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Open AccessFeature PaperArticle

Bifurcatriol, a New Antiprotozoal Acyclic Diterpene from the Brown Alga Bifurcaria bifurcata

by Vangelis Smyrniotopoulos, Christian Merten, Marcel Kaiser and Deniz Tasdemir

Mar. Drugs 2017, 15(8), 245; https://doi.org/10.3390/md15080245 - 2 Aug 2017

Cited by 44 | Viewed by 5492

Abstract

Linear diterpenes that are commonly found in brown algae are of high chemotaxonomic and ecological importance. This study reports bifurcatriol (1), a new linear diterpene featuring two stereogenic centers isolated from the Irish brown alga Bifurcaria bifurcata. The gross structure of this [...] Read more.

Linear diterpenes that are commonly found in brown algae are of high chemotaxonomic and ecological importance. This study reports bifurcatriol (1), a new linear diterpene featuring two stereogenic centers isolated from the Irish brown alga Bifurcaria bifurcata. The gross structure of this new natural product was elucidated based on its spectroscopic data (IR, 1D and 2D-NMR, HRMS). Its absolute configuration was identified by experimental and computational vibrational circular dichroism (VCD) spectroscopy, combined with the calculation of ¹³C-NMR chemical shielding constants. Bifurcatriol (1) was tested for in vitro antiprotozoal activity towards a small panel of parasites (Plasmodium falciparum, Trypanosoma brucei rhodesiense, T. cruzi, and Leishmania donovani) and cytotoxicity against mammalian primary cells. The highest activity was exerted against the malaria parasite P. falciparum (IC₅₀ value 0.65 μg/mL) with low cytotoxicity (IC₅₀ value 56.6 μg/mL). To our knowledge, this is the first successful application of VCD and DP4 probability analysis of the calculated ¹³C-NMR chemical shifts for the simultaneous assignment of the absolute configuration of multiple stereogenic centers in a long-chain acyclic natural product. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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1629 KiB

Open AccessArticle

Chemoinformatic Analysis as a Tool for Prioritization of Trypanocidal Marine Derived Lead Compounds

by Yunjiang Feng, Marc Campitelli, Rohan A. Davis and Ronald J. Quinn

Mar. Drugs 2014, 12(3), 1169-1184; https://doi.org/10.3390/md12031169 - 4 Mar 2014

Cited by 9 | Viewed by 7935

Abstract

Marine trypanocidal natural products are, most often, reported with trypanocidal activity and selectivity against human cell lines. The triaging of hits requires a consideration of chemical tractability for drug development. We utilized a combined Lipinski’s rule-of-five, chemical clustering and ChemGPS-NP principle analysis to [...] Read more.

Marine trypanocidal natural products are, most often, reported with trypanocidal activity and selectivity against human cell lines. The triaging of hits requires a consideration of chemical tractability for drug development. We utilized a combined Lipinski’s rule-of-five, chemical clustering and ChemGPS-NP principle analysis to analyze a set of 40 antitrypanosomal natural products for their drug like properties and chemical space. The analyses identified 16 chemical clusters with 11 well positioned within drug-like chemical space. This study demonstrated that our combined analysis can be used as an important strategy for prioritization of active marine natural products for further investigation. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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583 KiB

Open AccessArticle

Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

by Laurent Calcul, Carrie Waterman, Wai Sheung Ma, Matthew D. Lebar, Charles Harter, Tina Mutka, Lindsay Morton, Patrick Maignan, Alberto Van Olphen, Dennis E. Kyle, Lilian Vrijmoed, Ka-Lai Pang, Cedric Pearce and Bill J. Baker

Mar. Drugs 2013, 11(12), 5036-5050; https://doi.org/10.3390/md11125036 - 12 Dec 2013

Cited by 56 | Viewed by 10299

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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749 KiB

Open AccessArticle

Assessment of Dual Life Stage Antiplasmodial Activity of British Seaweeds

by Jasmine Spavieri, Andrea Allmendinger, Marcel Kaiser, Maurice Ayamba Itoe, Gerald Blunden, Maria M. Mota and Deniz Tasdemir

Mar. Drugs 2013, 11(10), 4019-4034; https://doi.org/10.3390/md11104019 - 22 Oct 2013

Cited by 25 | Viewed by 7150

Abstract

Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts [...] Read more.

Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS) and liver stage (LS) Plasmodium parasites. The majority (14) of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC₅₀s around 3 μg/mL). The extracts generally had high selectivity indices (>10). Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7) cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC₅₀ values 14.9 to 28.8 μg/mL). The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II) pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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413 KiB

Open AccessArticle

Synthesis of Marine α-Methoxylated Fatty Acid Analogs that Effectively Inhibit the Topoisomerase IB from Leishmania donovani with a Mechanism Different from that of Camptothecin

by Néstor M. Carballeira, Nashbly Montano, Raquel Alvarez-Velilla, Christopher F. Prada, Rosa M. Reguera and Rafael Balaña-Fouce

Mar. Drugs 2013, 11(10), 3661-3675; https://doi.org/10.3390/md11103661 - 30 Sep 2013

Cited by 16 | Viewed by 6519

Abstract

Sponges biosynthesize α-methoxylated fatty acids with unusual biophysical and biological properties and in some cases they display enhanced anticancer activities. However, the antiprotozoal properties of the α-methoxylated fatty acids have been less studied. In this work, we describe the total synthesis of (5 [...] Read more.

Sponges biosynthesize α-methoxylated fatty acids with unusual biophysical and biological properties and in some cases they display enhanced anticancer activities. However, the antiprotozoal properties of the α-methoxylated fatty acids have been less studied. In this work, we describe the total synthesis of (5Z,9Z)-(±)-2-methoxy-5, 9-eicosadienoic acid (1) and its acetylenic analog (±)-2-methoxy-5,9-eicosadiynoic acid (2), and report that they inhibit (EC₅₀ values between 31 and 22 µM) the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB). The inhibition of LdTopIB (EC₅₀ = 53 µM) by the acid (±)-2-methoxy-6-icosynoic acid (12) was studied as well. The potency of LdTopIB inhibition followed the trend 2 > 1 > 12, indicating that the effectiveness of inhibition depends on the degree of unsaturation. All of the studied α-methoxylated fatty acids failed to inhibit the human topoisomerase IB enzyme (hTopIB) at 100 µM. However, the α-methoxylated fatty acids were capable of inhibiting an active but truncated LdTopIB with which camptothecin (CPT) cannot interact suggesting that the methoxylated fatty acids inhibit LdTopIB with a mechanism different from that of CPT. The diunsaturated fatty acids displayed low cytotoxicity towards Leishmania infantum promastigotes (EC₅₀ values between 260 and 240 µM), but 12 displayed a better cytotoxicity towards Leishmania donovani promastigotes (EC₅₀ = 100 µM) and a better therapeutic index. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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797 KiB

Open AccessArticle

Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents

by Cary F. C. Lam, A. Norrie Pearce, Shen H. Tan, Marcel Kaiser and Brent R. Copp

Mar. Drugs 2013, 11(9), 3472-3499; https://doi.org/10.3390/md11093472 - 9 Sep 2013

Cited by 22 | Viewed by 7433

Abstract

Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC₅₀ 3.1 μM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC₅₀ 3.3 μM) while exhibiting low [...] Read more.

Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC₅₀ 3.1 μM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC₅₀ 3.3 μM) while exhibiting low levels of cytotoxicity (L6, IC₅₀ 167 μM). A series of C-7 amide and Δ²⁽³⁾ analogues were prepared that explored the influence of lipophilicity and oxidation state on observed anti-protozoal activity and selectivity. Little variation in anti-malarial potency was observed (IC₅₀ 0.62–6.5 μM), and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and Δ²⁽³⁾-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while Δ²⁽³⁾-phenethylamide 8e (IC₅₀ 0.67 μM, SI 78) exhibited improved potency and selectivity towards T. brucei rhodesiense compared to the natural product hit. A second series of analogues were prepared that replaced the quinoline ring of 2 with benzofuran or benzothiophene moieties. While esters 10a/10b and 15 were once again found to exhibit cytotoxicity, carboxylic acid analogues exhibited potent anti-Pf activity (IC₅₀ 0.34–0.035 μM) combined with excellent selectivity (SI 560–4000). In vivo evaluation of a furan carboxylic acid analogue against P. berghei was undertaken, demonstrating 85.7% and 47% reductions in parasitaemia with ip or oral dosing respectively. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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Open AccessArticle

Natural and Semisynthetic Analogues of Manadoperoxide B Reveal New Structural Requirements for Trypanocidal Activity

by Giuseppina Chianese, Fernando Scala, Barbara Calcinai, Carlo Cerrano, Henny A. Dien, Marcel Kaiser, Deniz Tasdemir and Orazio Taglialatela-Scafati

Mar. Drugs 2013, 11(9), 3297-3308; https://doi.org/10.3390/md11093297 - 28 Aug 2013

Cited by 14 | Viewed by 7016

Abstract

Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1), namely 12-isomanadoperoxide B (2) and manadoperoxidic acid B (3). These compounds were isolated along with [...] Read more.

Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1), namely 12-isomanadoperoxide B (2) and manadoperoxidic acid B (3). These compounds were isolated along with a new short chain dicarboxylate monoester (4), bearing some interesting relationships with the polyketide endoperoxides found in this sponge. Some semi-synthetic analogues of manadoperoxide B (6–8) were prepared and evaluated for antitrypanosomal activity and cytotoxicity. These studies revealed crucial structure–activity relationships that should be taken into account in the design of optimized and simplified endoperoxyketal trypanocidal agents. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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Review

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Open AccessReview

Marine Algae as Source of Novel Antileishmanial Drugs: A Review

by Lauve Rachel Tchokouaha Yamthe, Regina Appiah-Opong, Patrick Valere Tsouh Fokou, Nole Tsabang, Fabrice Fekam Boyom, Alexander Kwadwo Nyarko and Michael David Wilson

Mar. Drugs 2017, 15(11), 323; https://doi.org/10.3390/md15110323 - 29 Oct 2017

Cited by 27 | Viewed by 8094

Abstract

Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the Leishmania genus and transmitted by the female Phlebotomus and Lutzomyia sand flies. The currently prescribed therapies still rely on pentavalent antimonials, pentamidine, paromomycin, liposomal amphotericin B, and miltefosine. However, their [...] Read more.

Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the Leishmania genus and transmitted by the female Phlebotomus and Lutzomyia sand flies. The currently prescribed therapies still rely on pentavalent antimonials, pentamidine, paromomycin, liposomal amphotericin B, and miltefosine. However, their low efficacy, long-course treatment regimen, high toxicity, adverse side effects, induction of parasite resistance and high cost require the need for better drugs given that antileishmanial vaccines may not be available in the near future. Although most drugs are still derived from terrestrial sources, the interest in marine organisms as a potential source of promising novel bioactive natural agents has increased in recent years. About 28,000 compounds of marine origin have been isolated with hundreds of new chemical entities. Recent trends in drug research from natural resources indicated the high interest of aquatic eukaryotic photosynthetic organisms, marine algae in the search for new chemical entities given their broad spectrum and high bioactivities including antileishmanial potential. This current review describes prepared extracts and compounds from marine macroalgae along with their antileishmanial activity and provides prospective insights for antileishmanial drug discovery. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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1043 KiB

Open AccessReview

Trypanocidal Activity of Marine Natural Products

by Amy J. Jones, Tanja Grkovic, Melissa L. Sykes and Vicky M. Avery

Mar. Drugs 2013, 11(10), 4058-4082; https://doi.org/10.3390/md11104058 - 22 Oct 2013

Cited by 41 | Viewed by 11285

Abstract

Marine natural products are a diverse, unique collection of compounds with immense therapeutic potential. This has resulted in these molecules being evaluated for a number of different disease indications including the neglected protozoan diseases, human African trypanosomiasis and Chagas disease, for which very [...] Read more.

Marine natural products are a diverse, unique collection of compounds with immense therapeutic potential. This has resulted in these molecules being evaluated for a number of different disease indications including the neglected protozoan diseases, human African trypanosomiasis and Chagas disease, for which very few drugs are currently available. This article will review the marine natural products for which activity against the kinetoplastid parasites; Trypanosoma brucei brucei, T.b. rhodesiense and T. cruzi has been reported. As it is important to know the selectivity of a compound when evaluating its trypanocidal activity, this article will only cover molecules which have simultaneously been tested for cytotoxicity against a mammalian cell line. Compounds have been grouped according to their chemical structure and representative examples from each class were selected for detailed discussion. Full article

(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)

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