scholarly journals Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Hangjun Ke ◽  
Joanne M. Morrisey ◽  
Shiwei Qu ◽  
Oraphin Chantarasriwong ◽  
Michael W. Mather ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Morphological Changes ◽  
Biological Activities ◽  
Hek293 Cells ◽  
Therapeutic Window ◽  
Malaria Parasites ◽  
Content Type ◽  
Lead Compounds ◽  
Antimalarial Agents ◽  
Transport Chain

ABSTRACT Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

scholarly journals In VitroandIn VivoAntimalarial Efficacies of Optimized Tetracyclines

2013 ◽  
Vol 57 (7) ◽  
pp. 3131-3136 ◽  
Author(s):  
Michael P. Draper ◽  
Beena Bhatia ◽  
Haregewein Assefa ◽  
Laura Honeyman ◽  
Lynne K. Garrity-Ryan ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Inhibitory Concentration ◽  
New Drugs ◽  
Malaria Parasites ◽  
Content Type ◽  
Antimalarial Agents ◽  
Content Model ◽  
Safety Margins ◽  
Malaria Model

ABSTRACTWith increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potentin vitroactivity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of culturedPlasmodium falciparumwith a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence ofin vitrophototoxicity. In a murinePlasmodium bergheimodel, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible.

scholarly journals Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4858 ◽  
Author(s):  
Despina Palla ◽  
Antonia I. Antoniou ◽  
Michel Baltas ◽  
Christophe Menendez ◽  
Philippe Grellier ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Infectious Diseases ◽  
Antimalarial Activity ◽  
Biological Evaluation ◽  
Antiplasmodial Activity ◽  
Malaria Parasites ◽  
Antimalarial Agents ◽  
New Compounds

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5–5.4 and 41.5–23.1 times more potent activities than FSM, respectively.

scholarly journals Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action

2016 ◽  
Vol 60 (11) ◽  
pp. 6650-6663 ◽  
Author(s):  
Darren J. Creek ◽  
Hwa H. Chua ◽  
Simon A. Cobbold ◽  
Brunda Nijagal ◽  
James I. MacRae ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
High Coverage ◽  
Content Type ◽  
Chemical Libraries ◽  
Lead Compounds ◽  
Traumatic Acid ◽  
Highly Correlated ◽  
Induced Changes ◽  
Malaria Box

ABSTRACTHigh-throughput phenotypic screening of chemical libraries has resulted in the identification of thousands of compounds with potent antimalarial activity, although in most cases, the mechanism(s) of action of these compounds remains unknown. Here we have investigated the mode of action of 90 antimalarial compounds derived from the Malaria Box collection using high-coverage, untargeted metabolomics analysis. Approximately half of the tested compounds induced significant metabolic perturbations inin vitrocultures ofPlasmodium falciparum. In most cases, the metabolic profiles were highly correlated with known antimalarials, in particular artemisinin, the 4-aminoquinolines, or atovaquone. Select Malaria Box compounds also induced changes in intermediates in essential metabolic pathways, such as isoprenoid biosynthesis (i.e., 2-C-methyl-d-erythritol 2,4-cyclodiphosphate) and linolenic acid metabolism (i.e., traumatic acid). This study provides a comprehensive database of the metabolic perturbations induced by chemically diverse inhibitors and highlights the utility of metabolomics for triaging new lead compounds and defining specific modes of action, which will assist with the development and optimization of new antimalarial drugs.

scholarly journals Antimalarial Activity of Tulathromycin in a Murine Model of Malaria

2015 ◽  
Vol 59 (6) ◽  
pp. 3672-3674 ◽  
Author(s):  
Nicolas Villarino ◽  
Joshua E. Denny ◽  
Nathan W. Schmidt
Keyword(s):  
Murine Model ◽  
Antimalarial Activity ◽  
Parasite Burden ◽  
Plasmodium Yoelii ◽  
Content Type ◽  
Antimalarial Agents ◽  
Progression Of Disease ◽  
Time Of Infection ◽  
And Control

ABSTRACTThere is an urgent need for new antimalarial agents and strategies to treat and control malaria. This study shows an antiplasmodium effect of tulathromycin in mice infected withPlasmodium yoelii. The administration of tulathromycin around the time of infection prevented the progression of disease in 100% of the animals. In addition, highly parasitized mice treated with tulathromycin showed a decreased parasite burden and cleared the parasite faster than did untreated infected mice.

scholarly journals Cell Swelling Induced by the Antimalarial KAE609 (Cipargamin) and Other PfATP4-Associated Antimalarials

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Adelaide S. M. Dennis ◽  
Adele M. Lehane ◽  
Melanie C. Ridgway ◽  
John P. Holleran ◽  
Kiaran Kirk
Keyword(s):  
Malaria Parasite ◽  
Antimalarial Activity ◽  
External Environment ◽  
Osmotic Fragility ◽  
Cell Swelling ◽  
Efflux Transporter ◽  
Extracellular Medium ◽  
Human Malaria Parasite ◽  
Content Type ◽  
Antimalarial Agents

ABSTRACTFor an increasing number of antimalarial agents identified in high-throughput phenotypic screens, there is evidence that they target PfATP4, a putative Na+efflux transporter on the plasma membrane of the human malaria parasitePlasmodium falciparum. For several such “PfATP4-associated” compounds, it has been noted that their addition to parasitized erythrocytes results in cell swelling. Here we show that six structurally diverse PfATP4-associated compounds, including the clinical candidate KAE609 (cipargamin), induce swelling of both isolated blood-stage parasites and intact parasitized erythrocytes. The swelling of isolated parasites is dependent on the presence of Na+in the external environment and may be attributed to the osmotic consequences of Na+uptake. The swelling of the parasitized erythrocyte results in an increase in its osmotic fragility. Countering cell swelling by increasing the osmolarity of the extracellular medium reduces the antiplasmodial efficacy of PfATP4-associated compounds, consistent with cell swelling playing a role in the antimalarial activity of this class of compounds.

scholarly journals In Vivo Antimalarial Activity of the Beta-Carboline Alkaloid Manzamine A

2000 ◽  
Vol 44 (6) ◽  
pp. 1645-1649 ◽  
Author(s):  
Kenny K. H. Ang ◽  
Michael J. Holmes ◽  
Tatsuo Higa ◽  
Mark T. Hamann ◽  
Ursula A. K. Kara
Keyword(s):  
Plasmodium Berghei ◽  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Single Injection ◽  
Morphological Changes ◽  
Rodent Malaria Parasite ◽  
Manzamine A ◽  
Antimalarial Agents ◽  
Single Intraperitoneal Injection

ABSTRACT Manzamine A, a β-carboline alkaloid present in several marine sponge species, inhibits the growth of the rodent malaria parasitePlasmodium berghei in vivo. More than 90% of the asexual erythrocytic stages of P. berghei were inhibited after a single intraperitoneal injection of manzamine A into infected mice. A remarkable aspect of manzamine A treatment is its ability to prolong the survival of highly parasitemic mice, with 40% recovery 60 days after a single injection. Oral administration of an oil suspension of manzamine A also produced significant reductions in parasitemia. The plasma manzamine A concentration peaked 4 h after injection and remained high even at 48 h. Morphological changes of P. berghei were observed 1 h after treatment of infected mice. (−)-8-Hydroxymanzamine A also displayed antimalarial activity, whereas manzamine F, a ketone analog of manzamine A, did not. Our results suggest that manzamine A and (−)-8-hydroxymanzamine A are promising new antimalarial agents.

scholarly journals The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

2015 ◽  
Vol 59 (10) ◽  
pp. 6203-6209 ◽  
Author(s):  
Thomas E. Kraft ◽  
Christopher Armstrong ◽  
Monique R. Heitmeier ◽  
Audrey R. Odom ◽  
Paul W. Hruz
Keyword(s):  
Glucose Transporter ◽  
Antimalarial Activity ◽  
Primary Source ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Malaria Parasites ◽  
Content Type ◽  
Growth And Survival ◽  
New Therapeutic Approaches ◽  
Mechanistic Basis

ABSTRACTMalaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance ofPlasmodiumspecies to existing therapies has increased the need for new therapeutic approaches. ThePlasmodiumglucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.

scholarly journals Four Foodborne Disease Outbreaks Caused by a New Type of Enterotoxin-Producing Clostridium perfringens

2015 ◽  
Vol 53 (3) ◽  
pp. 859-867 ◽  
Author(s):  
Chie Monma ◽  
Kaoru Hatakeyama ◽  
Hiromi Obata ◽  
Keiko Yokoyama ◽  
Noriko Konishi ◽  
...  
Keyword(s):  
Clostridium Perfringens ◽  
Morphological Changes ◽  
Biological Activities ◽  
Disease Outbreaks ◽  
Vero Cells ◽  
Ileal Loop ◽  
L929 Cells ◽  
Content Type ◽  
Foodborne Outbreaks ◽  
New Type

The epidemiological and bacteriological investigations on four foodborne outbreaks caused by a new type of enterotoxin-producingClostridium perfringensare described.C. perfringensisolated from patients of these outbreaks did not produce any known enterotoxin and did not carry theC. perfringensenterotoxin gene. However, the culture filtrates of these isolates induced the accumulation of fluid in rabbit ileal loop tests. The molecular weight of the new enterotoxin may be between 50,000 and 100,000, although the knownC. perfringensenterotoxin is ca. 35,000. This new enterotoxin was heat labile, and its biological activities were inactivated by heating for 5 min at 60°C. The new enterotoxin was sensitive to pH values higher than 11.0 and protease treatment but was resistant to trypsin treatment. These results suggest that the new enterotoxin may be a protein. AlthoughC. perfringensenterotoxin induced morphological changes in Vero cells, the changes induced by the new enterotoxin differed from those by the knownC. perfringensenterotoxin. The new enterotoxin also induced morphological changes in L929 cells, whereas the knownC. perfringensenterotoxin did not, because L929 cells lacked an appropriate enterotoxin receptor. AlthoughC. perfringensenterotoxin is recognized as the only diarrheagenic toxin responsible forC. perfringensfoodborne outbreaks, the results of the present study indicate thatC. perfringensisolated from these four outbreaks produced a new type of enterotoxin.

scholarly journals The Antimalarial Activities of Methylene Blue and the 1,4-Naphthoquinone 3-[4-(Trifluoromethyl)Benzyl]-Menadione Are Not Due to Inhibition of the Mitochondrial Electron Transport Chain

2013 ◽  
Vol 57 (5) ◽  
pp. 2114-2120 ◽  
Author(s):  
Katharina Ehrhardt ◽  
Elisabeth Davioud-Charvet ◽  
Hangjun Ke ◽  
Akhil B. Vaidya ◽  
Michael Lanzer ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Protoporphyrin Ix ◽  
Redox Properties ◽  
Mitochondrial Electron Transport Chain ◽  
Content Type ◽  
Antimalarial Agents ◽  
Redox Active ◽  
Transport Chain

ABSTRACTMethylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agentsin vitroandin vivo. The activity of these structurally diverse compounds against the human malaria parasitePlasmodium falciparummight involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione are “subversive substrates.” These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III)-protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenicP. falciparumcell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates.

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