Antimalarial activity of crambescidin 800 and synthetic analogues against liver and blood stage of Plasmodium sp.
ABSTRACT Structural features associated with the antimalarial activity of the marine natural product crambescidin 800 were studied using synthetic analogues of the related compound ptilomycalin A. The study suggests that the guanidine moiety is cytotoxic, whereas the spermidine-containing aliphatic chain increases activity. The most active analogue, compound 11, had in vitro activity against Plasmodium falciparum strain 3D7 (IC50=490 nM) that was stronger than the in vitro activity against murine L5178Y cells (IC50 = 8.5-59 microM). In vitro growth inhibition of liver stages of P. yoelii yoelii in mouse hepatocytes was observed (IC50 = 9.2 microM). The compound did not significantly prolong median survival time after a single subcutaneous administration of 80 mg/kg in P. berghei-infected mice. Compound 11 did not cause DNA fragmentation in an in vitro micronucleus assay.
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ABSTRACT: This review highlights recently discovered antimalarial natural products from marine and freshwater sources described in the literature from 2006 to 2008. The structures as well as bioactivities of compounds against the malaria parasites such as Plasmodium falciparum are discussed, including, for example, agelasine, xestoquinone, alisiaquinone, crambescidin, venturamide, dragomabin, gragonamide, viridamide, salinosporamide, chaetoxanthone, nodulisporacid, tumonoic acid, girolline, oroidin, nostocarboline, aerucyclamide, and microcylamide 7806 and its revised structure. Synthetic derivatives of natural products are presented including plakortin, isoaaptamine, curcuphenol, pseudopyronine, manzamine, and nostocarboline. Consequences of these discoveries for the development of novel natural product agents against malaria are discussed.The Chemical Record 06/2009; 9(3):187-98. · 4.38 Impact Factor
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ABSTRACT: For more than 25 years, the ISI assay and ILSDA have been used to study the development of the malaria parasite in the liver, to discover and characterize sporozoite and liver-stage antigens, to support the development of malaria vaccine candidates, and to search for immunological correlates of protection in animals and in humans. Although both assays have been limited by low sporozoite invasion rates, significant biological variability, and the subjective nature of manually counting hepatocytes containing parasites as the read-out, they have nevertheless been useful tools for exploring parasite biology. This review describes the origin, application and current status of these assays, critically discusses the need for improvements, and explores the roles of these assays in supporting the development of an effective vaccine against Plasmodium falciparum malaria.Trends in Parasitology 09/2009; 25(11):525-33. · 5.51 Impact Factor
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ABSTRACT: This review focuses on six important parasitic diseases that adversely affect the health and lives of over one billion people worldwide. In light of the global human impact of these neglected tropical diseases (NTDs), several initiatives and campaigns have been mounted to eradicate these infections once and for all. Currently available therapeutics summarized herein are either ineffective and/or have severe and deleterious side effects. Resistant strains continue to emerge and there is an overall unmet and urgent need for new antiparasitic drugs. Marine-derived small molecules (MDSMs) from invertebrates comprise an extremely diverse and promising source of compounds from a wide variety of structural classes. New discoveries of marine natural product privileged structures and compound classes that are being made via natural product library screening using whole cell in vitro assays are highlighted. It is striking to note that for the first time in history the entire genomes of all six parasites have been sequenced and additional transcriptome and proteomic analyses are available. Furthermore, open and shared, publicly available databases of the genome sequences, compounds, screening assays, and druggable molecular targets are being used by the worldwide research community. A combined assessment of all of the above factors, especially of current discoveries in marine natural products, implies a brighter future with more effective, affordable, and benign antiparasitic therapeutics.Current opinion in biotechnology 10/2010; 21(6):808-18. · 7.82 Impact Factor
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