and antiinflammatory activities., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: The spread of antimalarial drug resistance parasites is a major obstacle in eliminating malaria in endemic areas. This increases the urgency for developing novel antimalarial drugs with improved profiles to eliminate both sensitive and resistant parasites in populations. The invention of the drug candidates needs a model for sensitive and resistant parasites on a laboratory scale., Methods: Repeated Incomplete Treatment (RIcT) method was followed in raising the rodent malaria parasite, Plasmodium berghei, resistant to sulfadoxine. Plasmodium berghei were exposed to an adequate therapeutic dose of sulfadoxine without finishing the treatment to let the parasite recover. Cycles of drug treatment and parasite recovery were repeated until phenotypic resistance appeared., Results: After undergoing 3-4 cycles, phenotypic resistance was not yet found in mice treated with sulfadoxine. Nevertheless, the molecular biology of dhps gene (the target of sulfadoxine) was analyzed at the end of the RIcT cycle. There was no mutations found in the gene target. Interestingly, the appearance of gametocytes at the end of every cycle of drug treatment and parasite recovery was observed. These gametocytes later on would no longer extend their life in the RBC stage, unless mosquitoes bite the infected host. This phenomenon is similar to the case in human malaria infections treated with sulfadoxine-pyrimethamine (SP)., Conclusions: In this study, the antimalarial drug sulfadoxine induced gametocytogenesis in P. berghei, which could raise the risk factor for malaria transmission., (© 2024. The Author(s).)

Bovine lactoferrin (bLF) is a 77 kDa glycoprotein that is abundant in bovine breast milk and exerts various bioactive functions, including antibacterial and antiviral functions. Few studies have explored bLF activity against parasites. We found that bLF affects hemozoin synthesis by binding to heme, inhibiting heme iron polymerization necessary for Plasmodium berghei ANKA survival in infected erythrocytes, and also binds to hemozoin, causing it to disassemble. In a challenge test, bLF administration inhibited the growth of murine malaria parasites compared to untreated group growth. To determine whether the iron content of bLF affects the inhibition of malaria growth, we tested bLFs containing different amounts of iron (apo-bLF, native-bLF, and holo-bLF), but found no significant difference in their effects. This indicated that the active sites were located within the bLFs themselves. Further studies showed that the C-lobe domain of bLF can inhibit hemozoin formation and the growth of P. berghei ANKA. Evaluation of pepsin degradation products of the C-lobe identified a 47-amino-acid section, C-1, as the smallest effective region that could inhibit hemozoin formation. This study highlights bLF's potential as a novel therapeutic agent against malaria, underscoring the importance of its non-iron-dependent bioactive sites in combating parasite growth., (© 2024. The Author(s).)

This research aimed to produce and analyze zinc oxide nanoparticles (ZNPs) loaded with linalool (LZNPs), and to evaluate their in vitro and in vivo efficacy through targeting the inflammation and oxidative stress. LZNPs were synthesized using an ethanolic solution of polyvinyl alcohol. The Malstat technique was used to evaluate the effectiveness of LZNPs against both sensitive and resistant strains of Plasmosium falciparum. In vivo effects of ZNPs and LZNPs on parasite growth suppression, survival rate, oxidative stress markers, antioxidant genes, and gene and protein levels of inflammatory cytokines were evaluated by Real-time PCR and Western blot techniques. The results indicated that LZNPs demonstrated noteworthy (P < 0.001) antiplasmodial activity against both susceptible and resistant strains of P. falciparum. P. berghei NK65 strain-infected mice treated with the ZNPs and LZNPs at doses of 5-15 mg/kg notably (p < 0.001) increased the survival rates and parasite growth suppression. LZNPs at 5-15 mg/kg demonstrated a significant (p < 0.001) decrease in oxidative stress markers, increased the expression level of antioxidant genes, and reduced the gene and protein expression level of inflammatory cytokines. The current experimental study demonstrated the potent in vitro antiplasmodial activity of LZNPs against chloroquine-resistant and sensitive strains of P. falciparum compared to ZNPs alone. Additionally, the study identified the potential benefits of this nanocomposite in suppressing the parasite and extending the survival rate in mice infected with P. berghei by targeting inflammation and oxidative stress. It also showed minimal toxicity in liver and kidney function in healthy mice. Nevertheless, further research is essential to elucidate the comprehensive mechanisms and practical effectiveness of LZNPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Malaria eradication has been a major goal of the Indonesian government since 2020. Medicinal plants, such as Strychnos lucida R. Br., are empirically used to treat malaria through traditional preparation methods. However, the safety and efficacy of these plants have not yet been confirmed. Therefore, further investigations are necessary to confirm the safety and efficacy of S. lucida as an antimalarial agent., Aims of the Study: To quantify the concentration of brucine in the S. lucida extract, determine the acute oral toxicity of the standardized extract, and evaluate the in vivo antimalarial potency of S. lucida tablet (SLT)., Materials and Methods: Acute oral toxicity of S.lucida extract was determined using the Organization for Economic Co-operation and Development 420 procedure, and the analytical method for brucine quantification was validated using high-performance liquid chromatography. In addition, antimalarial activity was determined using the Peter's four-day suppressive method., Results: Acute toxicity analysis revealed S. lucida as a low-toxicity compound with a cut-off median lethal dose of 2000-5000 mg/kg body weight [BW], which was supported by the hematological and biochemical profiles of the kidneys, liver, and pancreas (p > 0.05). Extract standardization revealed that S. lucida contained 3.91 ± 0.074% w/w brucine, adhering to the limit specified in the Indonesian Herbal Pharmacopeia. Antimalarial test revealed that SLT inhibited the growth of Plasmodium berghei by 27.74-45.27%. Moreover, SLT improved the hemoglobin and hematocrit levels. White blood cell and lymphocyte counts were lower in the SLT-treated group than in the K (+) group (p < 0.05)., Conclusion: Histopathological and biochemical evaluations revealed that S. lucida extract was safe at a dose of 2000 mg/kg BW with low toxicity. SLT inhibited Plasmodium growth and improved the hemoglobin, hematocrit, and red blood cell profiles. Additionally, SLT reduced the lymphocyte and WBC counts and increased the monocyte and thrombocyte counts as part of the immune system response against Plasmodium infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Infection with Plasmodium falciparum is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming inflammatory response and mechanical obstruction of cerebral microvascular. PI3Kγ is a critical component of intracellular signal transduction and plays a central role in regulating cell chemotaxis, migration, and activation. The purpose of this study was to examine the relationship between inhibiting the PI3Kγ pathway and the outcome of experimental cerebral malaria (ECM) in C57BL/6J mice infected with the mouse malaria parasite, Plasmodium berghei ANKA. We observed that oral administration of the PI3Kγ inhibitor IPI549 after infection completely protected mice from ECM. IPI549 treatment significantly dampened the magnitude of inflammatory responses, with reduced production of pro-inflammatory factors, decreased T cell activation, and altered differentiation of antigen-presenting cells. IPI549 treatment protected the infected mice from neuropathology, as assessed by an observed reduction of pathogenic T cells in the brain. Treating the infected mice with IPI549 three days after parasite inoculation improved the murine blood brain barrier (BBB) integrity and helped the mice pass the onset of ECM. Together, these data indicate that oral administration of the PI3Kγ inhibitor IPI549 has a suppressive role in host inflammation and alleviates cerebral pathology, which supports IPI549 as a new malaria treatment option with potential therapeutic implications for cerebral malaria., Competing Interests: Declaration of competing interest The research was conducted without commercial or financial relationships for any of the authors. Contributions from all authors were reviewed and approved before the article was submitted. The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Malaria remains a major public health issue worldwide, with high rates of morbidity and mortality. The resistance of Plasmodium parasites to commonly used antimalarial drugs has necessitated the development of novel drugs and targets for malaria treatment. Lycopene is a natural compound present in tomatoes and other red fruits and vegetables. This study aimed to evaluate the antimalarial activity of lycopene and its co-administration with chloroquine against chloroquine-resistant malaria, as well as to assess its impact on hematological abnormalities associated with malaria infection. The experimental animals for this study were infected with 10 7 NK65 Plasmodium berghei-infected red blood cells via intraperitoneal injection. The animals were then treated with artemether-lumefantrine, chloroquine, and varying doses of lycopene. The study evaluated percentage parasitemia, mean survival time, and various hematological parameters, including red blood cell count, hematocrit, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, red blood cell distribution width - coefficient of variation, red blood cell distribution width - standard deviation, white blood cell count, granulocyte count, lymphocyte count, monocyte count, and procalcitonin level. The study revealed that lycopene demonstrated significant (p < 0.05) antimalarial activity and the ability to ameliorate hematological abnormalities associated with acute malaria infection. The findings of this study highlight the potential of lycopene as a novel antimalarial agent. The results of this study may contribute to the development of new drugs for malaria treatment, particularly in low- and middle-income countries., Competing Interests: Declaration of competing interest The Authors declare that there is no conflict of interest regarding the research, authorship and publication of this article., (Copyright © 2023. Published by Elsevier B.V.)

Oxidative stress is involved in the pathogenesis of malaria, causing anemia, respiratory complications, and cerebral malaria. To mitigate oxidative stress, we investigated the effect of nutritional supplementation whit lycopene (LYC) on the evolution of parasitemia and survival rate in mice infected with Plasmodium berghei ANKA (Pb), comparing to the effects promoted by N-acetylcysteine (NAC). Therefore, 175 mice were randomly distributed into 4 groups; Sham: untreated and uninfected animals; Pb: animals infected with Pb; LYC+Pb: animals treated with LYC and infected with Pb; NAC+Pb: animals treated with NAC and infected with Pb. The animals were followed for 12 days after infection, and survival and parasitemia rates were evaluated. There was a 40.1% increase in parasitemia in the animals of the Pb group on the 12th day, and a survival rate of 45%. LYC supplementation slowed the development of parasitemia to 19% and promoted a significative increase in the survival rate of 80% on the 12th day after infection, compared to the Pb group, effects superior to those promoted by NAC, providing strong evidence of the beneficial effect of LYC on in vivo malaria and stressing the importance of antioxidant supplementation in the treatment of this disease.

Background: Malaria continues to wreak havoc on the well-being of the community. Resistant parasites are jeopardizing the treatment. This is a wake-up call for better medications. Folk plants are the key starting point for antimalarial drug discovery. After crushing and mixing the leaves of Coriandrum sativum with water, one cup of tea is drunk daily for a duration of three to five days as a remedy for malaria by local folks in Ethiopia. Additionally, in vitro experiments conducted on the plant leaf extract elsewhere have also demonstrated the plant's malaria parasite inhibitory effect. There has been no pharmacologic research to assert this endowment in animals, though. This experiment was aimed at evaluating the antimalarial efficacy of C. sativum in Plasmodium berghei infected mice., Methods: The plant's leaf was extracted using maceration with distilled water. The extract was examined for potential acute toxicity. An evaluation of secondary phytoconstituents was done. Standard antimalarial screening models (prophylactic, chemosuppressive, curative tests) were utilized to assess the antiplasmodial effect. In each test, thirty mice were organized into groups of five. To the three categories, the test substance was given at doses of 100, 200 and 400 mg/kg/day before or after the commencement of P. berghei infection. Positive and negative control mice were provided Chloroquine and distilled water, respectively. Rectal temperature, parasitemia, body weight, survival time and packed cell volume were ultimately assessed. Analysis of the data was performed using Statistical Package for Social Sciences., Results: No toxicity was manifested in mice. The extract demonstrated a significant inhibition of parasitemia (p < 0.05) in all the models. The inhibition of parasite load was highest with the upper dose in the suppressive test (82.74%) followed by the curative procedure (78.49%). Likewise, inhibition of hypothermia, weight loss hampering, improved survival and protection against hemolysis were elicited by the extract., Conclusions: The results of our experimental study revealed that the aqueous crude leaf extract of C. sativum exhibits significant antimalarial efficacy in multiple in vivo models involving mice infected with P. berghei. Given this promising therapeutic attribute, in depth investigation on the plant is recommended., (© 2024. The Author(s).)

The emergence of clinically drug-resistant malaria parasites requires the urgent development of new drugs. Mosquitoes are vectors of multiple pathogens and have developed resistance mechanisms against them, which often involve antimicrobial peptides (AMPs). An-cecB is an AMP of the malaria-transmitting mosquito genus Anopheles , and we herein report its antimalarial activity against Plasmodium falciparum 3D7, the artemisinin-resistant strain 803, and the chloroquine-resistant strain Dd2 in vitro . We also demonstrate its anti-parasite activity in vivo , using the rodent malaria parasite Plasmodium berghei (ANKA). We show that An-cecB displays potent antimalarial activity and that its mechanism of action may occur through direct killing of the parasite or through interaction with infected red blood cell membranes. Unfortunately, An-cecB was found to be cytotoxic to mammalian cells and had poor antimalarial activity in vivo . However, its truncated peptide An-cecB-1 retained most of its antimalarial activity and avoided its cytotoxicity in vitro . An-cecB-1 also showed better antimalarial activity in vivo . Mosquito-derived AMPs may provide new ideas for the development of antimalarial drugs against drug-resistant parasites, and An-cecB has potential use as a template for antimalarial peptides., Competing Interests: The authors declare no conflict of interest.

The rapid emergence of drug resistance against the mainstream antimalarial drugs has increased the need for development of novel drugs. Recent approaches have embarked on the repurposing of existing drugs to induce cell death via programmed cell death pathways. However, little is known about the ER stress response and programmed cell death pathways of the malaria parasite. In this study, we treated ex vivo Plasmodium berghei cultures with tunicamycin, 5-fluorouracil, and chloroquine as known stress inducer drugs to probe the transcriptional changes of autophagy and apoptosis-related genes (PbATG5, PbATG8, PbATG12, and PbMCA2). Treatments with 5-fluorouracil and chloroquine resulted in the upregulation of all analyzed markers, yet the levels of PbATG5 and PbATG12 were dramatically higher in chloroquine-treated ex vivo cultures. In contrast, tunicamycin treatment resulted in the downregulation of both PbATG8 and PbATG12, and upregulation of PbMCA2. Our results indicate that the malaria parasite responds to various ER stressors by inducing autophagy- and/or apoptosis-like pathways., (© 2024. The Author(s).)

Artemisinin and its derivatives have been commonly used to treat malaria. However, the emergence of resistance against artemisinin derivatives has posed a critical challenge in malaria management. In the present study, we have proposed a combinatorial approach, utilizing pH-responsive acetal-dextran nanoparticles (Ac-Dex NPs) as carriers for the delivery of withaferin-A (WS-3) and artesunate (Art) to improve treatment efficacy of malaria. The optimized WS-3 and Art Ac-Dex NPs demonstrated enhanced pH-responsive release profiles under parasitophorous mimetic conditions (pH 5.5). Computational molecular modeling reveals that Ac-Dex's polymeric backbone strongly interacts with merozoite surface protein-1 (MSP-1), preventing erythrocyte invasion. In-vitro antimalarial activity of drug-loaded Ac-Dex NPs reveals a 1-1.5-fold reduction in IC 50 values compared to pure drug against the 3D7 strain of Plasmodium falciparum. Treatment with WS-3 Ac-Dex NPs (100 mg/kg) and Art Ac-Dex NPs (30 mg/kg) to Plasmodium berghei-infected mice resulted in 78.11 % and 100 % inhibition of parasitemia. Notably, the combination therapy comprised of Art and WS-3 Ac-Dex NPs achieved complete inhibition of parasitemia even at a half dose of Art, indicating the synergistic potential of the combinations. However, further investigations are necessary to confirm the safety and effectiveness of WS-3 and Art Ac-Dex NPs for their successful clinical implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: A global death toll of 608,000 in 2022 and emerging parasite resistance to artemisinin, the mainstay of antimalarial chemotherapy derived from the Chinese herb Artemisia annua, urge the development of novel antimalarials. A clinical trial has found high antimalarial potency for aqueous extracts of A. annua as well as its African counterpart Artemisia afra, which contains only trace amounts of artemisinin. The artemisinin-independent antimalarial activity of A. afra points to the existence of other antimalarials present in the plant. However, the publication was retracted due to ethical and methodological concerns in the trial, so the only evidence for antimalarial activity of A. afra is built on in vitro studies reporting efficacy only in the microgram per milliliter range., Hypothesis: Our study aims to shed more light on the controversy around the antimalarial activity of A. afra by assessing its efficacy in mice. In particular, we are testing the hypothesis that A. afra contains a pro-drug that is inactive in vitro but active in vivo after metabolization by the mammalian host., Methods: Plasmodium berghei-infected mice were treated once or thrice (on three consecutive days) with various doses of A. afra, A. annua, or pure artemisinin., Results: Aqueous powder suspensions of A. annua but not A. afra showed antimalarial activity in mice., Conclusion: Our experiments conducted in mice do not support the pro-drug hypothesis., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier GmbH.)

The spread of malarial parasites resistant to first-line treatments such as artemisinin combination therapies is a global health concern. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one) originally found in the cellular slime mould Dictyostelium discoideum. We previously showed that some derivatives of DIF-1, particularly DIF-1(+2) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) octan-1-one), exert potent antimalarial activities. In this study, we synthesised DIF-1(+3) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) nonan-1-one). We then evaluated the effects of DIF-1(+3) in vitro on Plasmodium falciparum and in vivo over 7 days (50-100 mg/kg/day) in a mouse model of Plasmodium berghei. DIF-1(+3) exhibited a half-maximal inhibitory concentration of approximately 20-30 % of DIF-1(+2) in three laboratory strains with a selectivity index > 263, including in strains resistant to chloroquine and artemisinin. Parasite growth and multiplication were almost completely suppressed by treatment with 100 mg/kg DIF-1(+3). The survival time of infected mice was significantly increased (P = 0.006) with no apparent adverse effects. In summary, addition of an acyl group to DIF-1(+2) to prepare DIF-1(+3) substantially enhanced antimalarial activity, even in drug-resistant malaria, indicating the potential of applying DIF-1(+3) for malaria treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Plasmodium resistance to antimalarial drugs raises the urgent need to seek for alternative treatments. Aqueous extract of Hibiscus asper leaves is currently used in malaria management but remains less documented., Aim of the Study: The study aims to evaluate antimalarial effects of the aqueous extract of Hibiscus asper. UHPLC/MS, was used to identify some likely compounds present in the plant that were thereafter docked to some malaria parasite proteins., Study Design: In vitro anti-plasmodium and antioxidant, UHPLC/Ms analysis, in vivo antimalarial of the plant extract, and in silico molecular docking prediction of some identified compounds were performed to investigate the pharmacological effects of H. asper., Material and Methods: The in vitro antiplasmodial activity of the extract was carried out on Plasmodium falciparum strains using SYBR-green dye; then, the curative antimalarial activity was conducted on Plasmodium berghei NK65-infected male Wistar rats. The UHPLC/MS analysis was used to identify plant compounds, followed by interactions (docking affinity) between some compounds and parasitic enzymes such as P. falciparum purine nucleoside phosphorylase (2BSX) and 6-phosphogluconate dehydrogenase (6FQY) to explore potential mechanisms of action at the molecular level., Results: No hemolysis effect of the extract was observed at concentrations up to 100 mg/mL. In vitro test of the aqueous leaves extract of H. asper showed inhibitory activity against P. falciparum Dd2 and 3D7 strains with IC 50 values of 19.75 and 21.97 μg/mL, respectively. The curative antimalarial test of the H. asper extract in infected rats exhibited significant inhibition of the parasite growth (p < 0.001) with inhibition percentage of 95.11%, 97.68% and 95.59% at all the doses (50, 100 and 200 mg/kg) respectively. The extract corrected major physiological alterations such as liver and kidney impairments, oxidative stress and architectural disorganization in liver, spleen and kidneys tissues. The UHPLC/MS analysis identified 7 compounds, namely chlorogenic acid, azulene, quercetin, rhodine, 1-ethyl-2,4-dimethyl benzene and phthalan. Out of seven compounds identified in the extract quercetin and phthalan showed higher in silico inhibitory activity against P. falciparum purine nucleoside phosphorylase and Plasmodium falciparum 6-phosphosgluconate dehydrogenase parasite enzymes., Conclusion: These findings indicate that H. asper could be a promising complementary medicine to manage malaria. Meanwhile, the affinity of annoted compounds with these enzymes should be further confirmed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Parasite-derived new permeation pathways (NPPs) expressed at the red blood cell (RBC) membrane enable Plasmodium parasites to take up nutrients from the plasma to facilitate their survival. Thus, NPPs represent a potential novel therapeutic target for malaria. The putative channel component of the NPP in the human malaria parasite P. falciparum is encoded by mutually exclusively expressed clag3.1/3.2 genes. Complicating the study of the essentiality of these genes to the NPP is the addition of three clag paralogs whose contribution to the P. falciparum channel is uncertain. Rodent malaria P. berghei contains only two clag genes, and thus studies of P. berghei clag genes could significantly aid in dissecting their overall contribution to NPP activity. Previous methods for determining NPP activity in a rodent model have utilised flux-based assays of radioisotope-labelled substrates or patch clamping. This study aimed to ratify a streamlined haemolysis assay capable of assessing the functionality of P. berghei NPPs. Several isotonic lysis solutions were tested for their ability to preferentially lyse infected RBCs (iRBCs), leaving uninfected RBCs (uRBCs) intact. The osmotic lysis assay was optimised and validated in the presence of NPP inhibitors to demonstrate the uptake of the lysis solution via the NPPs. Guanidinium chloride proved to be the most efficient reagent to use in an osmotic lysis assay to establish NPP functionality. Furthermore, following treatment with guanidinium chloride, ring-stage parasites could develop into trophozoites and schizonts, potentially enabling use of guanidinium chloride for parasite synchronisation. This haemolysis assay will be useful for further investigation of NPPs in P. berghei and could assist in validating its protein constituents.

Our previous work identified a series of 12 xanthoquinodin analogues and 2 emodin-dianthrones with broad-spectrum activities against Trichomonas vaginalis , Mycoplasma genitalium , Cryptosporidium parvum , and Plasmodium falciparum . Analyses conducted in this study revealed that the most active analogue, xanthoquinodin A1, also inhibits Toxoplasma gondii tachyzoites and the liver stage of Plasmodium berghei , with no cross-resistance to the known antimalarial targets PfACS, PfCARL, PfPI4K, or DHODH. In Plasmodium , inhibition occurs prior to multinucleation and induces parasite death following 12 h of compound exposure. This moderately fast activity has impeded resistance line generation, with xanthoquinodin A1 demonstrating an irresistible phenotype in both T. gondii and P. falciparum .

Malaria impedes the ability of primary cells of the immune system to generate an efficacious inflammatory and immune response. Black seed ( Nigella sativa ) is a core dietary supplement and food additive in folklore. This study investigated the antioxidant, immunomodulatory, and anti-inflammatory effects of N. sativa cookies in Plasmodium berghei -infected mice. Aqueous extract of black seed was prepared, and the total phenol and flavonoid contents were determined. The mice were infected with standard inoculum of the strain NK65 P. berghei . The mice weight and behavioral changes were observed. The mice were fed with the N. sativa cookies (2.5%, 5%, and 10%) and 10 mg/kg chloroquine for 5 consecutive days after the infection was established. The reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase, catalase, and hematological parameters (red cell indices, leukocytes, and its differentials) in the infected mice were determined. The inflammatory mediators, C-reactive protein (CRP), and myeloperoxidase (MPO) were also assayed. The result revealed that black seed had a total phenol content of 18.73 mgGAE/g and total flavonoid content of 0.36 mgQUE/g. The infected mice treated with N. sativa cookies showed significantly decreased parasitaemia, MDA, and ROS levels. Furthermore, the results showed significant suppression in proinflammatory mediators (CRP and MPO) levels and enhanced antioxidant status of infected mice treated with N. sativa . The study suggests that N. sativa could function as nutraceuticals in the management of Plasmodium infection associated with inflammatory and immunomodulatory disorders.

Purpose: Artemisinin combination therapies, the first-line antimalarials in Nigeria, have reportedly suffered multiple failures in malaria treatment, hence the search for novel combination of other compounds. Methyl gallate and palmatine have been reported to exhibit antiplasmodial activities but the antimalarial activity of their combination has not been evaluated. Therefore, the evaluation of the combination of methyl gallate and palmatine for antimalarial activity in vitro and in vivo in the presence of piperine was carried out., Materials and Methods: The inhibitory potential of methyl gallate and palmatine combination on β-hematin (hemozoin) formation was studied in vitro. Also, the antimalarial activity of methyl gallate and palmatine combination with/without a bioenhancer (piperine) was evaluated in Plasmodium berghei NK65-infected mice., Results: Methyl gallate and palmatine in the ratio 3:2 acted synergistically in vitro and had the highest inhibitory effect (IC 50  = 0.73 µg/mL) on β-hematin (hemozoin) formation. The 3:2 combination of methyl gallate and palmatine exhibited no antimalarial activity in vivo in the absence of piperine but caused reduction in parasitemia that exceeded 40% in the presence of piperine at the dose of 25 mg/kg body weight on days 6 and 8 post-inoculation in mice., Conclusion: The 3:2 combination of methyl gallate and palmatine in the presence of piperine exhibited antimalarial activity in vivo, possibly by synergistic inhibition of hemozoin formation which may cause accumulation of haem within the food vacuole of Plasmodium spp. and its death., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

With the inexorable prevalence and spread of drug-resistant malaria strains, many efforts have been made to find alternative chemotherapeutic agents. In this regard, scientists have developed the concept of hybridization of two or more active pharmacophores into a single chemical compound, resulting in "antimalarial hybrids." The aim of this study was planned based on the highly synergistic effect of the physical hybrid of dihydroartemisinin (DHA) with eosin B (EB). Therefore, a chemical hybrid of the two compounds (DHA-EB) was synthesized, and its antimalarial activity was investigated in vitro and in vivo. The drug hybrid was fabricated through a propionyl ester linker between DHA and EB. The antiplasmodial activity of the new hybrid was tested in vitro on the blood stages of Plasmodium falciparum (chloroquine-sensitive, 3D7 strain) and also evaluated in vivo by Peters' standard test in mice infected with Plasmodium berghei. The hybrid compound was also assessed for in vivo toxicity. Among all the compounds studied, a DHA-EB hybrid showed an appropriate inhibition percentage (53%) was at a very low dose (0.65 nM). The highest in vivo antimalarial activity until the 9 th day was related to DHA-EB in a low dose (0.5 mg/kg). Also, the most survival rate was observed in the test group of hybrid compound at a dose of 1.5 mg/kg for 22 days. No external changes were identified in the toxicity assay. The weight of internal organs of treated animals and that of controls indicated nontoxicity of DHA-EB even after 60 days of consumption. In vitro and in vivo studies substantiated that DHA-EB hybrid has the potential for developing as a safe antimalarial drug., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Three new antiplasmodial compounds, named akedanones A ( 1 ), B ( 2 ), and C ( 3 ), were discovered from the cultured material of Streptomyces sp. K20-0187 isolated from a soil sample collected at Takeda, Kofu, Yamanashi prefecture in Japan. The structures of compounds 1 - 3 were elucidated as new 2,3-dihydronaphthoquinones having prenyl and reverse prenyl groups by mass spectrometry and nuclear magnetic resonance analyses. Compound 1 and the known furanonaphthoquinone I ( 4 ) showed potent in vitro antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with half-maximal inhibitory concentration values ranging from 0.06 to 0.3 μM. Compounds 1 and 4 also displayed potent in vivo antiplasmodial activity against drug-sensitive rodent malaria Plasmodium berghei N strain, with inhibition rates of 47.6 and 43.1%, respectively, on intraperitoneal administration at a dose of 5 mg kg -1 day -1 for 4 days.

In Indonesia, malaria remains a problem, with 94,610 active cases in 2021 and its current therapy includes chloroquine and artemisinin; however, resistance has been commonly reported. To overcome this problem, studies about potential medicinal plants that can be used as antimalaria, such as moringa ( Moringa oleifera ) started to receive more attention. The aim of this study was to investigate the effects of moringa in parasitemia, monocyte activation, and organomegaly on animal model malaria. This experimental study used male Mus musculus , infected by Plasmodium berghei ANKA, as an animal malaria model. The extract was made by maceration of dry moringa leaves, which were then divided into three concentrations: 25%, 50%, and 75%. Dihydroartemisinin-piperazine was used as a positive control treatment, and distilled water as a negative control treatment. The animals were observed for six days to assess the parasitemia count and the number of monocyte activation. On day 7, the animals were terminated, and the liver, spleen, and kidney were weighed. The results showed that the effective concentrations in reducing parasitemia and inducing monocyte activation were 50% and 25% of moringa leaf extract, respectively. The smallest liver and spleen enlargement was observed among animals within the group treated with a 50% concentration of M. oleifera extract. In contrast, the smallest kidney enlargement was observed in the group treated with 25% of M. oleifera extract. Further analysis is recommended to isolate compounds with antimalarial properties in moringa leaves., Competing Interests: All the authors declare that there are no conflicts of interest., (© 2024 by the authors.)

Introduction: Owing to evolution of parasite strains that are resistant to existing antimalarial drugs, research for novel antimalarial medicines is progressing on numerous fronts., Purpose: Herein, we evaluated the in vivo anti-Plasmodium berghei activity of β-ionone including its ameliorative potential towards P. berghei-associated anaemia and oxidative organ damage., Methods: Mice were infected with chloroquine-sensitive strain of P. berghei and then treated with β-ionone at doses of 10 and 20 mg/kg body weight (BW) for seven days. The parasitemia, packed cell volume and redox sensitive biomarkers in the liver, brain and spleen were estimated., Results: Our result showed that β-ionone, in a dose-dependent fashion, significantly (p < 0.05) repressed the multiplication of P. berghei. More so, the compound, at doses of 10 and 20 mg/kg BW, significantly (p < 0.05) mitigated anaemia and organ damage induced by P. berghei., Conclusion: Overall, the findings demonstrated that β-ionone has antiplasmodial actions and plays a mitigative role against P. berghei-induced anaemia and oxidative organ damage., (© 2023. The Author(s) under exclusive licence to Witold Stefański Institute of Parasitology, Polish Academy of Sciences.)

Background: Malaria is still the deadliest parasitic disease caused by Plasmodium spp. Due to drug resistance and their unpleasant side effects, of conventional researchers are enormously seeking to achieve antimalarial drugs with more curative effective, less toxic and cost-affordable drugs using more advanced technology such as nanodrugs., Purpose: The present study aimed to examine the antimalarial effects of a novel synthesized nonochloroquine-loaded curcumin relying on dendrimer G2 in susceptible mice., Methods: Antimalarial activity and toxicity of the nanocomposite were examined on BALB/C mice with microscopy, checking RBCs morphology and related enzymatic activity rate., Results: The maximum inhibitory effect of the nanocomposite was seen at 10 mg/kg, killing 98% of P. berghei compared to sole chloroquine, whereas ED50 was reported at 5.5 mg/kg. The safety of the synthesized nanocomposite was confirmed with biochemical tests with no detrimental effects on mice. The sustainability and longevity of the nanodrug increased significantly with the NDC-CQ assay compared to the control groups., Conclusion: The study showed that nonochloroquine-loaded curcumin had a promising inhibitory effect on P. berghei growth in infected mice compared to standard drugs. However, further studies and clinical trials with large samples are recommended to study different aspects of using nanodrug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The increasing resistance to most antimalarial drugs suggests a need for better alternatives. This study evaluated in vivo antimalarial and liver antioxidant profile of dry plantain leaf extract (Musa paradisiaca) on mice infected with Plasmodium berghei., Methods: Six groups of ten mice each grouped as control, P. berghei, artesunate, and P. berghei infected mice were orally administered 250,500 and 1000mg/kg Musa paradisiaca leaf extract for 5 days. Blood smears were evaluated for parasitaemia on the 10 th day and the mice sacrificed. Catalase, Malondialdehyde, protein, Glutathione peroxidase and reduced glutathione was estimated using Colorimetric, Biuret and spectrophotometric methods respectively with data analyzed using SPSS version 21., Results: Catalase activity (umol/ml/mins) was 24.62 ± 0.99, 10.04 ± 0.50, 19.35 ± 0.38, 22.13 ± 0.00, 22.79 ± 0.00 and 23.66 ± 0.20 while Glutathione Peroxidase(u/l) was 332.34± 0.64, 205.22± 4.61, 218.26± 0.63, 310.59± 0.00, 305.20± 0.00. and 295.97± 0.02 at Control, P.berghei, artesunate, 250mg, 500mg and1000mg extracts. Glutathione (mM) was 1.60 ± 0.12, 0.64 ± 0.09, 1.06 ± 0.16, 0.72 ± 0.00, 0.92 ± 0.00 and 1.26 ± 0.08 while Malondialdehye (uM) was 16.93 ± 3.59, 61.65 ± 1.72, 27.80 ± 0.26, 36.90 ± 0.00, 34.30 ± 0.00 and 32.68 ± 0.27 and Protein(g/dl) was 22.37 ± 1.87, 7.91 ± 0.13, 11.78 ± 1.19, 11.79 ± 0.00, 13.20 ± 0.00 and 17.04 ±0.03 at control, P.berghei, artesunate, 250mg, 500mg and1000mg respectively., Conclusion: The study suggested that ethanolic extract of Musa paradisiaca reduced liver oxidative stress caused by P.berghei., (© 2023 Gerorge- Opuda M.I., et al.)

Ethnopharmacological Relevance: The choice of extraction solvent is a significant consideration in ethnomedicine as optimal extraction could influence the bioactivity of the herbal medicinal product., Aim of Study: This study investigated the possible influence of the choice of solvents (methanol and water) for extracting MAMA Powder (MP) against Plasmodium berghei-infected mice to optimize its antimalarial activity and for developing other pharmaceutical dosage forms., Materials and Methods: Aqueous and methanol extracts of MP, obtained through the decoction and soxhlet methods, respectively, were subjected to liquid chromatography-mass spectroscopy (LC-MS) for their respective fingerprints. The antimalarial activities of the methanol and aqueous extracts (12.5-100 mg/kg) were evaluated orally using the chemosuppressive test model on chloroquine-sensitive Plasmodium berghei-infected mice. The methanol extract was subjected to the established infection and prophylactic antimalarial tests with chloroquine (10 mg/kg) and pyrimethamine (1.25 mg/kg) as positive controls, respectively. The aqueous extract was investigated in chloroquine-resistant P. berghei using the chemosuppressive (12.5-800 mg/kg) and established infection (25-400 mg/kg) antimalarial models., Results: The LC-MS fingerprints of both aqueous and methanol extracts revealed similar indole alkaloid contents. Chemosuppressive activity of the aqueous extract (75.3%) was significantly (p < 0.05) higher than the methanol extract (67.6%). In the chloroquine-resistant P. berghei infection experiments, the aqueous extract (400 mg/kg) exhibited significant parasite clearance (72%)., Conclusion: The study concluded that the water extract with higher antimalarial activity could be optimized for chloroquine-resistant malaria and can thus facilitate the production of liquid and solid dosage forms., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In malaria, anti-parasite immune response of the host may lead to dysregulated inflammation causing severe neuropathology arising from extensive damage to the Blood Brain Barrier (BBB). Use of anti-malarial drugs alone can control parasitemia and reduce inflammation but it cannot reduce pathology if chronic inflammation has already set in. In the present study, we have tested the efficacy of a new oral artemsinin based combination therapy (ACT) regimen using a combination of anti-malarial compounds like nanoartemisinin and nanoallylated-chalcone9 [{1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy) phenyl]-prop-2-en-1-one}]given together with anti-inflammatory-cum- anti-malarial compounds like nanoandrographolide and nanocurcumin to C57BL/6 mice infected with P. berghei ANKA. Untreated infected mice developed Experimental Cerebral Malaria (ECM) and died between 10 to 12 days after infection from severe BBB damage. We observed that oral treatments with nanoartemisinin or nano allylated chalcone 9 or nanoandrographolide alone, for 4 days after the onset of ECM, delayed the development of severe neurolopathology but could not prevent it. Nanocurcumin treatment for 4 days on the other hand, prevented damage to the BBB but the mice died because of hyperparasitemia. A single time oral administration of our ACT controlled blood parasitemia and prevented damage to the BBB, but recrudescence occurred due to persistence of parasites in the spleen. However the recrudescent parasites failed to induce ECM and BBB damage, leading to prolonged survival of the animals. A second time treatment at the start of recrudescence led to complete parasite clearance and survival of mice without pathology or parasitemia for 90 days. FACS analysis of spleen cells and gene expression profile in brain and spleen as well as quantitation of serum cytokine by ELISA showed that P. berghei ANKA infection in C57Bl/6 mice leads to a Th1-skewed immune response that result in severe inflammation and early death from ECM. Oral treatment with our ACT prevented a heightened pro-inflammatory response by modulating the Th1, Th2 and Treg immune responses and prevented ECM and death., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mukherjee, Ray, Saha and Kar.)

Background: Malaria is a global health problem for which novel therapeutic compounds are needed. To this end, a recently published novel family of antiplasmodial macrolides, strasseriolides A-D, was herein subjected to in vivo efficacy studies and preclinical evaluation in order to identify the most promising candidate(s) for further development., Methods: Preclinical evaluation of strasseriolides A-D was performed by MTT-based cytotoxicity assay in THLE-2 (CRL-2706) liver cells, cardiotoxicity screening using the FluxOR™ potassium assay in hERG expressed HEK cells, LC-MS-based analysis of drug-drug interaction involving CYP3A4, CYP2D6 and CYP2C9 isoforms inhibition and metabolic stability assays in human liver microsomes. Mice in vivo toxicity studies were also accomplished by i.v. administration of the compounds (vehicle: 0.5% HPMC, 0.5% Tween 80, 0.5% Benzyl alcohol) in mice at 25 mg/kg dosage. Plasma were prepared from mice blood samples obtained at different time points (over a 24-h period), and analysed by LC-MS to quantify compounds. The most promising compounds, strasseriolides C and D, were subjected to a preliminary in vivo efficacy study in which transgenic GFP-luciferase expressing Plasmodium berghei strain ANKA-infected Swiss Webster female mice (n = 4-5) were treated 48 h post-infection with an i.p. dosage of strasseriolide C at 50 mg/kg and strasseriolide D at 22 mg/kg for four days after which luciferase activity was quantified on day 5 in an IVIS ® Lumina II imager., Results: Strasseriolides A-D showed no cytotoxicity, no carditoxicity and no drug-drug interaction problems in vitro with varying intrinsic clearance (CLint). Only strasseriolide B was highly toxic to mice in vivo (even at 1 mg/kg i.v. dosage) and, therefore, discontinued in further in vivo studies. Strasseriolide D showed statistically significant activity in vivo giving rise to lower parasitaemia levels (70% lower) compared to the controls treated with vehicle., Conclusions: Animal efficacy and preclinical evaluation of the recently discovered potent antiplasmodial macrolides, strasseriolides A-D, led to the identification of strasseriolide D as the most promising compound for further development. Future studies dealing on structure optimization, formulation and establishment of optimal in vivo dosage explorations of this novel compound class could enhance their clinical potency and allow for progress to later stages of the developmental pipeline., (© 2021. The Author(s).)

Malaria, which is caused by protozoa of the genus Plasmodium, remains a major endemic public health problem worldwide. Since artemisinin combination therapies are used as a first-line treatment in all endemic regions, the emergence of parasites resistant to these regimens has become a serious problem. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone originally found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivatives exhibit a range of biological activities. In the present study, we investigated the effects of 41 DIF derivatives on the growth of Plasmodium falciparum in vitro using four laboratory strains and 12 field isolates. Micromolar concentrations of several DIF derivatives strongly suppressed the growth of the four laboratory strains, including strains that exhibited resistance to chloroquine and artemisinin, as well as strains that were susceptible to these drugs. In addition, DIF-1(+2), the most potent derivative, strongly suppressed the growth of 12 field isolates. We also examined the effects of DIF-1(+2) on the activity of the rodent malarial parasite Plasmodium berghei in mice. Intraperitoneal administration of DIF-1(+2) over 4 days (50 or 70 mg/kg/day) significantly suppressed the growth of the parasite in the blood with no apparent adverse effects, and a dose of 70 mg/kg/day significantly prolonged animal survival. These results suggest that DIF derivatives, such as DIF-1(+2), could serve as new lead compounds for the development of antimalarial agents., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Plant-derived antimalarials are indispensable for malaria treatment and a platform for new drugs. The present study explores sinigrin, for malaria using in vitro, in silico and in vivo strategies and the immune response generated after administration. The compound exhibited promising activity against chloroquine (CQ)-resistant (RKL-9) IC 50 5.14 μg/mL and CQ-sensitive (3D7) IC 50 5.47 μg/mL strains of P. falciparum and was safe in both in vitro (CC 50  > 640 μg/mL) and in vivo (LD 50  > 2 g/kg) toxicity studies. In addition, virtual screening showed hydrogen bonding, hydrophobic and van der Waals interactions with amino acid residues of 3BPM (falcipain-3). In vivo studies revealed promising antimalarial activity of sinigrin (200 mg/kg) with 87.44% chemo-suppression on day 5 and significantly (p < 0.0001) enhanced the mean survival time (21 ± 4.74 days) in contrast to the infected control (5.4 ± 1.14 days). In combination therapy, sinigrin (100 mg/kg and 200 mg/kg) augmented the efficacy of artesunate (AS 50 mg/kg) with 100% survival and no recrudescence. These observations are further corresponded and supported by DLC, NO production, cytokine analysis, biochemical and histopathological studies. Treatment with the combination resulted in a regulated interplay of immune cells and cytokines aiding in parasite clearance in addition to its specific inhibitory activity. We report the antimalarial activity of sinigrin first time with best D-score against falcipain-3. These findings highlight sinigrin as a HIT molecule, which may potentially be used in drug and vaccine development approaches., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Malaria remains one of the most important parasitic diseases in the world. The multidrug-resistant Plasmodium strains make the treatment currently available for malaria less effective. Therefore, the development of new drugs is necessary to overcome therapy resistance. Triazole derivatives exhibit several biological activities and provide a moiety that is promising from the biological perspective. Due to the structural similarity to NADH, it is believed that triazoles can bind to the active site of the Plasmodium lactate dehydrogenase (pLDH) enzyme. The present work evaluates the antimalarial activity of 1,2,3-triazole derivatives by in silico, in vitro, and in vivo studies. Preliminary in silico ADMET studies of the compounds demonstrated good pharmacokinetic properties. In silico docking analysis against LDH of Plasmodium berghei (PbLDH) showed that all compounds presented interactions with the catalytic residue in the active site and affinity similar to that presented by chloroquine; the most common antimalarial drug. Cytotoxicity and hemolysis by these derivatives were evaluated in vitro. The compounds 1, 2, 5, 8, and 9 proved to be non-cytotoxic in the performed tests. In vivo antimalarial activity was evaluated using mice infected with Plasmodium berghei NK65. The five compounds tested exhibited antimalarial activity until nine days post-infection. The compound 5 showed promising activities, with about 70% parasitemia suppression. Considering the in vitro and in vivo studies, we believe the compound 5 to be the most promising molecule for further studies in antimalarial chemotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The rise of the resistance of the malaria parasite to the currently approved therapy urges the discovery and development of new efficient agents. Previously we have demonstrated that harmicines, hybrid compounds composed from β-carboline alkaloid harmine and cinnamic acid derivatives, linked via either triazole or amide bond, exert significant antiplasmodial activity. In this paper, we report synthesis, antiplasmodial activity and cytotoxicity of expanded series of novel triazole- and amide-type harmicines. Structure-activity relationship analysis revealed that amide-type harmicines 27, prepared at N-9 of the β-carboline core, exhibit superior potency against both erythrocytic stage of P. falciparum and hepatic stages of P. berghei. Notably, harmicine 27a, m-(trifluoromethyl)cinnamic acid derivative, exhibited the most favourable selectivity index (SI = 1105). Molecular dynamics simulations revealed the ATP binding site of P. falciparum heat shock protein 90 as a druggable binding location, confirmed the usefulness of the harmine's N-9 substitution and identified favourable N-H … π interactions involving Lys45 and the aromatic phenyl unit in the attached cinnamic acid fragment as crucial for the enhanced biological activity. Thus, those compounds were identified as promising and valuable leads for further derivatization in the search of novel, more efficient antiplasmodial agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Ethnopharmacological Relevance: Milk production, processing and consumption are integral part of traditional practices in Fulani tribe of Cameroon. It has been observed that Fulani are resistant to malaria. Dairy products traditionally processed by Fulani are intensively used in the ritual treatment of malarial, inflammations and behavioural disorders. Many studies have demonstrated that fermented milk is a rich source of probiotic bacteria. However, the antimalarial activity of probiotics isolated from this natural source has not been experimentally tested., Aim of the Study: Hence, this study was therefore aimed at evaluating the antimalarial activity of a probiotic bacterium Lactobacillus sakei isolated from traditionally fermented milk in mice infected with chloroquine sensitive Plasmodium berghei ANKA., Materials and Methods: The probiotic bacterium was isolated from the Cameroonian Mborro Fulani's traditionally fermented milk and identified using the 16S r RNA gene sequencing. The schizontocidal activity of Lactobacillus sakei on established malaria infection was evaluated. Eighty-four healthy young adult Balb/c mice infected with Plasmodium berghei parasite were randomly divided into two sets of seven group of six mice each, and were given three different doses of Lactobacillus sakei, chloroquine and sulfadoxine/pyrimethamine for seven and fourteen days respectively. The level of parasitaemia, body temperature, survival time and haematological parameters were evaluated., Results: The parasite growth inhibition was observed to increase with increasing dose of probiotic bacterium with maximum suppression being 100 % at dose 3 on day 20. Also, the probiotic bacterium significantly prevented body weight loss and was associated with body temperature reduction and prevented (p<0.05) a decrease in haematological parameters compared to that untreated malaria infected mice., Conclusion: The results obtained suggest that Lactobacillus sakei is a probiotic bacterium with antimalarial activity in mice infected with chloroquine sensitive Plasmodium berghei., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Malaria remains a dire health challenge, particularly in sub-Saharan Africa. In Uganda, it is the most ordinary condition in hospital admission and outpatient care. The country's meager health services compel malaria patients to use herbal remedies such as Schkuhria pinnata (Lam.) Kuntze ex Thell (Asteraceae). Although in vivo studies tested the antimalarial activity of S. pinnata extracts, plant developmental stages and their effect at different doses remain unknown., Aim of the Study: This study aims to determine the effect of the plant developmental stage on the antimalarial activity of S. pinnata in mice and to document the acute oral toxicity profile., Methods: Seeds of S. pinnata were grown, and aerial parts of each developmental stage were harvested. Extraction was done by maceration in 70% methanol. The antimalarial activity was evaluated using chloroquine-sensitive Plasmodium berghei on swiss albino mice, in a chemosuppressive test, at 150, 350, and 700 mg/kg, p.o. Standard drugs used were artemether-lumefantrine (0.57 + 3.43) mg/kg and chloroquine (10 mg/kg) as positive controls. Distilled water at 1 mL/100g was used as a negative control. The Lorke method was adopted to determine the acute toxicity of extracts., Results: The flowering stage extract had a maximum suppression of parasitemia at 700 mg/kg (68.83 ± 4.49%). Extract at other developmental stages also significantly suppressed the parasitemia (in the ascending order) fruiting (50.71 ± 1.87%), budding (54.92 ± 7.56%), vegetative (55.39 ± 2.01%) compared to the negative control (24.7 ± 2.7%), p < 0.05. Extracts from all developmental stages increased survival time, with the flowering stage having the highest survival time at 20.33 ± 0.88 days. All extracts had an LD 50 of 2157 mg/kg, implying that extracts are safe at lower doses., Conclusion: Together, our findings revealed that the S. pinnata extracts at the flowering stage had superior antimalarial activity compared to other plant developmental stages. Extracts from all developmental stages have demonstrated a dose-dependent suppression of malarial parasites and increased survival time with an LD 50 of 2157 mg/kg. Thus, for better antimalarial activity, local communities could consider harvesting S. pinnata at the flowering stage. Further studies are needed to isolate pure compounds from S. pinnata and determine their antimalarial activity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The leaves of Ranunculus multifidus Forsk. are traditionally used for the treatment of malaria in several African countries. In the present study, 80% methanol (RM-M) and hydrodistilled (RM-H) extracts of fresh leaves from R. multifidus and its major constituent anemonin were tested for their in vivo antimalarial activity against Plasmodium berghei in mice. Anemonin was also tested for its in vitro antimycobacterial activity against Mycobacterium smegmatis and M. abscessus in a microbroth dilution assay, and bacterial growth was analyzed by OD measurement. The isolation of anemonin from RM-H was carried out using preparative thin layer chromatography (PTLC). The chemical structures of anemonin and its hydrolysis product were elucidated using spectroscopic methods (HR-MS; 1D and 2D-NMR). Results of the study revealed that both RM-M and RM-H were active against P. berghei in mice, although the latter demonstrated superior activity ( p < 0.001), as compared to the former. At a dose of 35.00 mg/kg/day, RM-H demonstrated a chemosuppression value of 70% in a 4-day suppressive test. In a 4-day suppressive, Rane's and prophylactic antimalarial tests, anemonin showed median effective doses (ED 50 s) of 2.17, 2.78 and 2.70 μM, respectively. However, anemonin did not inhibit the growth of M. smegmatis and M. abscessus .

Background: In vitro and in vivo testing of new technology was performed to evaluate the antiplasmodial activity of Photonic Multiphase Modulators (PMM) in cultures and in mice previously infected with Plasmodium falciparum and Plasmodium berghei parasites., Methods: Cultures of P. falciparum infected-erythrocytes were exposed overnight to two generations of different APSE™ and BioPhoton-X™ PMM (C#1, R#1, R#2, D8 and D9). Growth of parasites was determined through flow cytometry or microscopy. Mice of the strain C57BL/6 were infected and treated with water exposed to second-generation APSE™ and BioPhoton-X™ PMM plus one previously untested first-generation PMM (AGN10). Parasitemia and weight loss were monitored throughout the infection until death or point of euthanasia was reached. After death, necropsy was performed on all animals and the number of days each survived was recorded., Results: In vitro and in vivo testing using different APSE™- and BioPhoton-X™-designed PMM revealed an effect of D8 in lowering the growth of the parasite in vitro, while the best effect in mice was observed with D9 PMM, with a reduced weight loss and an increase in survival, although the results in lowering the parasitemia were inconclusive. D9 PMM did not generate ROS in vitro., Conclusions: APSE™ and BioPhoton-X™ optic circuit technologies can affect the growth of parasites and show protective effects in mice drinking from water treated with their PMM., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Genetic changes conferring drug resistance are generally believed to impose fitness costs to pathogens in the absence of the drug. However, the fitness of resistant parasites against sulfadoxine/pyrimethamine has been inconclusive in Plasmodium falciparum. This is because resistance is conferred by the complex combination of mutations in dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr), which makes it difficult to separately assess the extent and magnitude of the costs imposed by mutations in dhps and dhfr. To assess the fitness costs imposed by sulfadoxine resistance alone, we generated a transgenic rodent malaria parasite, P. berghei clone harboring an A394G mutation in dhps (PbDHPS-A394G), corresponding to the causative mutation for sulfadoxine resistance in P. falciparum (PfDHPS-A437G). A four-day suppressive test confirmed that the PbDHPS-A394G clone was resistant to sulfadoxine. PbDHPS-A394G and wild-type clones showed similar growth rates and gametocyte production. This observation was confirmed in competitive experiments in which PbDHPS-A394G and wild-type clones were co-infected into mice to directly assess the survival competition between them. In the mosquitoes, there were no significant differences in oocyst production between PbDHPS-A394G and wild-type. These results indicate that the PbDHPS-A394G mutation alters the parasites to sulfadoxine resistance but may not impose fitness disadvantages during the blood stages in mice and oocyst formation in mosquitoes. These results partly explain the persistence of the PfDHPS-A437G mutant in the natural parasite populations., (Copyright © 2021. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Malaria remains one of the most prevalent infectious diseases in tropical regions of the world, particularly in sub-Saharan Africa, where it remains epidemiologically holoendemic. The absence of effective vaccines and Plasmodium resistance to antimalarial drugs have been the major challenges to malaria control measures. An alternative strategy could be the application of validated and standardized herbal formulations., Aim of the Study: To evaluate the antimalarial activity of a polyherbal mixture (APM) and compare it to those of its individual constituent plants., Methods: APM consisted of stem barks of Mangifera indica (MI), Azadirachta indica (AI), Nauclea latifolia (and roots, NL) and roots of Morinda lucida (ML). Dihydroartemisinin-piperaquine (DHP) and pyronaridine-artesunate (PA) served as positive controls. Antimalarial activity was evaluated using suppressive, curative and prophylactic assays in mice infected with Plasmodium berghei., Results: All the herbal mixtures, individually and in combination, showed significant (p < 0.05) antiplasmodial activities in the various assays. They produced considerable parasite suppression (>50%), substantial clearance (>70%), and notable prophylaxis (>60%, except for NL: 35%). APM (95.4-98.7%) and AI (92%), respectively, elicited greater and comparable suppression relative to DHP (88%) and PA (87.3%). However, all the herbal decoctions, individually (72-93.6%) and in combination (82.5-91%), showed lower parasite clearance than DHP (100%) and PA (99.5%). Meanwhile, APM showed relatively greater suppression and prophylaxis than its constituent plants, suggesting that the combination produced synergistic or additive effects., Conclusion: These findings could substantiate the use of these plants, singly or in combination, as traditional remedies for malaria. Further studies are recommended to evaluate their clinical usefulness., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Malaria is a global health problem with the greatest burden in sub-Saharan Africa (sSA). The resistance to available antimalarial agents necessitate for the development of new and safe drugs for which medicinal plants provides credible alternative sources for discovering new and cheap therapeutic agents. Calotropis procera is used in several folk or traditional medicines for the treatment of various diseases across different regions of the world. In Nigeria traditional medicine, C. procera latex is used either alone or in combination with other herbs to cure common diseases including malaria. In Malaka district (Indonesia), Calotropis gigantea (a member of Apocyanceae), is one of the most used herbs to treat malaria patient via the massage method., Aim of the Study: This study aimed to evaluate the anti-plasmodial activity of phosphate buffer extract of Calotropis procera latex in mice infected with Plasmodium berghei., Materials and Methods: The plant's anti-plasmodial agent was extracted using 0.2 M-phosphate buffer (pH 7.0), followed by precipitation using acetone. 90 (ninety) mice were divided into three main groups of 30 (thirty) mice each, used for the curative, suppressive and prophylactic tests, respectively. The 30 (thirty) mice in each of the main groups were sub-divided into five groups of 6 (six) mice. The mice in the group 1, 2 and 3 (test groups) were made to receive graded doses of 25 mg/kg, 50 mg/kg and 75 mg/kg of the extract of C. procera latex intraperitoneally; group 4 (negative control group) received 0.2 ml of normal saline; while group 5 (positive control group) were administered with 5 mg/kg chloroquine. The phytochemical constituents of the plant and its intraperitoneal median lethal dose (LD 50 ) were also undertaken., Results: The freeze-dried acetone extract exhibited acute toxicity with median lethal dose (LD 50 ) of 745 mg/kg body weight in mice. The highest percentage parasite suppression (61.85%), percentage parasite cure (50.26%), and percentage parasite prophylaxis (65.47%), were obtained for the groups treated with 75 mg/kg bodyweight/day of the extract. The least percentage parasite suppression (44.74%), percentage parasite cure (35.21%), and percentage parasite prophylaxis (45.21%), were obtained for the groups treated with 25 mg/kg body weight of the extract. Also, a dose-dependent percentage parasite suppression (53.03%), percentage parasite cure (39.70%), and percentage parasite prophylaxis (49.82%) were obtained for the groups treated with 50 mg/kg body weight. This is comparable to the groups treated with standard chloroquine. The extract also produced a significant elevation in body weight of the animals for suppressive and curative tests. However, there were observable significant decreases in body weight of the animals in the case of prophylactic test., Conclusion: This study showed that the phosphate buffer extract of C. procera latex possess anti-plasmodial activity. The results of this study can be used as a basis for further phytochemical investigations in the search for new and locally affordable antimalarial agents., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Some antimalarial drugs are immune-modulators that impact multiple pathways of innate immunity in malarial treatment. However, information on the immunomodulatory effects of artequine and rutin in the treatment of malaria remains elusive. Twenty-five Swiss mice (18 ± 2 g) were used for this study. Twenty were infected with Plasmodium berghei (NK65). Parasitemia was confirmed, and the animals were grouped (n = 5) as follows: Group A was not infected but treated orally with vehicle. Groups B to E were infected and treated (B) orally with vehicle (10 ml/kg), (C) with 10 mg/kg artequine, (D) with 10 mg/kg of artequine supplemented with 100 mg rutin/kg, and (D) with 10 mg/kg of artequine supplemented with 200 mg rutin/kg, for 7 days. Blood was collected for hematological, inflammatory cytokines, and immunoglobulins G and M assays. Post mitochondrial supernatant fraction was used for antioxidant assays. Rutin co-administration (200 mg/kg) significantly (P < 0.001) increased platelet and neutrophil counts (P < 0.01) but significantly (P < 0.01) decreased white blood cell count and lymphocyte relative to parasitized control. Also, it significantly (P < 0.05) decreased lipid peroxidation, xanthine oxidase, and superoxide dismutase activities but significantly (P < 0.05) increased reduced glutathione and glutathione S-transferase activity. Rutin co-administration also caused a significant (P < 0.001) increase in tumor necrosis factor-alpha, interleukin-6, and immunoglobulin M levels, while interleukin-1β and immunoglobulin G decreased significantly (P < 0.001) compared with parasitized control. These results showed that rutin co-administration with artequine improved host antioxidant status and modulated the immune and inflammatory responses., (© American Society of Parasitologists 2021.)

Hydroxyethylamine (HEA)-based novel compounds were synthesized and their activity against Plasmodium falciparum 3D7 was assessed, identifying a few hits without any apparent toxicity. Hits 5c and 5d also exhibited activity against resistant field strains, Pf RKL-9 and Pf C580Y. A single dose, 50 mg/Kg, of hits administered to the rodent parasite Plasmodium berghei ANKA exhibited up to 70% reduction in the parasite load. Compound 5d tested in combination with artesunate produced an additional antiparasitic effect with a prolonged survival period. Additionally, compound 5d showed 50% inhibition against hepatic P. berghei infection at 1.56 ± 0.56 μM concentration. This compound also considerably delayed the progression of transmission stages, ookinete and oocyst. Furthermore, the toxicity of 5d assessed in mice supported the normal liver and kidney functions. Altogether, HEA analogues ( 5a-m ), particularly 5d , are nontoxic multistage antiplasmodial agents with therapeutic and transmission-blocking efficacy, along with favorable preliminary pharmacokinetic properties.

The consumption of dietary acrylamide (ACR), a carcinogen, results in the dysfunction of various organs and the immune system. However, the impact of ACR exposure on the progression of infectious diseases is unknown. This study investigated the effect of ACR on the progression of malaria infection using a mouse model of malaria. C57BL/6 mice were continuously treated with ACR at a dose of 20 mg/kg bodyweight/day for six weeks (long-term exposure) or phosphate-buffered saline (PBS). Next, the mice were infected with the rodent malaria parasite, Plasmodium berghei NK65 (PbNK). Parasitemia and survival rate were analyzed in the different treatment groups. Magnetic resonance imaging (MRI) and histopathological analyses were performed to evaluate the effect of ACR exposure on the morphology of various organs. Long-term ACR exposure exacerbated PbNK-induced multiorgan dysfunction. MRI and histopathological analysis revealed signs of encephalomeningitis and acute respiratory distress syndrome in the PbNK-infected long-term ACR exposure mice, which decreased the survival rate of mice, but not in the PbNK-infected long-term PBS exposure group. These findings enhance our understanding of the impact of ACR on the progression of infectious diseases, such as malaria., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The quest for the development of a novel antimalarial drug informed the decision to subject phytol to in vivo trials following a demonstration of therapeutic potential against chloroquine sensitive strain of Plasmodium falciparum under in vitro condition. On this basis, the in vivo anti-Plasmodium berghei activity of phytol including the ameliorative effects of the compound on P. berghei-associated anaemia and organ damage were investigated. Mice were infected with chloroquine-sensitive strain of P. berghei and were treated with phytol at a dose of 10 and 20 mg/kg body weight (BW) for four days. The levels of parasitemia, packed cell volume and redox sensitive biomarkers of liver, brain and spleen tissues were determined. Our result revealed that phytol significantly (p < 0.05) suppressed the multiplication of P. berghei in a dose-dependent manner. Additionally, the phytol significantly (p < 0.05) ameliorated the P. berghei-induced anaemia and brain damage. Data from the present study demonstrated that phytol has suppressive effect on P. berghei and could ameliorate some P. berghei-induced pathological changes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1 H -benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1 H -benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei -infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.

Antibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum circumsporozoite protein (CSP Repeat ) can protect against malaria. However, it has also been suggested that the CSP Repeat is a decoy that prevents the immune system from mounting responses against other domains of CSP. Here, we show that, following parasite immunization, B cell responses to the CSP Repeat are immunodominant over responses to other CSP domains despite the presence of similar numbers of naive B cells able to bind these regions. We find that this immunodominance is driven by avid binding of the CSP Repeat to cognate B cells that are able to expand at the expense of B cells with other specificities. We further show that mice immunized with repeat-truncated CSP molecules develop responses to subdominant epitopes and are protected against malaria. These data demonstrate that the CSP Repeat functions as a decoy, but truncated CSP molecules may be an approach for malaria vaccination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine 23 , which exhibited significantly improved in vitro metabolic stability (8 and 42 μL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress parasitemia in the Peters 4-day test with a mean ED 50 value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.

3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains of Plasmodium falciparum (with IC 50 values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in the Plasmodium berghei mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in P. falciparum .

Ethnopharmacological Relevance: Diospyros mespiliformis Hochst. ex A. DC. and Mondia whitei (Hook.f.) Skeels are traditionally used in Africa for the treatment of malaria. However, scientific evidence to substantiate this folkloric claim and their effects on liver mitochondria during malaria treatment have not been reported., Aim of the Study: This study investigated the efficacy of D. mespiliformis and M. whitei against chloroquine-sensitive and resistant strains of malarial parasites in mice. It also investigated the toxicity and protection against cellular organelles like mitochondria., Materials and Methods: Male Swiss mice were infected with a chloroquine resistant (ANKA) strain of Plasmodium berghei and were treated via oral gavage with methanol extracts of D. mespiliformis and M. whitei reconstituted in diluted dimethylsulfoxide as vehicle (DMSO, 5% v/v) for five consecutive days. Percentage parasite load and clearance were assessed by microscopy. The infected control was treated with the vehicle. Hematological indices were assessed using standard procedures. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were determined using assay kits. Hepatic mitochondria were isolated via centrifugation, and their permeability transition (mPT), ATPase (mATPase) activity and lipid peroxidation (mLPO) were determined spectroscopically. Liver tissue histology was carried out by standard laboratory procedures. Phytochemical analysis of both extracts were performed using LC-MS to identify the most prominent compounds from each of the extracts., Results: After treatment on day 5, D. mespiliformis and M. whitei at 400 mg/kg decreased mean values for: percentage parasitemia (5.0 ± 1.0, 2.0 ± 0.2), increased Packed Cell Volume (PCV) (36.0 ± 1.4, 36.0 ± 0.0%) and platelets (2.0 ± 1.4, 2.0 ± 2.8 × 10 5 mm 3 ) relative to the untreated control (20.0 ± 5.2; 30.0 ± 0.0%; 1.4 ± 1.4 × 10 5 mm 3 , respectively). At the same dose, D. mespiliformis and M. whitei decreased ALT (8.0 ± 3.8, 24.2 ± 4.0U/L), AST (6.2 ± 0.8, 8.0 ± 0.9U/L) and ALP (56.0 ± 0.7, 51.0 ± 1.0U/L) activities compared to the infected control (77.0 ± 10.9U/L, 14.0 ± 0.7U/L and 76.0 ± 6.0U/L, respectively). Both D. mespiliformis and M. whitei reversed mPT opening, decreased mATPase enhancement and mLPO, relative to the control. Histopathology of the liver showed extensive hemorrhagic lesions and severe disseminated congestion in the infected control while both D. mespiliformis and M. whitei were well tolerated at the highest dose. The LC-MS analysis of D. mespiliformis showed the presence of betulinic acid, tocopherol and kaempferol with antimalarial and antioxidant properties while the M. whitei sample contained coumarin and chlorogenic acid that have antimalarial and hepato-protective properties., Conclusions: D.mespiliformis and M. whitei show antimalarial effects against resistant Plasmodium berghei infection, enhanced cell viability, mito-protection and are not toxic in mice., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The ancient people of Iwo communities consisting of Ile-Ogbo, Olupona, Iwo and Ogbagba continue to engage in the traditional use of medicinal plants for the treatment and management of common diseases especially malaria., Aims of This Study: This study conducted an ethnomedicinal survey of plants used to treat malaria and feverish conditions by the people of Iwo, Nigeria. It also evaluated the antiplasmodial activity of the morphological parts of Kigelia africana (Lam.) Benth., and isolated, as well as characterised pure compounds from the semi-purified fractions of the fruit extract., Materials and Methods: The ethnomedicinal survey was conducted using semi-structured questionnaires administered to only herb sellers in Iwo, Ile-Ogbo, Olupona, and Ogbagba areas of Osun State. Extracts of K. africana morphological parts; leaf, root, stem bark, and fruit were obtained by cold maceration in methanol, followed by assessment of acute toxicity (LD 50 ) and antiplasmodial activity in Plasmodium berghei infected rats using the 4-day suppressive test model. The most active fruit extract was further subjected to activity-guided fractionation and purification using n-hexane, dichloromethane, ethyl acetate (EtOAc), n-butanol (n-BuOH), and methanol (MeOH) in gradients to obtain the semi-purified fractions and two pure isolated compounds using various chromatographic and spectroscopic techniques., Results and Discussion: From the survey, thirty-one plant species were identified for treating malaria in Iwo area. Azadirachta indica leaf was the most frequently used (78.3% of the respondents) while Manihot esculenta leaf (3.33%) was the least. The identified plants are distributed among 24 families, with Anacardiaceae and Asteraceae (11.67% each) been the most occurring families. Kigelia africana (Bignoniaceae) ranked the 6th position with 60% frequency of occurrence. The LD 50 values obtained for the extracts were greater than 5000 mg/kg (p.o). The chemo-suppression activity of the extracts at 125 mg/kg was in the order of stem bark (26.59%), leaf (41.75%), root (43.95%), and fruit (54.54%). The semi-purified methanol fraction of the fruit showed the most antiplasmodial activity with a percent chemo-suppression of 69.94 and yielded 4-(2,3-dihydroxypropoxy)-3,5-dihydroxy-5-methylfuran-2-one and sucrose., Conclusion: The use of herbs and medicinal plants either singly or in combination for the treatment of malaria among the people of Iwo community in Nigeria is still well practised. Lack of formal education among most of the respondents and use of same local name for different plants species or plant parts; which often lead to wrong plant collection were among the constrains encountered. Kigelia africana has antiplasmodial activity in the order of fruit > root > leaf > stem bark., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Multi-stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine-based families of compounds that combine the structural features of primaquine and chloroquine. Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages of chloroquine-sensitive and -resistant Plasmodium falciparum strains, and against the hepatic stages of Plasmodium berghei, hence acting as dual-stage antiplasmodial hits., (© 2020 Wiley-VCH GmbH.)