Plasmodium Yoelii Nigeriensis Research Articles

Novel saturated 1,2,4-trioxanes and their antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in Swiss mice model via oral route

Novel saturated 6-(4′-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1–3)–12d(1–3) and 13a(1–3)–13d(1–3) have been designed and synthesized, in one single step from diimide reduction of 11a(1–3)–11d(1–3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1, provided 100 % protection to the infected mice at 24 mg/kg × 4 days. The most active compound of the series, trioxane 12b1, provided 100 % protection even at 12 mg/kg × 4 days and 60 % protection at 6 mg/kg × 4 days. The currently used drug, β-arteether provides only 20 % protection at 24 mg/kg × 4 days.

Isoliquiritigenin from licorice root: A multi-stage anti-malarial with synergistic impact on multidrug-resistant P. falciparum

IntroductionMalaria control is hindered by drug-resistant parasites, leading to a shortage of effective drugs. There is a need to find new, better antimalarial drug. Traditional Chinese Medicine (TCM) are more accessible and cheaper alternative for combating resistance in the treatment of malaria, therefore the anti-malarial efficacy of root extracts and isolated phytomolecules from Glycyrrhiza glabra L was assessed. MethodsThe anti-plasmodial potential of root extracts and isolated phytomolecules from Glycyrrhiza glabra L. was assessed using the Giemsa staining method. In- vivo, antimalarial efficacy was evaluated by conducting a four-day suppression test in a mouse model. The mechanistic studies of ISL were carried out using caspase-like activity, mitochondrial membrane potential, and reactive oxygen species (ROS) assay. Further, proteomics analysis was carried out by LC-MS/MS. The interaction of the combinations was evaluated using the fixed ratio method by calculating the fractional inhibitory concentration (FIC). ResultsExtracts of G. glabra contain Phytomolecule(s) with moderate anti-plasmodial activity against multidrug-resistant strain (K1) of P. falciparum. Isoliquiritigenin (ISL) exhibited a significant reduction in parasitemia, resulting in an enhancement of the mean survival time in Plasmodium yoelii nigeriensis infected mice. ISL showed potent activity with no cytotoxic effect and increased caspase-3 activity, leading increasing reactive oxygen species (ROS) and loss of mitochondrial potential. ISL also displayed synergy with chloroquine, glabridin and liquiritigenin against multi-drug-resistant P. falciparum. DiscussionThe present study found ISL to be a potential phytomolecule of G. glabra. The study explored the mechanism of action of ISL and suggested its suitability for further study in managing drug-resistant malaria.

Characteristics of splenic PD-1+ γδT cells in Plasmodium yoelii nigeriensis infection.

Although the functions of programmed death-1 (PD-1) on αβ T cells have been extensively reported, a role for PD-1 in regulating γδT cell function is only beginning to emerge. Here, we investigated the phenotypic and functional characteristics of PD-1-expressing γδT cells, and the molecular mechanism was also explored in the Plasmodium yoelii nigeriensis (P. yoelii NSM)-infected mice. Flow cytometry and single-cell RNA sequencing (scRNA-seq) were performed. An inverse agonist of RORα, SR3335, was used to investigate the role of RORα in regulating PD-1+ γδT cells. The results indicated that γδT cells continuously upregulated PD-1 expression during the infection period. Higher levels of CD94, IL-10, CX3CR1, and CD107a; and lower levels of CD25, CD69, and CD127 were found in PD-1+ γδT cells from infected mice than in PD-1- γδT cells. Furthermore, GO enrichment analysis revealed that the marker genes in PD-1+ γδT cells were involved in autophagy and processes utilizing autophagic mechanisms. ScRNA-seq results showed that RORα was increased significantly in PD-1+ γδT cells. GSEA identified that RORα was mainly involved in the regulation of I-kappaB kinase/NF-κB signaling and the positive regulation of cytokine production. Consistent with this, PD-1-expressing γδT cells upregulated RORα following Plasmodium yoelii infection. Additionally, in vitro studies revealed that higher levels of p-p65 were found in PD-1+ γδT cells after treatment with a RORα selective synthetic inhibitor. Collectively, these data suggest that RORα-mediated attenuation of NF-κB signaling may be fundamental for PD-1-expressing γδT cells to modulate host immune responses in the spleen of Plasmodium yoelii nigeriensis-infected C57BL/6 mice, and it requires further investigation.

Novel amino- and hydroxy-functionalized 1,2,4-trioxanes and their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via intramuscular and oral route

Following the economic and social state of humanity, Malaria is categorized as one of the life-threatening illness epidemics in under developed countries. For the eradication of the same, 1,2,4-trioxanes 17a1-a2, 17b1-b2, 17c1-c2 15a-c, 18 and 19 have been synthesized continuing the creation of a novel series. Additionally, these novel compounds were tested for their effectiveness against the multidrug-resistant Plasmodium yoelii nigeriensis in mice model using both oral and intramuscular (im) administration routes. The two most potent compounds of the series, 17a1 and 17a2, demonstrated 100 % protection at 48 mg/kg x 4 days via oral route, which is twice as potent as artemisinin. In this model artemisinin provided 100 % protection at a dose of 48 mg/kg × 4 days and 80 % protection at 24 mg/kg × 4 days via im route.

Immunological characteristics of CD103+CD8+ Tc cells in the liver of C57BL/6 mouse infected with plasmodium NSM.

CD103 is an important marker of tissue-resident memory T cells (TRM) which play important roles in fighting against infection. However, the immunological characteristics of CD103+ T cells are not thoroughly elucidated in the liver of mouse infected with Plasmodium. Six- to eight-week-old C57BL/6 mice were infected with Plasmodium yoelii nigeriensis NSM. Mice were sacrificed on 12-16days after infection and the livers were picked out. Sections of the livers were stained, and serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were measured. Moreover, lymphocytes in the liver were isolated, and the expression of CD103 was determined by using qPCR. The percentage of CD103 on different immune cell populations was dynamically observed by using flow cytometry (FCM). In addition, the phenotype and cytokine production characteristics of CD103+CD8+ Tc cell were analyzed by using flow cytometry, respectively. Erythrocyte stage plasmodium infection could result in severe hepatic damage, a widespread inflammatory response and the decrease of CD103 expression on hepatic immune cells. Only CD8+ Tc and γδT cells expressed higher levels of CD103 in the uninfected state.CD103 expression in CD8+ Tc cells significantly decreased after infection. Compared to that of CD103- CD8+ Tc cells, CD103+ CD8+ Tc cells from the infected mice expressed lower level of CD69, higher level of CD62L, and secreted more IL-4, IL-10, IL-17, and secreted less IFN-γ. CD103+CD8+ Tc cells might mediate the hepatic immune response by secreting IL-4, IL-10, and IL-17 except IFN-γ in the mice infected with the erythrocytic phase plasmodium, which could be involved in the pathogenesis of severe liver damage resulted from the erythrocytic phase plasmodium yoelii nigeriensis NSM infection.

SHIP1 modulates antimalarial immunity by bridging the crosstalk between type I IFN signaling and autophagy.

Stringent control of the type I interferon (IFN-I) signaling is critical for host immune defense against infectious diseases, yet the molecular mechanisms that regulate this pathway remain elusive. Here, we show that Src homology 2 containing inositol phosphatase 1 (SHIP1) suppresses IFN-I signaling by promoting IRF3 degradation during malaria infection. Genetic ablation of Ship1 in mice leads to high levels of IFN-I and confers resistance to Plasmodium yoelii nigeriensis (P.y.) N67 infection. Mechanistically, SHIP1 promotes the selective autophagic degradation of IRF3 by enhancing K63-linked ubiquitination of IRF3 at lysine 313, which serves as a recognition signal for NDP52-mediated selective autophagic degradation. In addition, SHIP1 is downregulated by IFN-I-induced miR-155-5p upon P.y. N67 infection and severs as a feedback loop of the signaling crosstalk. This study reveals a regulatory mechanism between IFN-I signaling and autophagy, and verifies SHIP1 can be a potential target for therapeutic intervention against malaria and other infectious diseases. IMPORTANCE Malaria remains a serious disease affecting millions of people worldwide. Malaria parasite infection triggers tightly controlled type I interferon (IFN-I) signaling that plays a critical role in host innate immunity; however, the molecular mechanisms underlying the immune responses are still elusive. Here, we discover a host gene [Src homology 2-containing inositol phosphatase 1 (SHIP1)] that can regulate IFN-I signaling by modulating NDP52-mediated selective autophagic degradation of IRF3 and significantly affect parasitemia and resistance of Plasmodium-infected mice. This study identifies SHIP1 as a potential target for immunotherapies in malaria and highlights the crosstalk between IFN-I signaling and autophagy in preventing related infectious diseases. SHIP1 functions as a negative regulator during malaria infection by targeting IRF3 for autophagic degradation.

Molecular and immunological characterization of the calcyclin binding protein in rodent malaria parasite

Malaria remains as a global life-threatening disorder due to the emergence of resistance against standard antimalarials. Consequently, there is a serious need to better understand the biology of the malaria parasite in order to determine appropriate targets for new interventions. Calcyclin binding protein (CacyBP) is a multi-functional and multi-ligand protein that is not well characterized in malaria disease. In this study, we have cloned CacyBP from rodent species Plasmodium yoelii nigeriensis and purified the recombinant protein to carry out its detailed molecular, biophysical and immunological characterization. Molecular characterization indicates that PyCacyBP is a ∼27 kDa protein in parasite lysate and exists in monomer and dimer forms. Bioinformatic analysis of CacyBP showed significant sequence and structural similarities between rodent and human malaria parasites. CacyBP is expressed in all blood stages of P. yoelii nigeriensis parasite. In silico studies proposed the immunogenic potential of CacyBP. The rPyCacyBP immunized mice exhibited elevated levels of IgG1, IgG2a, IgG2b and IgG3 in their serum. Notably, cellular immune response in splenocytes from immunized mice showed increased expression of pro-inflammatory cytokines such as IL-12, IFN-γ and TNF-α. This CacyBP exhibited pro-inflammatory immune response in rodent host. These finding revealed that CacyBP may have the potential to boost the host immunity for protection against malaria infection. The present study provides basis for further exploration of the biological function of CacyBP in malaria parasite.

Characteristics of γδTCR on myeloid cells from C57BL/6 mice with Plasmodium yoelii nigeriensis infection

Recently, there is a paucity of studies focus on the characteristics of myeloid cells which expressed γδTCR. The aim of this study was to observe the properties of γδTCR-expressing myeloid cells in the spleen of C57BL/6 mice infected by P. yoelii nigeriensis NSM. Haematoxylin-eosin (HE) staining was used to observe pathological changes in the spleens from infected mice. The differentially expressed genes (DEGs) between the infection and control groups were analyzed by RNA sequencing (RNA -seq). Flow cytometry (FCM) was used to evaluate the frequency of γδTCR+ cells and the characteristics of γδTCR+ cells in P. yoelii nigeriensis NSM-infected mice. Obvious infiltration of inflammatory were observed in the spleens from infected C57BL/6 mouse. The proportions of γδTCR+ cells and CD11b+ γδTCR+ cells from infected group were higher than that from normal group. CD11b+ γδTCR+ cells expressed high levels of activated-mediated genes and inflammatory-mediated genes. The heterogeneous pathway activities among CD11b+ γδTCR+ cells from normal and infected group were characterized. The oxidative phosphorylation, respiratory electron transport chain and leukocyte activation involved in immune response pathways were up-regulated, while the alpha-beta T cell activation and myeloid leukocyte migration pathways were down-regulated in infected mice. Importantly, Ly6c2 was higher expressed in CD11b+ γδTCR+ cells than Ly6g. Consistent with it, flow cytometry results revealed that a subset of Ly6C+ cells was higher than Ly6G+ cells in the spleen. Taken together, our data suggest the existence of a population of γδTCR-expressing myeloid cells and they might be multifunctional cells, which play a role in couse of Plasmodium infection.

Anti-malarial effect of a combination of risedronate and azithromycin against Plasmodium yoelii nigeriensis infection in Swiss mice.

Combination therapy is used to retard the selection of malaria parasite strains resistant to individual components of a combination of drugs. This approach has proved to be a success in the combination of sulphadoxine and pyrimethamine, which targets two different steps in the folate pathway of malaria parasites. However, after the success of this therapeutic combination, the efficacy of other combinations of drugs that target different enzymes in a particular metabolic pathway has, apparently, not been reported. In the current study, the antimalarial effect of a combination of risedronate (RIS), which is known for its anti-osteoporosis activity, and azithromycin (AZT) was investigated. Peter's suppression test was carried out on mice infected with 1×107P. yoelii infected erythrocytes. Drug efficacy was analyzed by comparing the percent reduction in parasitaemia on day 4 post-infection. RIS was observed to be a blood schizonticidal agent against P. yoelii infection which showed ED50 7.0 (4.04-12.13) mg/kg/day x 4. Normalized isobologram showed additive action between RIS 1mg/kg/day x 4 and AZT 10mg/kg/day x 4, and antagonistic action for the rest of the combinations (RIS 1+AZT 20, RIS 1+AZT 40, RIS 5+AZT 10, RIS 5+AZT 20, RIS 5+AZT 40, RIS 10+AZT 10, RIS 10+AZT 20 and RIS 10+AZT 40mg/kg/day x 4). Furthermore, a combination of RIS with AZT showed inferior efficacy as compared to AZT treatment alone. This antagonistic interaction may be due to the high accumulation of AZT in WBCs, which will reduce its serum bio-availability, whereas RIS has anti-parasitic activity by increasing WBCs.

Pharmacological Study of Azadirachta indica (Neem) for their possible Antimalarial Activity with Emphasis on Resistance and Resistant Reversal

Malaria is one of the deadliest and oldest disease known to mankind for more than 2000 years that causes the death of 0.4 million individuals in 2009. In the era of resistance, multi-drug resistance, finding a new efficacious & potent molecule is always a challenge for Pharmacological science. Researcher across the globe see resistance threat in every molecule. Every drug, molecule whether new or old have resistance possibility. Therefore, researcher in this study tried to understand the behavior of chloroquine-resistant plasmodium yoelii nigeriensis (PYn) which is most experimented & reported animal malaria model equivalent to plasmodium vivax in human with chloroquine & the possibility of resistance reversal for some herbal extracts. 2-20 times chloroquine doses (10-100 mg/ kg) are not able to produce sufficient efficacy in chloroquine resistant PYn. Where 5 mg/ kg dose of chloroquine is effective dose against the chloroquine sensitive dose. Same while, most of the plant extracts are also not able to produce minimal therapeutic response on Chloroquine resistant plasmodium when given alone. However, plant extracts Azadirachta indica (AI) at 300 mg/ kg & 1000 mg/ kg shows a better effect when given with chloroquine 20 mg/ kg then alone. Out of all plant extracts hydroalcoholic extracts of dried leaves & ethanolic extract of dried bark of AI. Current approach of multi-drug dosage supports also supported here in the study with a thought of using antimalarial plant extracts during regular malaria treatment. Genesis of idea of referring standardized plant extract(s) in combination as oral dosage with prophylactic (travelers) malaria & malaria treatment or side-food for malaria will also possible. Positive results may pave a path for inclusion of herbal extracts or herbs as side treatment or drug resistance-breaker food for malaria.

Activation of cGAS-STING by Lethal Malaria N67C Dictates Immunity and Mortality through Induction of CD11b+ Ly6Chi Proinflammatory Monocytes.

Cyclic GMP‐AMP synthase (cGAS) and stimulator of interferon genes (STING) play critical roles in the innate immunity against infectious diseases and are required to link pathogen DNA sensing to immune responses. However, the mechanisms by which cGAS‐STING‐induced cytokines suppress the adaptive immune response against malaria infections remain poorly understood. Here, cGAS‐STING signaling is identified to play a detrimental role in regulating anti‐malaria immunity. cGAS or STING deficiency in mice markedly prolongs mouse survival during lethal malaria Plasmodium yoelii nigeriensis N67C infections by reducing late interleukin (IL)‐6 production. Mechanistically, cGAS/STING recruits myeloid differentiation factor 88 (MyD88) and specifically induces the p38‐dependent signaling pathway for late IL‐6 production, which, in turn, expands CD11b+Ly6Chi proinflammatory monocytes to inhibit immunity. Moreover, the blockage or ablation of the cGAS‐STING‐MyD88‐p38‐IL‐6 signaling axis or the depletion of CD11b+Ly6Chi proinflammatory monocytes provides mice a significant survival benefit during N67C and other lethal malaria‐strain infections. Taken together, these findings identify a previously unrecognized detrimental role of cGAS‐STING‐MyD88‐p38 axis in infectious diseases through triggering the late IL‐6 production and proinflammatory monocyte expansion and provide insight into how targeting the DNA sensing pathway, dysregulated cytokines, and proinflammatory monocytes enhances immunity against infection.

Properties and Roles of γδT Cells in Plasmodium yoelii nigeriensis NSM Infected C57BL/6 Mice.

BackgroundMany kinds of immune cells are involved in malaria infection. γδT cells represent a special type of immune cell between natural and adaptive immune cells that play critical roles in anti-parasite infection.MethodsIn this study, malaria infection model was constructed. Distribution of γδT cells in various immune organs and dynamic changes of γδT cells in the spleens of C57BL/6 mice after infection were detected by flow cytometry. And activation status of γδT cells was detected by flow cytometry. Then γδT cells in naive and infected mice were sorted and performed single-cell RNA sequencing (scRNA-seq). Finally, γδTCR KO mice model was constructed and the effect of γδT cell depletion on mouse T and B cell immunity against Plasmodium infection was explored.ResultsHere, splenic γδT cells were found to increase significantly on day 14 after Plasmodium yoelii nigeriensis NSM infection in C57BL/6 mice. Higher level of CD69, ICOS and PD-1, lower level of CD62L, and decreased IFN-γ producing after stimulation by PMA and ionomycin were found in γδT cells from infected mice, compared with naive mice. Moreover, 11 clusters were identified in γδT cells by scRNA-seq based t-SNE analysis. Cluster 4, 5, and 7 in γδT cells from infected mice were found the expression of numerous genes involved in immune response. In the same time, the GO enrichment analysis revealed that the marker genes in the infection group were involved in innate and adaptive immunity, pathway enrichment analysis identified the marker genes in the infected group shared many key signalling molecules with other cells or against pathogen infection. Furthermore, increased parasitaemia, decreased numbers of RBC and PLT, and increased numbers of WBC were found in the peripheral blood from γδTCR KO mice. Finally, lower IFN-γ and CD69 expressing CD4+ and CD8+ T cells, lower B cell percentage and numbers, and less CD69 expressing B cells were found in the spleen from γδTCR KO infected mice, and lower levels of IgG and IgM antibodies in the serum were also observed than WT mice.ConclusionsOverall, this study demonstrates the diversity of γδT cells in the spleen of Plasmodium yoelii nigeriensis NSM infected C57BL/6 mice at both the protein and RNA levels, and suggests that the expansion of γδT cells in cluster 4, 5 and 7 could promote both cellular and humoral immune responses.

Plasmodium yoelii nigeriensis

This datasheet on Plasmodium yoelii nigeriensis covers Identity, Distribution, Hosts/Species Affected.

Novel hydrazone derivatives of N-amino-11-azaartemisinin with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via intramuscular route

Novel hydrazone derivatives 10a-m were prepared from N-Amino-11-azaartemisinin (9) and screened for their antimalarial activity by oral and intramuscular (i.m.) routes against multidrug-resistant Plasmodium yoelii in Swiss mice model. Several of the hydrazone derivatives showed higher order of antimalarial activity. Compounds 10b, 10g, 10m provided 100% protection to the infected mice at the dose of 24 mg/kg × 4 days via oral route. Fluorenone based hydrazone 10m the most active compound of the series, provided 100% protection at the dose of 6 mg/kg × 4 days via intramuscular route and also provided 100% protection at the dose of 12 mg/kg × 4 days via oral route. While artemisinin gave 100% protection at 48 mg/kg × 4 days and only 60% protection at 24 mg/kg × 4 days via intramuscular (i.m.) route. Compound 10m found to be four-fold more active than artemisinin via intramuscular route.

Reduction of the Double Bond of 6-Arylvinyl-1,2,4-trioxanes Leads to a Remarkable Increase in Their Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii nigeriensis in a Swiss Mice Model.

Novel 6-arylethyl-1,2,4-trioxanes6a–i and 7a–i are easily accessible in one step from the diimide reduction of 6-arylvinyl-1,2,4-trioxanes 5a–i. All of these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in a Swiss mice model. Most of the saturated trioxanes 6c, 6f, 6g, 6h, and 6i, the active compounds of the series, provided 100% protection to the malaria-infected mice at a dose of 24 mg/kg × 4 days. Further, trioxane 6i, the most active compound of the series, also showed 100% protection even at a dose of 12 mg/kg × 4 days and 20% protection at a dose of 6 mg/kg × 4 days. In this model, β-arteether provided 100% protection at a dose of 48 mg/kg × 4 days and only 20% protection at a dose of 24 mg/kg × 4 days via the oral route, which was found to exhibit 4-fold antimalarial activity compared with the currently used drug β-arteether.

Inhibition of heme detoxification pathway in malaria parasite by 3-hydroxy-11-keto-β-boswellic acid isolated from Boswellia serrata

Malaria eradication is still a major global health problem in developing countries, which has been of more concern ever since the malaria parasite has developed resistance against frontline antimalarial drugs. Historical evidence proves that the plants possess a major resource for the development of novel anti-malarial drugs. In the present study, the bioactivity guided fractionation of the oleogum-resin of Boswellia serrata Roxb. yielded the optimum activity in the ethyl acetate fraction with an IC50 of 22 ± 3.9 μg/mL and 26.5 ± 4.5 μg/mL against chloroquine sensitive (NF54) and resistant (K1) strains of Plasmodium falciparum respectively. Further, upon fractionation, the ethyl acetate fraction yielded four major compounds, of which 3-Hydroxy-11-keto-β-boswellic acid (KBA) was found to be the most potent with IC50 values 4.5 ± 0.60 µg/mL and 6.25 ± 1.02 μg/mL against sensitive and resistant strains respectively. KBA was found to inhibit heme detoxification pathways, one of the most common therapeutic targets, which probably lead to an increase in reactive oxygen species (ROS) and nitric oxide (NO) detrimental to P. falciparum. Further, the induced intracellular oxidative stress affected the macromolecules in terms of DNA damage, increased lipid peroxidation, protein carbonylation as well as loss of mitochondrial membrane potential. However, it did not exhibit any cytotoxic effect in VERO cells. Under in vivo conditions, KBA exhibited a significant reduction in parasitemia, retarding the development of anaemia, resulting in an enhancement of the mean survival time in Plasmodium yoelii nigeriensis (chloroquine-resistant) infected mice. Further, KBA did not exhibit any abnormality in serum biochemistry of animals that underwent acute oral toxicity studies at 2000 mg/kg body weight.

Novel naphthyl based 1,2,4-trioxanes: Synthesis and in vivo efficacy in the Plasmodium yoelii nigeriensis in Swiss mice

A new series of 1,2,4-trioxanes 9a1-a4, 9b1-b4, 10–13 and 9c1-c4 were synthesized and evaluated against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via oral and intramuscular (i.m.) routes. Adamantane-based trioxane 9b4, the most active compound of the series, provided 100% protection to the infected mice at the dose 48 mg/kg × 4 days and 100% clearance of parasitemia at the dose 24 mg/kg × 4 days via oral route. Adamantane-based trioxane 9b4, is twice active than artemisinin.We have also studied the photooxygenation behaviour of allylic alcohols 6a-b (3-(4-alkoxynaphthyl)-but-2-ene-1-ols) and 6c (3-[4-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-but-2-en-1-ol). Being behaving as dienes, they furnished corresponding endoperoxides, while behaving as allylic alcohols, they yielded β-hydroxyhydroperoxides. All the endoperoxides (7a-c) and β-hydroxyhydroperoxides (8a-c) have been separately elaborated to the corresponding 1,2,4-trioxanes, except from endoperoxide 7c. It is worthy to note that TBDMS protected naphthoyl endoperoxide 7c unable to deliver 1,2,4-trioxane, which demonstrated the strength of the O-Si bond is not easy to cleave under acidic condition.

Synthesis of novel 1,2,4-trioxanes and antimalarial evaluation against multidrug-resistant Plasmodium yoelii nigeriensis

Malaria epidemics represent one of the life-threatening diseases to low-income lying countries which subsequently affect the economic and social condition of mankind. In continuation in the development of a novel series of 1,2,4-trioxanes 13a1-c1, 13a2-c2, and 13a3-c3 have been prepared and further converted into their hemisuccinate derivatives 14a1-c1, 14a2-c2, and 14a3-c3 respectively. All these new compounds were evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular (im) routes. Hydroxy-functionalized trioxane 13a1 showed 80% protection and its hemisuccinate derivative 14a1 showed 100% protection at a dose of 48 mg/kg × 4 days by both routes, which is twice active than artemisinin by oral route.

Pharmacological Study of Andrographis paniculata (Kalmegh) for their possible Antimalarial Activity with Emphasis on Resistance and Resistant Reversal

Antimalarial effect of some medicinal plants found in Uttarakhand (India) is least explored by the scientific community locally. Advent of resistance to various antimalarial drugs by plasmodium made malaria more fatal and life-threatening disease. Therefore, present need is to invest more effort and interest in research for antimalarials from medicinal plants. Plasmodium yoelii nigeriensis (PYn) is multi drug resistance malaria parasite known for resistance to chloroquine (CQ), quinine, quinidine, amodiaquine, halofantrine, mepacrine, and mefloquine. The P. yoelii produces 100% infections in animals. Researchers in this study tried to understand the behavior of CQ -resistant plasmodium PYn with CQ, whole plant extracts of Andrographis paniculata (AP) with possibility of their resistance reversal. Wherever, 3–4 times CQ doses are not able to produce sufficient antimalarial effect in resistant PYn. Most of the pure plant extracts are also not able to produce minimal therapeutic response when given alone. Whereas, plant extract shows a better effect when given with minimal dose CQ than alone. AP whole plant hydroalcoholic (HA) extract doses 300 mg/kg when combining CQ 20 mg/kg shows the best effect among the other extracts alone. Parasitemia and red blood cells count parameters significantly improved. Hemoglobin, survival days and weight are benefitted with HA extract then ethanolic extract. Unexpectedly, HA extract at higher dosage 1000 mg/kg produce efficacy then 300 mg/kg dose group. Higher doses of HA extract causes some sort of negative effect on almost all selected parameters even though with ethanolic extract. Present approach of multi-drug dosage supports also supported here in the study with a thought of using antimalarial plant extracts during regular malaria treatment. Genesis of idea of referring standardized plant extract(s) in combination as oral dosage with prophylactic (travelers) malaria and malaria treatment or side-food for malaria will also possible. Positive results may pave a path for inclusion of herbal extracts or herbs as side treatment or resistance-breaker food for malaria.

Synthesis and Antimalarial Activity of 4-Methylaminoquinoline Compounds against Drug-Resistant Parasite.

A series of novel 4-aminoquinoline analogues bearing a methyl group at 4-aminoquinoline moiety were synthesized via a new and robust synthetic route comprising in situtert-butoxycarbonyl (Boc) deprotection–methylation cascade resulting in the corresponding N-methylated secondary amine using Red-Al and an efficient microwave-assisted strategy for the fusion of N-methylated secondary amine with 4-chloroquinoline nucleus to access the series of novel 4-N-methylaminoquinoline analogues. The new series of compounds were evaluated for their antimalarial activity in in vitro and in vivo models. Among 21 tested compounds, 9a–i have shown a half-maximal inhibitory concentration (IC50) value less than 0.5 μM (i.e., <500 nM) against both chloroquine-sensitive strain 3D7 and chloroquine-resistant strain K1 of Plasmodium falciparum with acceptable cytotoxicity. Based on the in vitro antimalarial activity, selected compounds were screened for their in vivo antimalarial activity against Plasmodium yoelii nigeriensis (a multidrug-resistant) parasite in Swiss mice. Most of the compounds have shown significant inhibition on day 4 post infection at the oral dose of 100 mg/kg. Compound 9a has shown 100% parasite inhibition on day 4, and out of five treated mice, two were cured till the end of the experiment. The present study suggests that 4-methylamino substitution is well tolerated for the antiplasmodial activity with reduced toxicity and therefore will be highly useful for the discovery of a new antimalarial agent against drug-resistant malaria.