Two new 9-thiocyanatopupukeanane sesquiterpene isomers were isolated as major metabolites from the MeOH extract of the sponge Axinyssa aculeata and from its nudibranch predator Phyllidia varicosa. The presence of the sesquiterpenes was monitored by GC-MS, and the structures were confirmed by both 1D and 2D NMR spectroscopy. The isolated sesquiterpenes were found to be toxic toward brine shrimp at LC(50) of 5 ppm. At a dose level of 20 microg, they were found to be weakly and moderately active against B. subtilis and C. albicans, respectively.

The supply problem with regard to drug development and sustainable production lies in the limited amounts of biomass of most marine invertebrates available from wild stocks. Thus, most pharmacologically active marine natural products can only be isolated in minute yields. Total synthesis of pharmacologically active natural products has been successfully established but is in many cases economically not feasible due to the complexity of the molecular structures and the low yields. To solve the pressing supply issue in marine drug discovery, other strategies appear to be more promising. One of these is mariculture which has successfully been established with the bryozoan Bugula neritina (the source of the bryostatins) and the tunicate Ecteinascidia turbinata (the source of ET-743). Another strategy involves partial synthesis from precursors which are biotechnologically available. An example is ET-743 that can be partially synthesized from safracin B which is a metabolite of Pseudomonas fluorescens. There have been many examples of striking structural similarities between natural products obtained from marine invertebrates and those of microbial origin which suggests that microorganisms living in their invertebrate hosts could be the actual producers of these secondary metabolites. With regard to sustainable biotechnological production of pharmacologically important metabolites from marine invertebrates and their “endosymbionts”, a more advanced strategy is to focus on cloning and expression of the respective key biosynthetic gene clusters. This molecular biological approach will open up new avenues for biotechnological production of drugs or drug candidates from the sea

In view of the clinical need for new anti-epileptic drugs (AEDs) with novel modes of action, we used a zebrafish seizure model to screen the anticonvulsant activity of medicinal plants used for traditional epilepsy treatment in the Congo, identifying 4 crude plant extracts that inhibited pentylenetetrazol (PTZ)-induced seizures in zebrafish larvae. Zebrafish bioassay-guided fractionation of an anticonvulsant Fabaceae species, Indigofera arrecta, identified indirubin, an bis-indole alkaloid with known inhibitory activity at glycogen synthase kinase (GSK)-3, a well known protein kinase. Target validation experiments with partial loss of function of GSK-3 via antisense knockdown in zebrafish showed anticvonvulant activity against PTZ-induced seizures. Subsequently, indirubin, together with the more potent and GSK-3 specific derivative 6-bromoindirubin-3'-oxime (BIOacetoxime) and the structurally unrelated GSK-3β inhibitor 2-methyl-5-[3-[4-(methylsulfinyl)phenyl]-5-benzofuranyl]-1,3,4-oxadiazole (TCS2002), were tested in zebrafish and rodent seizure assays. All 3 compounds revealed anticonvulsant activity in PTZ-treated zebrafish larvae, with electroencephalographic recordings revealing reduction of epileptiform discharges. All 3 compounds also showed anticonvulsant activity in the pilocarpine rat model for limbic seizures and in the 6-Hz psychomotor refractory seizure mouse model. Moreover, BIOacetoxime, the most potent GSK-3 inhibitor was also able to exert anticonvulsant actions in 6-Hz fully kindled mice. Our findings provide the first evidence for anticonvulsant activity of selective GSK-3 inhibitors, thereby implicating GSK-3 as a potential new drug target for epilepsy. Our results also support the use of zebrafish bioassay-guided fractionation of anti-epileptic medicinal plant extracts as an effective strategy for the discovery of new AEDs with novel mechanisms of action.

Several approaches have been dedicated to activate the cryptic gene clusters in the genomes of actinomycetes for the targeted discovery of new fascinating biomedical lead structures. In the current study, N-acetylglucosamine was used to maximize the chemical diversity of sponge-derived actinomycete Actinokineospora spheciospongiae sp. nov. HR–ESI–MS was employed for dereplication study and orthogonal partial least square-discriminant analysis was applied to evaluate the HR–ESI–MS data of the different fractions. As a result, two new fridamycins H (1) and I (2), along with three known compounds actinosporin C (3), D (4), and G (5) were isolated from the solid culture of sponge-associated actinomycete Actinokineospora spheciospongiae sp. nov., elicited with N-acetylglucosamine. Characterization of the isolated compounds was pursued using mass spectrometry and NMR spectral data. Fridamycin H (1) exhibited significant growth inhibitory activity towards Trypanosoma brucei strain TC221. These results highlight the potential of elicitation in sponge-associated actinomycetes as an effective strategy for the discovery of new anti-infective natural products.Electronic supplementary materialThe online version of this article (10.1186/s13568-018-0730-0) contains supplementary material, which is available to authorized users.

Twelve propolis samples from different parts of Libya were investigated for their phytochemical constituents. Ethanol extracts of the samples and some purified compounds were tested against Trypanosoma brucei, Plasmodium falciparum and against two helminth species, Trichinella spiralis and Caenorhabditis elegans, showing various degrees of activity. Fourteen compounds were isolated from the propolis samples, including a novel compound Taxifolin-3-acetyl-4’-methyl ether (4), a flavanonol derivative. The crude extracts showed moderate activity against T. spiralis and C. elegans, while the purified compounds had low activity against P. falciparum. Anti-trypanosomal activity (EC50 = 0.7 µg/mL) was exhibited by a fraction containing a cardol identified as bilobol (10) and this fraction had no effect on Human Foreskin Fibroblasts (HFF), even at 2.0 mg/mL, thus demonstrating excellent selectivity. A metabolomics study was used to explore the mechanism of action of the fraction and it revealed significant disturbances in trypanosomal phospholipid metabolism, especially the formation of choline phospholipids. We conclude that a potent and highly selective new trypanocide may be present in the fraction.

Our search for biologically active marine natural products has led to the isolation of two new steroidal saponins, eryloside K (2) and eryloside L (3) together with the known antitumor and antifungal glycoside eryloside A (1) from the organic extract of the sponge Erylus lendenfeldi (Geodiidae) collected in the Red Sea. The structures of the new compounds were elucidated on the basis of comprehensive spectral analyses ( 1 H, 13 C, COSY, HMQC, HMBC and TOCSY NMR) as well as GC/MS analysis to infer the absolute stereochemistry of the sugar moieties. Eryloside K (2) is the 24,25-didehydro congener of 1, while eryloside L (3) features an unusual 8α,9α-epoxy-4α-methyl-8,9-secocholesta-7,9(11),14-triene skeleton which appears to be unprecedented in nature. Eryloside A (1) displayed antibacterial activity against Bacillus subtilis and Escherichia coli together with antifungal activity against Candida albicans.

Investigation of the marine sponge Dysidea avara, family Dysideidae, afforded a new sesquiterpene (-)-N-methylmelemeleone-A (5), in addition to four known sesquiterpenes (+)-avarol (1), (+)-avarone (2), (-)-3'-methylaminoavarone (3) and (-)-4'-methylaminoavarone (4). The structure elucidation of compound 5 was based on 1D and 2D NMR spectroscopic, and HR-MS studies, as well as by comparison with the literature. Cytotoxicity, protein kinase inhibition, inhibition of NFkB-activity and insecticidal activity were evaluated for the isolated compounds.

The discovery of new secondary metabolites from natural origins has become more challenging in natural products research. Different approaches have been applied to target the isolation of new bioactive metabolites from plant extracts. In this study, bioactive natural products were isolated from the crude organic extract of the mangrove plant Avicennia lanata collected from the east coast of Peninsular Malaysia in the Setiu Wetlands, Terengganu, using HRESI-LCMS-based metabolomics-guided isolation and fractionation. Isolation work on the crude extract A. lanata used high-throughput chromatographic techniques to give two new naphthofuranquinone derivatives, hydroxyavicenol C (1) and glycosemiquinone (2), along with the known compounds avicenol C (3), avicequinone C (4), glycoquinone (5), taraxerone (6), taraxerol (7), β-sitosterol (8) and stigmasterol (9). The elucidation and identification of the targeted bioactive compounds used 1D and 2D-NMR and mass spectrometry. Except for 6–9, all isolated naphthoquinone compounds (1–5) from the mangrove plant A. lanata showed significant anti-trypanosomal activity on Trypanosoma brucei brucei with MIC values of 3.12–12.5 μM. Preliminary cytotoxicity screening against normal prostate cells (PNT2A) was also performed. All compounds exhibited low cytotoxicity, with compounds 3 and 4 showing moderate cytotoxicity of 78.3% and 68.6% of the control values at 100 μg/mL, respectively.