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Marine natural products (MNPs) continue to be tested primarily in cellular toxicity assays, both mammalian and microbial, despite most being inactive at concentrations relevant to drug discovery. These MNPs become missed opportunities and represent a wasteful use of precious bioresources. The use of cheminformatics aligned with published bioactivity data can provide insights to direct the choice of bioassays for the evaluation of new MNPs. Cheminformatics analysis of MNPs found in MarinLit ( n = 39,730) up to the end of 2023 highlighted indol-3-yl-glyoxylamides (IGAs, n = 24) as a group of MNPs with no reported bioactivities. However, a recent review of synthetic IGAs highlighted these scaffolds as privileged structures with several compounds under clinical evaluation. Herein, we report the synthesis of a library of 32 MNP-inspired brominated IGAs ( 25 - 56 ) using a simple one-pot, multistep method affording access to these diverse chemical scaffolds. Directed by a meta-analysis of the biological activities reported for marine indole alkaloids (MIAs) and synthetic IGAs, the brominated IGAs 25 - 56 were examined for their potential bioactivities against the Parkinson's Disease amyloid protein alpha synuclein (α-syn), antiplasmodial activities against chloroquine-resistant (3D7) and sensitive (Dd2) parasite strains of Plasmodium falciparum , and inhibition of mammalian (chymotrypsin and elastase) and viral (SARS-CoV-2 3CL pro ) proteases. All of the synthetic IGAs tested exhibited binding affinity to the amyloid protein α-syn, while some showed inhibitory activities against P. falciparum , and the proteases, SARS-CoV-2 3CL pro , and chymotrypsin. The cellular safety of the IGAs was examined against cancerous and non-cancerous human cell lines, with all of the compounds tested inactive, thereby validating cheminformatics and meta-analyses results. The findings presented herein expand our knowledge of marine IGA bioactive chemical space and advocate expanding the scope of biological assays routinely used to investigate NP bioactivities, specifically those more suitable for non-toxic compounds. By integrating cheminformatics tools and functional assays into NP biological testing workflows, we can aim to enhance the potential of NPs and their scaffolds for future drug discovery and development.

Covering: January to the end of December 2022This review covers the literature published in 2022 for marine natural products (MNPs), with 645 citations (633 for the period January to December 2022) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, the submerged parts of mangroves and other intertidal plants. The emphasis is on new compounds (1417 in 384 papers for 2022), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of NP structure class diversity in relation to biota source and biome is discussed.

Covering: marine indole alkaloids ( n = 2048) and their reported bioactivities up to the end of 2021Despite increasing numbers of marine natural products (MNPs) reported each year, most have only been examined for cytotoxic, antibacterial, and/or antifungal biological activities with the majority found to be inactive in these assays. In this context, why are natural products continuing to be examined in assays they are unlikely to show significant activity in, and what targets might be more useful for expanding knowledge of their biologically relevant chemical space? We have undertaken a meta-analysis of the biological activities for 2048 marine indole alkaloids (MIAs), a diverse sub-class of MNPs reported up to the end of 2021, and this has highlighted that the bioactivity potentials for up to 86% of published MIAs remains underexplored and/or undefined. Although most published MIAs are not cytotoxic or antimicrobial, there is a continued focus on using these assays to evaluate new structurally related analogues. Using cheminformatics analyses, the chemical diversity of the 2048 MIAs were clustered using fragment based fingerprints and their reported bioactivity potency towards specific disease targets was assessed for structure activity trends. These analyses showed that there are groups of MIAs that possess potent and diverse activities and that many analogues, previously tested only in cellular toxicity assays, could be better exploited to generate structure activity relationships associated with leads to treat emerging diseases. A collection of indole drug and drug-lead structures from non-natural sources were also incorporated into the dataset providing complementary bioactivity profiles that were further used to predict underexplored areas of potential new activity and to better direct future testing of MIAs. Our findings clearly suggest the biological evaluation of MIAs continues to be conducted on a narrow range of bioassays and disease targets, and that shifting the focus to non-toxic disease targets should provide expanded knowledge of biologically relevant chemical space aimed at maximising the potential of MIAs for drug discovery.

Covering: January to December 2021This review covers the literature published in 2021 for marine natural products (MNPs), with 736 citations (724 for the period January to December 2021) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1425 in 416 papers for 2021), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of the number of authors, their affiliations, domestic and international collection locations, focus of MNP studies, citation metrics and journal choices is discussed.

Covering: 2020This review covers the literature published in 2020 for marine natural products (MNPs), with 757 citations (747 for the period January to December 2020) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1407 in 420 papers for 2020), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. A meta analysis of bioactivity data relating to new MNPs reported over the last five years is also presented.

Covering: 1877 to 2020A key challenge in natural products research is the selection of biodiversity to yield novel chemistry. Recently, marine microorganisms have become a preferred source. But how novel are marine microorganism natural products compared to those reported from terrestrial microbes? Cluster analysis of chemical fingerprints and molecular scaffold analysis of 55 817 compounds reported from marine and terrestrial microorganisms, and marine macro-organisms showed that 76.7% of the compounds isolated from marine microorganisms are closely related to compounds isolated from terrestrial microorganisms. Only 14.3% of marine microorganism natural products are unique when marine macro-organism natural products are also considered. Studies targeting marine specific and understudied microbial phyla result in a higher likelihood of finding marine specific compounds, whereas the depth and geographic location of microorganism collection have little influence. We recommend marine targeted strain isolation, incorporating early use of genomic sequencing to guide strain selection, innovation in culture media and cultivation techniques and the application of cheminformatics tools to focus on unique natural product diversity, rather than the dereplication of known compounds.

This review covers the literature published in 2019 for marine natural products (MNPs), with 719 citations (701 for the period January to December 2019) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1490 in 440 papers for 2019), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. Methods used to study marine fungi and their chemical diversity have also been discussed.

This review covers the literature published between January and December in 2018 for marine natural products (MNPs), with 717 citations (706 for the period January to December 2018) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1554 in 469 papers for 2018), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. The proportion of MNPs assigned absolute configuration over the last decade is also surveyed.

Covering: January to December 2017This review covers the literature published in 2017 for marine natural products (MNPs), with 740 citations (723 for the period January to December 2017) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1490 in 477 papers for 2017), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. Geographic distributions of MNPs at a phylogenetic level are reported.

Covering: 2016. Previous review: Nat. Prod. Rep., 2017, 34, 235-294This review covers the literature published in 2016 for marine natural products (MNPs), with 757 citations (643 for the period January to December 2016) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1277 in 432 papers for 2016), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included.

One of the major medical challenges of the twenty-first century is the treatment of incurable and fatal neurodegenerative disorders caused by misfolded prion proteins. Since the discovery of these diseases a number of studies have been conducted to identify small molecules for their treatment, however to date no curative treatment is available. These studies can be highly expensive and time consuming, but more recent experimental approaches indicate a significant application for yeast prions in these studies. We therefore used yeast prions to optimize previous high-throughput methods for the cheaper, easier and more rapid screening of natural extracts. Through this approach we aimed to identify natural yeast-prion inhibitors that could be useful in the development of novel treatment strategies for neurodegenerative disorders. We screened 500 marine invertebrate extracts from temperate waters in Australia allowing the identification of yeast-prion inhibiting extracts. Through the bioassay-driven chemical investigation of an active Suberites sponge extract, a group of bromotyrosine derivatives were identified as potent yeast-prion inhibitors. This study outlines the importance of natural products and yeast prions as a first-stage screen for the identification of new chemically diverse and bioactive compounds.

The discovery of novel and/or new bioactive natural products from biota sources is often confounded by the reisolation of known natural products. Dereplication strategies that involve the analysis of NMR and MS spectroscopic data to infer structural features present in purified natural products in combination with database searches of these substructures provide an efficient method to rapidly identify known natural products. Unfortunately this strategy has been hampered by the lack of publically available and comprehensive natural product databases and open source cheminformatics tools. A new platform, DEREP-NP, has been developed to help solve this problem. DEREP-NP uses the open source cheminformatics program DataWarrior to generate a database containing counts of 65 structural fragments present in 229 358 natural product structures derived from plants, animals, and microorganisms, published before 2013 and freely available in the nonproprietary Universal Natural Products Database (UNPD). By counting the number of times one or more of these structural features occurs in an unknown compound, as deduced from the analysis of its NMR ( 1 H, HSQC, and/or HMBC) and/or MS data, matching structures carrying the same numeric combination of searched structural features can be retrieved from the database. Confirmation that the matching structure is the same compound can then be verified through literature comparison of spectroscopic data. This methodology can be applied to both purified natural products and fractions containing a small number of individual compounds that are often generated as screening libraries. The utility of DEREP-NP has been verified through the analysis of spectra derived from compounds (and fractions containing two or three compounds) isolated from plant, marine invertebrate, and fungal sources. DEREP-NP is freely available at https://github.com/clzani/DEREP-NP and will help to streamline the natural product discovery process.

Sponges are a useful source of bioactive natural products. Members of the family Mycalidae, in particular, have provided a variety of chemical structures including alkaloids, polyketides, terpene endoperoxides, peptides, and lipids. This review highlights the compounds isolated from Mycalid sponges and their associated biological activities. A diverse group of 190 compounds have been reported from over 40 specimens contained in 49 references. Over half of the studies have reported on the biological activities for the compounds isolated. The polyketides, in particular the macrolides, displayed potent cytotoxic activities (< 1 µM), and the alkaloids, in particular the 2,5-disubstituted pyrrole derivatives, were associated with moderate cytotoxic activities (1-20 µM). The pyrrole alkaloids and the cyclic peroxides appear to be phylogenetically restricted to sponges and thus might prove useful when applied to sponge taxonomy. The observed diversity of chemical structures suggests this family makes a good target for targeted biodiscovery projects., (Georg Thieme Verlag KG Stuttgart · New York.)

In the period from January 1981 to December 2010, 1068 small-molecule new chemical entities (NCEs) were introduced, of which ca. 34% are either a natural product or a close analogue. While this metric reflects the impact natural products have played in delivering new chemical starting points (leads) for the pharmaceutical industry, it does not capture the decline this approach has suffered over the last 20 years as the high-throughput screening (HTS) of pure compound libraries has become more popular. An impediment to natural-product drug discovery in the HTS paradigm is the lack of a clear strategy that enables front-loading of an extract or fraction's chemical constituents so that they are compliant with lead- and drug-like chemical space. To address this imbalance, an approach based on lipophilicity, as measured by clog P has been developed that, together with advances being made in isolation and structural elucidation, can afford natural product leads in timelines compatible with pure compound screening., (Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.)

Bioassay-guided fractionation of a CH2Cl2/MeOH extract of the sponge Suberea clavata using the serine protease factor XIa to detect antithrombotic activity led to the isolation of the new marine natural products, clavatadines A and B. Clavatadines A and B inhibited factor XIa with IC50's of 1.3 and 27 microM, respectively. A crystal structure of protein-inhibitor (clavatadine A) complex was obtained and revealed interesting selective binding and irreversible inhibition of factor XIa. The cocrystal structure provides guidance for the design and synthesis of future factor XIa inhibitors as antithrombotic agents.

An NMR protocol that uses the residual proton signal from DMSO -d(6) (i.e., DMSO -d(5)) to determine the concentration of an analyte in a NMR sample was developed. This technique provides an alternative method for determining the molar concentration of compounds in solution without prior knowledge of their molecular weight. The method is particularly useful when submilligram quantities of compound are to be analyzed and is applicable to a variety of different research areas such as compound management, and natural product, combinatorial, and medicinal chemistry.

Addressing drug-like/lead-like properties of biologically active small molecules early in a lead generation program is the current paradigm within the drug discovery community. Lipinski's "rule of five" has become the most commonly used tool to assess the relationship between structures and drug-like properties. Sixty percent of the 126 140 unique compounds in The Dictionary of Natural Products had no violations of Lipinski's "rule of five". We have isolated 814 natural products based on their expected drug-like/lead-like properties to generate a natural product library (NPL) in which 85% of the isolated compounds had no Lipinski violations. The library demonstrates the feasibility of obtaining natural products known for rich chemical diversity with the required physicochemical properties for drug discovery. The knowledge generated in creation of the library of structurally characterized pure natural products may provide opportunities to front-load lead-like property space in natural product drug discovery programs.

Isoprenylcysteine methyltransferase (Icmt) catalyzes the carboxyl methylation of oncogenic proteins in the final step of a series of post-translational modifications. The inhibition of Icmt provides an attractive and novel anticancer target. A natural product high-throughput screening campaign was conducted to discover inhibitors of Icmt. The Australian marine sponge, Pseudoceratina sp., yielded spermatinamine, a novel alkaloid with a bromotyrosyl-spermine-bromotyrosyl sequence, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy. Spermatinamine is the first natural product inhibitor of Icmt.

The distribution of the P2X7 receptor in inflammatory cells suggests that P2X7 antagonists have a significant role to play in the treatment of inflammatory disease. We conducted a natural product high-throughput screening campaign to discover P2X7 receptor antagonists. The Australian marine sponge Stylissa flabellata yielded two new bisimidazo-pyrano-imidazole bromopyrrole ether alkaloids, stylissadines A (IC50 0.7 microM) and B (IC50 1.8 microM), as the specific bioactive constituents. The compounds inhibit BzATP-mediated pore formation in THP-1 cells. Also present in this extract was considerable nonspecific bioactivity in the hemeolysin specificity assay. A new pyrrole-imidazole alkaloid, konbu'acidin B, and the known pyrrole-imidazole alkaloids 4,5-dibromopalau'amine and massadine were also isolated and had nonspecific activity. ROESY and proton coupling constant data indicated that the stereochemistry at C12, C17, and C20 in 4,5-dibromopalau'amine should be revised to 12R, 17S, 20S. By analogy, the relative stereochemistry of palau'amine, 4-bromopalau'amine, styloguanidine, 3-bromostyloguanidine, and 2,3-dibromostyloguanidine should also be revised to 12R, 17S, 20S. Stylissadines A and B are the most potent natural product P2X7 antagonists to be isolated to date and provide a novel class of P2X7 receptor inhibitors. They are also the first examples of tetrameric pyrrole-imidazole alkaloids.