Literatura académica sobre el tema "Artemisinin activity"
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Artículos de revistas sobre el tema "Artemisinin activity"
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Bai, Jennifer, Xiaochun Chen y Curt I. Civin. "Nrf2 Regulates Sensitivity of Leukemias to Artemisinins". Blood 128, n.º 22 (2 de diciembre de 2016): 2324. http://dx.doi.org/10.1182/blood.v128.22.2324.2324.
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Abstract The artemisinins are a class of drugs widely used to treat severe malaria due to their potency and few adverse effects. In addition to antimalarial activity, artemisinins have been shown to have potent anti-cancer activity, specifically in leukemia. Therefore, artesunate (AS), the WHO-recommended treatment for severe malaria, and a new dimeric artemisinin derivative (ART-838) are promising agents to repurpose for leukemia treatment. Reactive oxygen species (ROS) have been implicated in the mechanism of artemisinin activity in both malaria and cancer; however, the full mechanisms of artemisinin activity in cancer have not yet been elucidated. In 2014, Ariey et al, published a paper on malaria identifying the Kelch (K13) propeller domain as a molecular marker for artemisinin resistance. Since Keap1 ̶ the human homolog of K13 ̶ is involved in ROS regulation, it may also play a role in artemisinin action in cancer. To investigate the role of Keap1-Nrf2 signaling cascades in mediating artemisinin action and resistance in leukemia, qPCRs and Western blots were performed to quantify endogenous levels of selected Keap1 pathway molecules (Keap1, Nrf2, Nqo1, and Gsta1) in 23 human acute leukemia cell lines. However no significant correlation was observed between the levels of these molecules (mRNA or protein) and AS/ART-838 sensitivity. Using an antioxidant response element (ARE) luciferase reporter that can be activated by Nrf2, a significant increase in ARE activity was observed in K562 cells upon AS or ART-838 treatment. In addition to increased transcription upon drug treatment, the ARE downstream proteins Nqo1 and Gsta1 were upregulated upon AS or ART-838 treatment. K562 cell lines with Keap1 and Nrf2 stably knocked down (KD) were generated. The Nrf2 KD K562 cell line had increased sensitivity to AS and ART-838. In contrast, KD of Keap1 did not result in a substantial change in drug sensitivity to either artemisinin. In conclusion, these studies suggest involvement of Nrf2 in human leukemia cell resistance to artemisinins. Further studies on Nrf2 may help us better understand the molecular actions of the artemisinins in order to optimize their efficacy as single agents or in drug combinations for leukemia treatment. Disclosures No relevant conflicts of interest to declare.
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KANNAN, Rangiah, Krishan KUMAR, Dinkar SAHAL, Shrikant KUKRETI y Virander S. CHAUHAN. "Reaction of artemisinin with haemoglobin: implications for antimalarial activity". Biochemical Journal 385, n.º 2 (7 de enero de 2005): 409–18. http://dx.doi.org/10.1042/bj20041170.
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Elucidation of the principal targets of the action of the antimalarial drug artemisinin is an ongoing pursuit that is important for understanding the action of this drug and for the development of more potent analogues. We have examined the chemical reaction of Hb with artemisinin. The protein-bound haem in Hb has been found to react with artemisinin much faster than is the case with free haem. It appears that the uptake of Hb and the accumulation of artemisinin into the food vacuole, together with the preferred reactivity of artemisinin with haem in Hb, may make Hb the primary target of artemisinin's antimalarial action. Both monoalkylated (HA) and dialkylated (HAA) haem derivatives of artemisinin have been isolated. These ‘haemarts’ bind to PfHRP II (Plasmodium falciparum histidine-rich protein II), inhibiting haemozoin formation, and possess a significantly decreased ability to oxidize ascorbic acid. The accelerated formation of HAA from Hb is expected to decrease the ratio of haem to its alkylated derivatives. The haemarts that are generated from ‘haemartoglobins’ may bring about the death of malaria parasite by a two-pronged effect of stalling the formation of haemozoin by the competitive inhibition of haem binding to its templates and creating a more reducing environment that is not conducive to the formation of haemozoin.
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Mishina, Yuliya V., Sanjeev Krishna, Richard K. Haynes y John C. Meade. "Artemisinins Inhibit Trypanosoma cruzi and Trypanosoma brucei rhodesiense In Vitro Growth". Antimicrobial Agents and Chemotherapy 51, n.º 5 (5 de marzo de 2007): 1852–54. http://dx.doi.org/10.1128/aac.01544-06.
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ABSTRACT Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.
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Zhelyazkova, Margarita Y., Nadya G. Hristova-Avakumova y Georgi Tsv Momekov. "Antitumor activity of the combination of artemisinin and epirubicin in human leukemia cells". Folia Medica 63, n.º 4 (31 de agosto de 2021): 488–95. http://dx.doi.org/10.3897/folmed.63.e55938.
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Aim: We evaluated the tumor-inhibiting effect of artemisinin applied separately and in combination with epirubicin on leukemia HL-60 and HL-60/Dox cell lines, its dose modulation effect and its potency to influence iron-induced oxidative damage of biologically relevant molecules. Materials and methods: MTT assay and the method of Chou-Talalay were used to show the inhibition of tumor cell proliferation and to evaluate the synergistic effect and modulation effect of artemisinin and epirubicin at varying concentrations. We also used spectrophotometric assays to determine the potency of artemisinin to influence iron-induced molecular degradation of lecithin and deoxyribose. Results: Artemisinin exhibits tumor-inhibiting effect on both the anthracycline-sensitive and anthracycline-resistant promyelocytic cell lines, reaching 88% and 61% (T/C), respectively, when applied at higher concentrations in a dose-dependent manner. The combination of artemisinin and epirubicin shows synergistic effects in all tested concentrations on doxorubicin-resistant cells (CI<0.7). Artemisinin sensitizes the resistant cells towards epirubicin as shown by the CI (combination index) values and has a dose-modulation effect as shown by DRI (dose reduction index). Artemisinin induces deoxyribose oxidative degradation when applied alone and exerts synergistic deoxyribose degradation effect when applied with iron. However, artemisinin does not influence the studied processes in the lecithin-containing model system and has no potential to induce lipid peroxidation. Conclusions: This study presents a new opportunity to enhance the effectiveness of epirubicin-based treatment regimens with addition of artemisinins for resistant tumors.
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Teoh, Keat H., Devin R. Polichuk, Darwin W. Reed y Patrick S. Covello. "Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annuaThis paper is one of a selection of papers published in a Special Issue from the National Research Council of Canada – Plant Biotechnology Institute." Botany 87, n.º 6 (junio de 2009): 635–42. http://dx.doi.org/10.1139/b09-032.
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Limitations in the supply of the antimalarial compound artemisinin from Artemisia annua L. have led to an interest in understanding its biosynthesis and enhancing its production. Recent biochemical and molecular genetic data have implicated dihydroartemisinic aldehyde as a precursor to the corresponding acid, which is then converted to artemisinin. Thus, it is important to understand the enzyme or enzymes involved in dihydroartemisinic aldehyde oxidation. Given its activity on artemisinic aldehyde, the cytochrome P450 CYP71AV1 was investigated for its ability to oxidize dihydroartemisinic aldehyde. However, no net activity was detected. In a search for alternative enzymes that could catalyze the oxidation, an expressed sequence tag (EST) collection from A. annua was investigated for relevant cDNAs. This led to the isolation of a full-length cDNA encoding an aldehyde dehydrogenase homologue, named Aldh1, which is highly expressed in trichomes. Expression of the cDNA in E. coli and characterization of the purified recombinant enzyme revealed that the gene product catalyses the NAD(P)-dependent oxidation of the putative artemisinin precursors, artemisinic and dihydroartemsinic aldehydes, and a limited range of other aldehydes. The observed enzyme activity of Aldh1 and the expression pattern of the corresponding gene suggest a role in artemisinin biosynthesis in the glandular secretory trichomes of A. annua.
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Zhu, Pan y Bing Zhou. "The Antagonizing Role of Heme in the Antimalarial Function of Artemisinin: Elevating Intracellular Free Heme Negatively Impacts Artemisinin Activity in Plasmodium falciparum". Molecules 27, n.º 6 (8 de marzo de 2022): 1755. http://dx.doi.org/10.3390/molecules27061755.
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The rich source of heme within malarial parasites has been considered to underly the action specificity of artemisinin. We reasoned that increasing intraparasitic free heme levels might further sensitize the parasites to artemisinin. Various means, such as modulating heme synthesis, degradation, polymerization, or hemoglobin digestion, were tried to boost intracellular heme levels, and under several scenarios, free heme levels were significantly augmented. Interestingly, all results arrived at the same conclusion, i.e., elevating heme acted in a strongly negative way, impacting the antimalarial action of artemisinin, but exerted no effect on several other antimalarial drugs. Suppression of the elevated free heme level by introducing heme oxygenase expression effectively restored artemisinin potency. Consistently, zinc protoporphyrin IX/zinc mesoporphyrin, as analogues of heme, drastically increased free heme levels and, concomitantly, the EC50 values of artemisinin. We were unable to effectively mitigate free heme levels, possibly due to an unknown compensating heme uptake pathway, as evidenced by our observation of efficient uptake of a fluorescent heme homologue by the parasite. Our results thus indicate the existence of an effective and mutually compensating heme homeostasis network in the parasites, including an uncharacterized heme uptake pathway, to maintain a certain level of free heme and that augmentation of the free heme level negatively impacts the antimalarial action of artemisinin. Importance: It is commonly believed that heme is critical in activating the antimalarial action of artemisinins. In this work, we show that elevating free heme levels in the malarial parasites surprisingly negatively impacts the action of artemisinin. We tried to boost free heme levels with various means, such as by modulating heme synthesis, heme polymerization, hemoglobin degradation and using heme analogues. Whenever we saw elevation of free heme levels, reduction in artemisinin potency was also observed. The homeostasis of heme appears to be complex, as there exists an unidentified heme uptake pathway in the parasites, nullifying our attempts to effectively reduce intraparasitic free heme levels. Our results thus indicate that too much heme is not good for the antimalarial action of artemisinins. This research can help us better understand the biological properties of this mysterious drug.
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Rosenberg, Alex, Madeline R. Luth, Elizabeth A. Winzeler, Michael Behnke y L. David Sibley. "Evolution of resistance in vitro reveals mechanisms of artemisinin activity inToxoplasma gondii". Proceedings of the National Academy of Sciences 116, n.º 52 (5 de diciembre de 2019): 26881–91. http://dx.doi.org/10.1073/pnas.1914732116.
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Artemisinins are effective against a variety of parasites and provide the first line of treatment for malaria. Laboratory studies have identified several mechanisms for artemisinin resistance inPlasmodium falciparum, including mutations in Kelch13 that are associated with delayed clearance in some clinical isolates, although other mechanisms are likely involved. To explore other potential mechanisms of resistance in parasites, we took advantage of the genetic tractability ofToxoplasma gondii, a related parasite that shows moderate sensitivity to artemisinin. Resistant populations ofT. gondiiwere selected by culture in increasing concentrations and whole-genome sequencing identified several nonconservative point mutations that emerged in the population and were fixed over time. Genome editing using CRISPR/Cas9 was used to introduce point mutations conferring amino acid changes in a serine protease homologous to DegP and a serine/threonine protein kinase of unknown function. Single and double mutations conferred a competitive advantage over wild-type parasites in the presence of drug, despite not changing EC50values. Additionally, the evolved resistant lines showed dramatic amplification of the mitochondria genome, including genes encoding cytochromeband cytochromecoxidase I. Prior studies in yeast and mammalian tumor cells implicate the mitochondrion as a target of artemisinins, and treatment of wild-type parasites with high concentrations of drug decreased mitochondrial membrane potential, a phenotype that was stably altered in the resistant parasites. These findings extend the repertoire of mutations associated with artemisinin resistance and suggest that the mitochondrion may be an important target of inhibition of resistance inT. gondii.
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Crespo-Ortiz, Maria P. y Ming Q. Wei. "Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug". Journal of Biomedicine and Biotechnology 2012 (2012): 1–18. http://dx.doi.org/10.1155/2012/247597.
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Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.
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Nagamune, Kisaburo, Wandy L. Beatty y L. David Sibley. "Artemisinin Induces Calcium-Dependent Protein Secretion in the Protozoan Parasite Toxoplasma gondii". Eukaryotic Cell 6, n.º 11 (31 de agosto de 2007): 2147–56. http://dx.doi.org/10.1128/ec.00262-07.
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ABSTRACT Intracellular calcium controls several crucial cellular events in apicomplexan parasites, including protein secretion, motility, and invasion into and egress from host cells. The plant compound thapsigargin inhibits the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA), resulting in elevated calcium and induction of protein secretion in Toxoplasma gondii. Artemisinins are natural products that show potent and selective activity against parasites, making them useful for the treatment of malaria. While the mechanism of action is uncertain, previous studies have suggested that artemisinin may inhibit SERCA, thus disrupting calcium homeostasis. We cloned the single-copy gene encoding SERCA in T. gondii (TgSERCA) and demonstrate that the protein localizes to the endoplasmic reticulum in the parasite. In extracellular parasites, TgSERCA partially relocalized to the apical pole, a highly active site for regulated secretion of micronemes. TgSERCA complemented a calcium ATPase-defective yeast mutant, and this activity was inhibited by either thapsigargin or artemisinin. Treatment of T. gondii with artemisinin triggered calcium-dependent secretion of microneme proteins, similar to the SERCA inhibitor thapsigargin. Artemisinin treatment also altered intracellular calcium in parasites by increasing the periodicity of calcium oscillations and inducing recurrent, strong calcium spikes, as imaged using Fluo-4 labeling. Collectively, these results demonstrate that artemisinin perturbs calcium homeostasis in T. gondii, supporting the idea that Ca2+-ATPases are potential drug targets in parasites.
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Smeilus, Toni, Farnoush Mousavizadeh, Johannes Krieger, Xingzhao Tu, Marcel Kaiser y Athanassios Giannis. "Synthesis and biological investigation of (+)-3-hydroxymethylartemisinin". Beilstein Journal of Organic Chemistry 15 (27 de febrero de 2019): 567–70. http://dx.doi.org/10.3762/bjoc.15.51.
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Herein, we describe a biomimetic entry to (+)-3-hydroxymethylartemisinin (2) as well as to the artemisinin derivatives (+)-3-hydroxymethyl-9-desmethylartemisinin (16) and (+)-3-hydroxymethyl-9-epi-artemisinin (18), starting from the known and readily available chiral aldehyde 3 and alkyne 4. Subsequently, the synthesized compounds have been evaluated for their antimalarial activity against the drug-sensitive P. falciparum NF54 strain. All of them were inactive. In addition, they did not show any toxicity against L6 cells (a primary cell line derived from rat skeletal myoblasts). These results contribute to a better understanding of artemisinins mechanism of action.
Tesis sobre el tema "Artemisinin activity"
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Jacobs, Suesan, Amanda Vonderfecht y Georg Wondrak. "Artemisinin-Based Combination Anti-malarials Do Not Enhance Anti-melanoma Activity of Artemisinin-Monotherapy". The University of Arizona, 2013. http://hdl.handle.net/10150/614262.
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Class of 2013 AbstractSpecific Aims: To determine if melanoma cells are more vulnerable to Amodiaquine (AQ) or Lumefantrine (LF)-based artemisinin combination therapy compared to artemisinin monotherapy. Methods: Tested anti-malarials in vitro for anti-melanoma activity, which contained 100,000 of the A375 human metastatic melanoma cells that were repeatedly treated independently three times. Main Results: Dihydroartemisinin (DHA) monotherapy induced significant cell death in melanoma cells. However, artemisinin combination therapy (ACT) did not enhance DHA-induced cell death. AQ protected against DHA-induced cell death causing morphological changes detected by electron microscopy. As for LF, it did not affect DHA-induced cell death. Conclusion: The results demonstrated that ACT does not display enhanced anti-melanoma activity compared to artemisinin monotherapy. It suggests that AQ may have anti-oxidant properties, but would need to be explored further in the context of anti-oxidant cyto-protection.
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Cloete, Theunis Theodorus. "Synthesis and antimalarial activity of amine derivatives of artemisinin / Theunis Cloete". Thesis, North-West University, 2012. http://hdl.handle.net/10394/9104.
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Malaria has since antiquity been a leading cause of morbidity and mortality throughout the world having serious health, sociological and financial implications. Today, the parasite kills an approximate 655 000 people annually, with most deaths being amongst pregnant women and children under the age of 5 in Africa. Plasmodium falciparum is the species that accounts for 91% of all case fatalities and predominates in Africa and Asia. The parasite is aggressive in its means of acquiring resistance, nullifying the majority of drugs used against it.
Artemisinin, a sesquiterpene lactone with a peroxide bridge, was discovered in 1971 and was found to possess remarkable antimalarial activity. Together with its semi synthetic derivatives, artemisinin not only lack cross-resistance with other antimalarials but also has the remarkable ability to induce a 10 000 fold reduction in parasitemia.
The artemisinin class of compounds is currently the basis of treatment favoured by the World Health Organisation (WHO) for the treatment of uncomplicated P. falciparum infection. Regrettably, resistance has started to emerge even against this class of compounds, characterised by a significantly longer in vivo parasite clearance time.
The global impact of this disease and its ability to circumvent most efforts to counter it justifies the search for new treatment methods and drugs.
The aim of this study was to synthesise three series of artemisinin-amine derivatives, to evaluate their antimalarial activity against both sensitive and resistant strains of P. falciparum and to determine their toxicity against mammalian cells. This may lead to new compounds with favourable properties and increased activity which can be used in the fight against malaria.
Chapter 3 describes the synthesis of eleven 10-aminoethylether derivatives of artemisinin, confirmation of their structures by physical means and the determination of their in vitro antimalarial activity against the chloroquine sensitive (D10) and resistant (Dd2) strains of P. falciparum as well as their toxicity against Chinese hamster ovarian (CHO) cells. All derivatives were active against both strains of the parasite, with no mentionable toxicity. The highest activity was displayed by compound 8, a short chain aromatic derivative containing only one nitrogen atom, which was found to have comparable activity to artesunate (AS). Long chain polyamine derivatives had the lowest activity against both strains. An interesting correlation between the IC50, pKa values and resistance index (RI) was found.
Chapter 4 compares the same 10-aminoethylether derivatives of artemisinin discussed in chapter 3 with eight 10-n-alkyl/aryl/aroyl ester derivatives previously synthesised in our group. The in vitro antimalarial activity of these nineteen compounds was determined against both the chloroquine sensitive (3D7) and resistant (K1) strains of P. falciparum, whilst their cytotoxicity was determined against both human embryonic kidney cells (HEK 293) and hepatocellular carcinoma cells (Hep G2). Both series of compounds showed activity versus the 3D7 and K1 strains, with the majority of compounds possessing potency either comparable with or higher than that of AS. None of the synthesised derivatives had any mentionable toxicity against the mammalian cells. The 10-n-propyl and 10-benzyl ester derivatives, 11 and 18 respectively, were the most active compounds against both strains, whilst the other ester derivatives also showed a slightly higher degree of activity than the aminoethers. Compound 29, featuring an isobutylamine substituent, was the most active of all aminoethers.
Chapter 5 entails the synthesis of seven artemisinin-triazine hybrids, confirmation of their structures and the determination of their in vitro antimalarial activity against the 3D7 and K1 strains of P. falciparum, whilst their cytotoxicity was determined against HEK 293, Hep G2, B-lymphocyte cells (Raji) and human fibroblast cells (BJ). The synthesised hybrids all showed activity against both strains and were found to be non-toxic to all mammalian cells. Compound 17, featuring p-anisidine and 2-(diisopropylamino)ethylamine substituents on the triazine ring, was the most active of all synthesised compounds and had comparable activity to that of AS and artemether (AM), while being significantly more potent than chloroquine (CQ).
Chapter 6 describes the synthesis and structure determination of six dimeric artemisinin triazine hybrids and the determination of their antimalarial activity and toxicity against the same strains of P. falciparum and mammalian cells as in chapter 5. All dimers showed activity against both strains and no noticeable toxicity towards any of the mammalian cell lines used. All synthesised compounds showed higher activity than CQ, irrespective of the P. falciparum strain considered. Compound 15, featuring aniline and morpholine substituents on the triazine ring, was not only meaningfully more potent than CQ but was also found to possess activity comparable to those of AS and AM against both malaria strains. Compounds 10, 11, 12 and 13 all had corresponding monomer equivalents as have been reported in chapter 5. Against both strains of P. falciparum, most dimer compounds were slightly more active than their monomer counterparts. This study delivered a number of compounds that exhibited activity comparable to that of potent antimalarial drugs currently on the market, and showed that there is ample scope for developments in the chemotherapy of malaria. These compounds stand as good candidates for in vivo and pharmacokinetic studies and may serve as leads for further investigations.Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013
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Vlok, Martha Carolina. "Artemisinin-quinoline hybrids :|bdesign, synthesis and antimalarial activity / Martha Carolina (Marli) Vlok". Thesis, North-West University, 2013. http://hdl.handle.net/10394/9543.
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Introduction -
Malaria is a major global health problem, with more than 500 million reported cases and at least 1 million deaths each year. The main problem with malaria control is the emerging drug resistance. Plasmodium falciparum (P. falciparum) developed widespread resistance to antimalarial drugs such as chloroquine (CQ) and mefloquine, but not to the artemisinins. The World Health Organization (WHO) recommended artemisinin combination therapy (ACT) for the treatment of uncomplicated malaria in all chloroquine resistance areas. However, P. falciparum has recently started to display resistance to these ACTs, highlighting the need for new chemotherapeutic approaches for the treatment of P. falciparum infections.
Aims -
The aims of this study were: (i) to design and synthesise a new series of antimalarial hybrid drugs, consisting of dihydroartemisinin (DHA) and aminoquinoline moieties bound covalently through different, very distinctive linkers; (ii) to determine the in vitro antiplasmodial activity and cytotoxicity of the synthesised series; (iii) to ascertain whether the in vitro antiplasmodial activity of the promising compounds would be carried over in vivo against Plasmodium vinckei (P. vinckei); and, (iv) to obtain an indication of the pharmacokinetic properties of this class of antimalarial drugs by performing snapshot pharmacokinetic analysis.
Methods -
DHA was coupled via an aminoethylether bond to various aminoquinolines to give hybrids and hybrid-dimers. CQ-susceptible (D10 and 3D7) and CQ-resistant (Dd2) strains of P. falciparum were used to determine the in vitro antiplasmodial activity. In vitro cytotoxicity was assessed using a mammalian cell-line (Chinese Hamster Ovarian, CHO). The antiproliferative activity of the hybrid-dimers was tested against three cell lines; renal adenocarcinoma (TK-10), breast adenocarcinoma (MCF-7) and melanoma (UACC-62). P. vinckei-infected mice were treated with the hybrid drugs for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip) or orally (po), with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg, in order to determine their antimalarial activity. A snapshot oral and intravenous (IV) pharmacokinetic study was performed.
Results -
All compounds were obtained as the 10-β-isomers and were isolated as the oxalate salts. Low nanomolar in vitro antiplasmodial activities were displayed by several compounds in this series, with IC50 values ranging from 5.15 to 29.5 nM, in comparison with the values of 2.09–5.11 nM and 21.54–157.90 nM for each of DHA and CQ respectively. All compounds displayed good selectivity towards P. falciparum in vitro (selectivity index (SI) ≥ 20). Two of the hybrids, featuring non-methylated and methylated two-carbon diaminoalkyl linkers, exerted potent in vivo antimalarial activities, with ED50 values of 1.1 and 1.4 mg/kg by ip route and 12 and 16 mg/kg po, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg ip and at 50 mg/kg po for these two hybrids, whereas artesunate was able to provide a complete cure only at 30 mg/kg ip and 80 mg/kg po.
Conclusions -
These compounds may provide a lead into a new class of antimalarial drugs so badly needed for treatment of resistant strains. Despite shorter half-lives and moderate oral bioavailability in comparison with DHA, two of the compounds of this series were able to cure malaria in mice at very low dosages, implicating extremely active metabolites. The optimum linker length for antimalarial activity was found to be a diaminoalkyl linker consisting of two carbon atoms, either unmethylated or bearing a single methyl group.Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013
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O'Neill, J. F. "Studies on the activity of artemisinin compounds against the liver fluke, Fasciola hepatica". Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.680237.
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Using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and histology, the effects of artemisinin compounds on the tegumental surface and ultrastructure of the liver fluke, Fasciola hepatica, were assessed. The histology and SEM findings revealed that treatment of flukes with the artemisinin-type compounds, artemether, artesunate and OZ78, resulted in relatively little disruption to the external tegumental surface when compared with other fasciolicides. In contrast, changes to the ultrastructure, as examined by TEM, were rapid, severe and progressive, particularly in the gut and reproductive tissues. That changes in the gut occurred rapidly following administration, and were more extensive than those observed in the tegument, suggests that an oral route of uptake may predominate for these compounds. Experiments were undertaken using three different fluke isolates, two of which have been previously confirmed as being resistant to the current drug of choice, triclabendazole (TCBZ). The nature and extent of the changes in fluke tissues appeared to be similar across the isolates, confirming that artemisinin-type compounds have equal activity against both TCBZ-susceptible and TCBZ-resistant fluke. With each of the three compounds, the changes observed in fluke tissues were distinct from those induced by other known fasciolicides, being typified by widespread disruption to the mitochondria and the cisternae of the ger, particularly in the gut. As time progressed post-treatment, inhibition of spermatogenesis and oogenesis became evident, with widespread apoptosis observed in both tissues. The observed changes, particularly to the cisternae of the ger, link well to the suggested mechanism of action for these compounds, via inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), but suggest that a less-specific dual mechanism of action may be more likely. Finally, the current study established a time-scale for the action of artemisinin-type compounds against fluke, and substantiated previous concerns over the potential toxicity of artesunate when administered at high doses.
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Steyn, Minette. "Synthesis and anti-malarial activity of ethylene glycol oligomeric ethers of artemisinin / Minette Steyn". Thesis, North-West University, 2010. http://hdl.handle.net/10394/5058.
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Malaria continues to be a major serious health problem and public health threat, with over two billion people at risk of contracting this deadly disease. Malaria is endemic in 92 countries and more than one million deaths per year are attributed to malaria, the mortality in African children being the highest.
Drug-resistance to classical and existing anti-malarial drugs is a challenging problem in malaria control in most parts of the world, contributing to the need of developing new compounds for malaria treatment. Artemisinin is a sesquiterpene lactone endoperoxide and the first natural 1,2,4-trioxane isolated from Artemisia annua. Artemisinin and its derivates are of special biological interest because of their outstanding anti-malarial activity against chloroquine-resistant P. falciparum and cerebral malaria.
The reason for this is their unusual chemical structures and the difference in their mechanism of action compared to other anti-malarials. The endoperoxide bridge of artemisinin and a heme iron play critical roles in the mechanism of action of artemisinin. The reaction mechanism consists of two distinct steps, the first step an activation step and the second step an alkylation step. During the activation step, the heme iron breaks the endoperoxide linkage of artemisinin and an oxygen free radical is produced, which is subsequently rearranged to form a carbon-centered (C4) free radical. In the alkylation step, the carbon free radical alkylates specific malarial proteins, which causes a lethal damage to malarial parasites.
However, the use of such endoperoxides is restricted by their poor oral bioavailability, poor solubility in oil and water, a short plasma half-life (30 minutes in plasma) and the high rate of recrudescent infections when used as monotherapy in short-course treatments, even though these drugs have a rapid onset of action and low reported toxicity. In order to overcome these pharmacokinetic deficiencies, a number of new analogues with improved efficacy and increased solubility were introduced, including oil-soluble artemether and arteether, but these compounds still have a short plasma half-life. Artemisinin, dihydroartemisinin, artemether and arteether are all poorly water-soluble compounds, which results in slower and incomplete absorption of these drugs into the systemic circulation.
Therefore, it may be worthwhile to produce new artemisinin derivatives to hopefully develop a compound with enhanced pharmacokinetic properties resulting in better bioavailability and increased effectiveness.
The aim of this study was to synthesise ethylene glycol oligomeric ethers of artemisinin, determine certain physicochemical properties and evaluate their anti-malarial activity compared to artemether and chloroquine.
In this study eight ethylene glycol derivatives of artemisinin were synthesised by linkage of a polyethylene glycol chain of various chain lengths to C-10 of dihydroartemisinin. The structures of the prepared derivatives were confirmed by nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS).
The experimental aqueous solubility of the synthesised compounds increased with the decrease in the experimental partition coefficients, as the polyethylene glycol (PEG) chain length increased, validating both structure-aqueous solubility and structure-lipophilicity relationships within the series.
The new ethylene glycol oligomeric ethers of artemisinin were tested in vitro against the chloroquine sensitive strain of Plasmodium falciparum (D-10). The results indicate that the anti-malarial activity increases with the elongating of the PEG chain length. The ethoxypoly (ethylene glycol) series (6a-8) showed higher anti-malarial activity than the methoxypoly (ethylene glycol) series (3-5b), thus showing that both hydrophilic and lipophilic properties are necessary for the enhancement of the anti-malarial activity. None of the synthesised compounds showed better anti-malarial efficacy than artemether. Compound (8), 2-[2-(2-ethoxyethoxy)ethoxy] ethoxy derivative, showed better anti-plasmodial activity than chloroquine and compounds (5a) and (6a) showed activity comparable to that of chloroquine. Compounds (3), (4), (5b), (6b) and (7) are less active than artemether and chloroquine. In all cases the anti-malarial activity of the β-isomers was higher than that of the
α-isomers.Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2010.
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Feng, Tzu-Shean. "Single and hybrid antimalarials based on artemisinin, chloroquine and ß-lactams : synthesis, antiplasmodial activity, cytotoxicity and effect of selected artemisinin-chloroquine hybrids on the parasitic endocytosis pathway". Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/6305.
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Includes abstract.Includes bibliographical references.
Malaria remains to be one of the leading causes of morbidity and mortality throughout recorded history. It is caused by protozoan parasites of the genus Plasmodium, where P. falciparum is the most lethal. Current estimates are that over 500 million people are afflicted, while 3 million people die annually. With the emergence of resistance to antimalarial drugs in the malaria parasite, it is critical to develop new chemotherapeutic agents that can combat the disease and/or overcome resistance. This may be achieved by identifying molecules that target or interfere with unique parasitic pathways such as haemoglobin degradation or parasitic endocytosis. This thesis describes the design and synthesis of novel antimalarial agents based on the ‘Designed Multiple Ligand’ approach. Compounds were synthesized via conjugate addition or multi-component condensation reaction. 4-Aminoquinolines were hybridized with artemisinin or 1,4-naphthoquinone derivatives; selected hybrids were further investigated for their effect on the parasitic endocytosis pathway and compared to the effect of chloroquine and artemisinin on the same pathway. The effects of drug treatment on the morphology and haemoglobin levels in the parasites as well as localization of transport vesicles via immunofluorescence microscopy were determined. A series of β-lactam derivatives containing a terminal acetylene moiety were synthesized via the Staudinger and Ugi 3-component 4-centre condensation reactions. The compound with the best activity from the series was used to couple these reactions to post-condensation chemical modifications via the Mannich reaction, another multi-component reaction, to create a more diversified library. A small series of 4-aminoquinoline analogues, including amodiaquine-like compounds and bisquinoline derivatives, was also prepared in an attempt to elucidate their structure-activity relationships. The antiplasmodial and cytotoxic activities were determined for all compounds; where applicable, assays on β-haematin inhibitory activity were also carried out.
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Wright, Colin W., Peter A. Linley, R. Brun, S. Wittlin y E. Hsu. "Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity". MDPI Publishing, 2010. http://hdl.handle.net/10454/4539.
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yesAncient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions.
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La, Pensée Louise Josephine Ilse. "Endoperoxides as antimalarials and the application of singlet oxygen to the synthesis of key intermediaries en route to synthetic 1,2,4-trioxanes and synthesis and biological activity of minor groove binding-artemisinin conjugates". Thesis, University of Liverpool, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533991.
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KIRCHNER, VALERIE. "L'artemisinine et ses derives : relations structure-activite et utilisation dans le paludisme". Strasbourg 1, 1994. http://www.theses.fr/1994STR15057.
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Joubert, Juan Paul. "Synthesis and antimalarial activity screening of artemisinin-acridine hybrids / Juan Paul Joubert". Thesis, 2013. http://hdl.handle.net/10394/12243.
Texto completoResumen
Malaria endemic areas not only pose a public health threat, but affects 3.3 billion people
worldwide. In 2011, estimated malaria related deaths amounted to 660 000 out of 219 million
reported cases, with 81% of these and 91% of malaria related mortality occurred in the African
region. Those most affected were pregnant women, children under the age of five and immunocompromised
individuals. Malaria is the fifth deadliest disease worldwide and accounts for the
second highest death rate in Africa, following HIV/Aids.
To combat this parasitic infection of antiquity, the ideal malaria pharmacotherapy would be a
cost effective and easily obtainable monotherapy. The malaria parasite, however, has an
intrinsic ability to develop drug resistance through various mechanisms. Widespread resistance
towards antimalarial drugs has rendered traditionally used drugs therapeutically ineffective,
hence accentuating the efficacy of the artemisinins as first line treatment option for
uncomplicated Plasmodium falciparum (P. falciparum). A devastating reality of the challenging
battle against malaria is the confirmed prolonged parasitic clearance times of the artemisinins,
despite adequate drug exposure, which emphasises the urgent need for identifying and
developing new, effective and safe therapies.
During this study, 9-aminoacridines and artemisinin-acridine hybrids were successfully
synthesised through nucleophillic substitution and their chemical structures confirmed by means
of nuclear magnetic resonance spectroscopy (NMR), high resolution mass spectroscopy
(HRMS) and infrared spectroscopy (IR). The hybrid compounds were synthesised through
microwave assisted radiation, by covalently linking the artemisinin- and amino-functionalised
acridine pharmacophores by means of a liable aminoethyl ether chain.
The target compounds were screened in vitro for antimalarial activity against both the
chloroquine sensitive (NF54) and chloroquine resistant (Dd2) strains of P. falciparum. Their
cytotoxicities were assessed against various mammalian cells of different origins, viz. the
Chinese hamster ovarian cells (CHO) from animal origin, and from human origin, hepatocellular-
(HepG2), neuroblastoma- (SH-SY5Y) and cervical cancer (HeLa) cells.
The synthesised hybrids exhibited antimalarial activity against both Plasmodium strains.
Compound 7, featuring an ethylenediamine moiety in the linker, was the most active hybrid, with
50% inhibitory concentration (IC50) values of 2.6 nM and 35.3 nM against the NF54 and Dd2
strains, respectively. It had gametocytocidal activity against the NF54 strain, comparable to
dihydroartemisinin (DHA) and artesunate (AS) and it is significantly more potent than chloroquine (CQ), whilst possessing a resistance index value of 14, indicative of a significant
loss of activity against the CQ resistant strain.
Contrary, the promising hybrid 10, containing a 2-methylpiperazine linker, had gametocytocidal
activity, comparable to CQ and was found to be six-fold more potent than CQ against the Dd2
strain, with a resistance index (RI) value of 2, whilst it further showed highly selective action
towards the parasitic cells. Compound 10 was also found to possess anticancer activity against
the HeLa cell line, comparable to DHA and AS, but fivefold higher than that of CQ, with the
same levels of hepatotoxicity and neurotoxicity.
The artemisinin-acridine hybrids displayed superior antimalarial activity, compared to the
derived 9-aminoacridines against both the Plasmodium strains. They, however, did not have the
ability to overcome resistance, reduce the toxicity of acridine, nor induce synergistic activity. The
hybrids, indeed displayed promising anticancer activity against HeLa cells. It is anticipated that
these compounds may stand as drug candidates for further investigation in the search for new
anti-cervical cancer drugs, rather than as antimalarials.MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014
Capítulos de libros sobre el tema "Artemisinin activity"
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Sertel, Serkan, Peter K. Plinkert y Thomas Efferth. "Activity of Artemisinin-Type Compounds Against Cancer Cells". En Evidence and Rational Based Research on Chinese Drugs, 333–62. Vienna: Springer Vienna, 2012. http://dx.doi.org/10.1007/978-3-7091-0442-2_8.
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"Use of Nanocarriers to Enhance Artemisinin Activity". En Artemisia annua, editado por Anna Rita Bilia, 271–93. Boca Raton : Taylor & Francis, 2018. | “A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F Informa plc.”: CRC Press, 2017. http://dx.doi.org/10.1201/b22102-12.
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"Structure–Activity Relationships of Peroxide-Based Artemisinin Antimalarials". En Biologically Active Natural Products, 127–38. CRC Press, 1999. http://dx.doi.org/10.1201/9781420048650-13.
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McLean, Graham, Arba Ager, Geoff Edwards y Mitchell Avery. "Structure-Activity Relationships of Peroxide-Based Artemisinin Antimalarials". En Biologically Active Natural Products. CRC Press, 1999. http://dx.doi.org/10.1201/9781420048650.ch9.
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Avery, Mitchell A., Maria Alvim-Gaston y John R. Woolfrey. "Synthesis and structure-activity relationships of peroxidic antimalarials based on artemisinin". En Advances in Medicinal Chemistry, 125–217. Elsevier, 1999. http://dx.doi.org/10.1016/s1067-5698(99)80005-4.
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Cumming, Jared N., Poonsakdi Ploypradith y Gary H. Posner. "Antimalarial Activity of Artemisinin (Qinghaosu) and Related Trioxanes: Mechanism (s) of Action". En Advances in Pharmacology, 253–97. Elsevier, 1996. http://dx.doi.org/10.1016/s1054-3589(08)60952-7.
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Luisi, Grazia. "Antimalarial Endoperoxides: from Natural Sesquiterpene Drugs to a Rising Generation of Synthetic Congeners". En Medicinal Chemistry Lessons From Nature, 158–227. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815123647123020007.
Texto completoResumen
Malaria is a vector-borne tropical disease caused by protozoans belonging to the genus Plasmodium, which has been scourging mankind for hundreds of millions of years. Despite the masterful progress in preventing disease transmission and reducing morbidity and fatal outcomes, malaria is on the rise again. Global concerns are focused on the spread of resistance to current drugs in the management of severe or ultimately lethal P. falciparum infection. To fully exploit the potential of existing agents and overcome their critical drawbacks, novel synthetic and formulation approaches have been explored. In this field, the clinical value of the natural drug artemisinin (ART) and its derivatives have been firmly established, and ART combination therapies (ACTs) have been recommended as first-line treatment against infection caused by chloroquine-resistant (CQR) P. falciparum strains. Over time, however, ART treatment options have become inadequate, and strict demand for new and effective agents has emerged. In this chapter, the medicinal chemistry aspects of artemisinins will be discussed, covering their unique mode of action and their structural features in relation to stability, pharmacokinetic profile, and antiplasmodial activity. Beyond ACT strategies, significant classes of compounds obtained through both ART covalent bitherapy and dimerization approaches will be presented as well. Furthermore, a special section will focus on the most recent endoperoxide-based synthetic antimalarials as new powerful and cost-effective alternatives to the “golden drug”. It is expected that reported results will provide a strong incentive for further studies, and that unceasing research efforts will succeed in reaching the eventual eradication of this endemic plague.
Actas de conferencias sobre el tema "Artemisinin activity"
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Fahy, Jacques, Frederic Marion, Frederic Lieby-Muller, Celine Mordant, Stephane Vispe, Viviane Brel, Bruno Gomes et al. "Abstract 1925: Trifluoromethylated artemisinin dimers demonstrate a potent anti-cancer activity in vitro and in vivo". En Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-1925.
Texto completoInformes sobre el tema "Artemisinin activity"
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Avery, Mitchell A. Drug Development of the Antimalarial Agent Artemisinin: Total Synthesis, Analog Synthesis, and Structure-Activity Relationship Studies. Fort Belvoir, VA: Defense Technical Information Center, agosto de 1990. http://dx.doi.org/10.21236/adb152141.
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