CNS and antimalarial activity of synthetic meridianin and psammopemmin analogs

Lebar, Matthew D.; Hahn, Kristopher N.; Mutka, Tina; Maignan, Patrick; McClintock, James B.; Amsler, Charles D.; Olphen, Alberto van; Kyle, Dennis E.; Baker, Bill J.

doi:10.1016/j.bmc.2011.08.033

Cited by 33 publications

(38 citation statements)

References 33 publications

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“…Using a robust and validated Plasmodium falciparum (3D7, a drug sensitive strain) screen [13], 96-well plated crude extract screening data was available to us weekly. Our workflow (Scheme 1) included decision points based on crude extract activity, leading to scaled-up cultivation, then new decision points based both on IC 50 values of parasite and mammalian (A549) cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…After transfer of 100 μL aliquots into 96-well plates, screening at two concentrations (5 and 50 μg/mL) using our previously published protocol [13] was conducted. Samples were prioritized as Active if they inhibited 3D7 by ≥67% at 5 µg/mL, and Partially Active if there was >67% inhibition at 50 µg/mL, leading to approximately 0.6% extracts categorized as Active, ~5% Partially Active, and more than 90% inactive.…”

Section: Resultsmentioning

confidence: 99%

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Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

et al. 2013

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We conducted a screening campaign to investigate fungi as a source for new antimalarial compounds. A subset of our fungal collection comprising Chinese mangrove endophytes provided over 5000 lipophilic extracts. We developed an accelerated discovery program based on small-scale cultivation for crude extract screening and a high-throughput malaria assay. Criteria for hits were developed and high priority hits were subjected to scale-up cultivation. Extracts from large scale cultivation were fractionated and these fractions subjected to both in vitro malaria and cytotoxicity screening. Criteria for advancing fractions to purification were developed, including the introduction of a selectivity index and by dereplication of known metabolites. From the Chinese mangrove endophytes, four new compounds (14–16, 18) were isolated including a new dimeric tetrahydroxanthone, dicerandrol D (14), which was found to display the most favorable bioactivity profile.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

et al. 2013

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“…Meridianin is a small family of alkaloids, meridianins F, G ( 94, 95 ) were reported from the ascidian Aplidium meridianum [ 62 ]. Compound ( 85 ) was synthesized by Lebar et al [ 92 ] and further investigation of meridianins A–G ( 95 ) which was physically synthesized by catalytic Domino amino reaction [ 93 ]. Compounds 85, 95, tested to anti-malarial inhibition against human malaria parasite P. falciparum, showed a moderate activity against both strains IC 50 50 and 4.4 µM [ 92 , 94 ].…”

Section: Pharmacological Activity Of Ascidian Compoundsmentioning

confidence: 99%

Natural Products Diversity of Marine Ascidians (Tunicates; Ascidiacea) and Successful Drugs in Clinical Development

Palanisamy

Rajendran

Marino

2017

Nat. Prod. Bioprospect.

104

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This present study reviewed the chemical diversity of marine ascidians and their pharmacological applications, challenges and recent developments in marine drug discovery reported during 1994–2014, highlighting the structural activity of compounds produced by these specimens. Till date only 5% of living ascidian species were studied from <3000 species, this study represented from family didemnidae (32%), polyclinidae (22%), styelidae and polycitoridae (11–12%) exhibiting the highest number of promising MNPs. Close to 580 compound structures are here discussed in terms of their occurrence, structural type and reported biological activity. Anti-cancer drugs are the main area of interest in the screening of MNPs from ascidians (64%), followed by anti-malarial (6%) and remaining others. FDA approved ascidian compounds mechanism of action along with other compounds status of clinical trials (phase 1 to phase 3) are discussed here in. This review highlights recent developments in the area of natural products chemistry and biotechnological approaches are emphasized.

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“…The cytotoxicity screen used for crude extracts, fractions, and isolated compounds was followed according to previously described methods . Briefly, cell line A549 (adenocarcinomic human alveolar epithelial cells) was cultured in F‐12K Nutrient Mixture (Kaighn's Modification) media containing l ‐glutamine, supplemented with 10% fetal bovine serum and 1% penicillin–streptomycin.…”

Section: Approachmentioning

confidence: 99%

Miniaturized Cultivation of Microbiota for Antimalarial Drug Discovery

Waterman

Calcul

Beau

et al. 2014

Medicinal Research Reviews

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The ongoing search for effective antiplasmodial agents remains essential in the fight against malaria worldwide. Emerging parasitic drug resistance places an urgent need to explore chemotherapies with novel structures and mechanisms of action. Natural products have historically provided effective antimalarial drug scaffolds. In an effort to search nature's chemical potential for antiplasmodial agents, unconventionally sourced organisms coupled with innovative cultivation techniques were utilized. Approximately 60,000 niche microbes from various habitats (slow-growing terrestrial fungi, Antarctic microbes, and mangrove endophytes) were cultivated on a small-scale, extracted, and used in high-throughput screening to determine antimalarial activity. About 1% of crude extracts were considered active and 6% partially active (≥ 67% inhibition at 5 and 50 μg/mL, respectively). Active extracts (685) were cultivated on a large-scale, fractionated, and screened for both antimalarial activity and cytotoxicity. High interest fractions (397) with an IC50 < 1.11 μg/mL were identified and subjected to chromatographic separation for compound characterization and dereplication. Identifying active compounds with nanomolar antimalarial activity coupled with a selectivity index tenfold higher was accomplished with two of the 52 compounds isolated. This microscale, high-throughput screening project for antiplasmodial agents is discussed in the context of current natural product drug discovery efforts.

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CNS and antimalarial activity of synthetic meridianin and psammopemmin analogs

Cited by 33 publications

References 33 publications

Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

Natural Products Diversity of Marine Ascidians (Tunicates; Ascidiacea) and Successful Drugs in Clinical Development

Miniaturized Cultivation of Microbiota for Antimalarial Drug Discovery

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