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Sponges are benthic filter-feeder invertebrates capable to produce a variety of high value bioactive compounds. Nevertheless, exploitation of sponges as bio-factories requires scalable and sustainable strategies to supply sponge biomass without threatening wild natural populations and to minimize the consumption of toxic organic solvents in metabolites extraction and purification procedures. Sponges farming in integrated facilities nearby fish mariculture cages represents a highly efficient strategy combining the production of sponge biomass with bioremediation. Here we report the results of the in situ rearing of the keratose sponge Sarcotragus spinosulus developed within three years in an innovative Integrated Multi-Trophic Aquaculture system in the Gulf of Taranto (Southern Italy, Mediterranean Sea), capable to supply large-scale sponge biomass with a minimal impact on wild populations. Moreover, we demonstrate the proof of concept that it is possible to produce polyprenyl hydroquinones, selected as well-known bioactive model metabolites, in good yields, high purity degree and low organic solvent consumption, by means of an innovative protocol based on the combination of supercritical carbon dioxide fluid extraction and gel permeation chromatography. Such a combination of eco-friendly techniques paves the way to eco-sustainable supply of bioactive compounds from marine organisms highly profitable in terms of working times, costs, solvents, and energy saving. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused by SARS-CoV-2 still lacks effective antiviral drugs. Therefore, a thorough receptor-based virtual screening study was conducted to screen different natural and synthetic drug libraries, such as the Asinex Antiviral, Seaweed Metabolite Database, Medicinal Fungi Secondary Metabolite and Therapeutics Library, and Comprehensive Marine Natural Products Database comprising 6,827, 1,191, 1,830, and 45,000 compounds, respectively, against the main protease enzyme of SARS-CoV-2. Accordingly, three drug molecules (BBB-26580140, BDE-32007849, and LAS-51378804) are highlighted as the best binding molecules to the main protease S1 pocket. The docking binding energy scores of BBB-26580140, BDE-32007849, and LAS-51378804 were −13.02, −13.0, and −12.56 kcal/mol, respectively. Compared to the control Z1741970824 molecule with a binding energy score of −11.59 kcal/mol, the lead structures identified herein showed robust hydrophilic and van der Waals interactions with the enzyme active site residues, such as His41 and Cys145, and achieved highly stable binding modes. The simulations showed a stable structure of the main protease enzyme with the shortlisted leads in the pocket, and the network of binding interactions remained intact during the simulations. The overall molecular mechanics with generalized Born and surface area solvation binding energies of the BBB-26580140, BDE-32007849, LAS-51378804, and control molecules are −53.02, −56.85, −55.44, and −48.91 kcal/mol, respectively. Similarly, the net molecular mechanics Poisson–Boltzmann surface area binding energies of BBB-26580140, BDE-32007849, LAS-51378804, and control are −53.6, −57.61, −54.41, and −50.09 kcal/mol, respectively. The binding entropy energies of these systems showed lower free energies, indicating their stable nature. Furthermore, the binding energies were revalidated using the water swap method that considers the role of the water molecules in bridging the ligands to the enzyme active site residues. The compounds also revealed good ADMET properties and followed all major rules of drug-likeness. Thus, these compounds are predicted as promising leads and can be subjected to further experimental studies for evaluation of their biological activities. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 2 (HSV-2) is the most common agent of sexually transmitted infections around the world. Currently, no vaccine is available, and acyclovir is the reference compound in treatment HSV-2 infections. However, the emergence of resistant strains has reduced the efficacy in treatment. Several studies have shown marine seaweed biological activities, but there are no studies yet about the activity anti-HSV-2 of two its secundary metabolites, atomaric acid (1) and marine dolastane (2), isolated from Stypopodium zonale and Canistrocarpus cervicornis respectively. Therefore, we evaluated the anti-HSV-2 activity of compounds 1 and 2. Both compounds showed anti-HSV-2 activity with low cytotoxicity and compound 1 inactivated 90% of the viral particles at 50 µM. Both compounds inhibited the penetration and results in silico indicated the compound 1 as possible therapy alternative anti -HSV-2. [ABSTRACT FROM AUTHOR]

With an estimated global prevalence of 32.4%, non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver condition. The marine ecosystem, distinguished by its distinctive environmental characteristics, is a treasure trove of novel lead compounds possessing unique chemical structures, offering promising avenues for the development of new therapeutic agents or dietary supplement targeting NAFLD. Marine bioactive substances from natural products, such as polysaccharides, polyphenols, polyunsaturated fatty acids, and peptides, have been shown to benefit liver health by alleviating metabolic dysfunction through multiple mechanisms. This paper reviews the effects of marine bioactive substances from various marine entities, including marine fauna, flora, and microorganisms, on the regulation of NAFLD. A brief overview of the predominant pathogenic mechanisms underlying the disease is also provided, thereby establishing a critical link between the therapeutic potential of marine bioactive substances and the management of NAFLD. [ABSTRACT FROM AUTHOR]

The "Natural Product Reports" journal published by The Royal Society of Chemistry features critical reviews in natural product research. The latest issue includes articles on the discovery and development of anticancer agents from marine cyanobacteria, marine natural products, enzymatic ester bond formation strategies in fungal macrolide skeletons, the chemical ecology of type I polyketide natural products, and an update on the chemistry and biology of natural stilbenes. Additionally, there is a review on human milk as a complex natural product. The journal aims to connect the world with the chemical sciences and reinvest profits back into the chemistry community. [Extracted from the article]

Covering: January to the end of December 2023 This review covers the literature published in 2023 for marine natural products (MNPs), with 582 citations (541 for the period January to December 2023) 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 (1220 in 340 papers for 2023), 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 progress in the study of prokaryote involvement in macro-invertebrate MNP production is discussed. [ABSTRACT FROM AUTHOR]

The study of sessile, soft-bodied marine invertebrates like sponges, ascidians, bryozoans etc. remains a cornerstone of marine natural product research. These invertebrates are an excellent repository of structurally complex and potent chemical entities, a fair number of which are believed to be derived from microbial symbionts. The associated epi/endo symbionts are a veritable gold mine of bioactive compounds with enormous potential for use in drug research and other fields. Considering the significance of invertebrate- microbial assemblages in the production of valuable marine microbial natural products, the present review is focused on the least explored sessile, colonial invertebrate zoanthids belonging to phylum Cnidaria. Bacteria affiliated with different phyla viz. Proteobacteria, Firmicutes, Bacteriodetes, Actinobacteria, Acidobacteria, Planctomycetes, Chloroflexi etc., archaea of Crenarchaeota and Euryarchaeota, fungi of ascomycetes and basidiomycetes and dinoflagellates especially of family Symbiodiniaceae were reported among diverse zoanthids. Novel natural products could be identified among the zoanthid-associated microbes with potential pharmaceutical, industrial, agricultural and environmental applications. By leveraging genomics, transcriptomics, proteomics, and metabolomics, researchers can gain a holistic understanding of how these microbes interact with their hosts, adapt to their environment, and contribute to the symbiotic relationship. Due to the dearth of available information on this particular aspect, the current review addresses the significance of zoanthids in marine environments and the diversity of associated microbes, biotechnological applications of symbionts and the derived metabolites and existing challenges and future directions to decode these complex interactions and to explore the potential of zoanthid-associated microbes for successful therapeutic applications. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic inflammatory condition that affects the intestines. Research has shown that reducing the activity of DDR1 can help maintain intestinal barrier function in UC, making DDR1 a promising target for treatment. However, the development of DDR1 inhibitors as drugs has been hindered by issues such as toxicity and poor binding stability. As a result, there are currently no DDR1-targeting drugs available for clinical use, highlighting the need for new inhibitors. In a recent study, a dataset of 85 DDR1 inhibitors was analyzed to identify key characteristics for effective inhibition. A pharmacophore model was constructed and validated to screen a library of marine natural products for potential DDR1 inhibitors. Through high-throughput virtual screening and precise docking, 17 promising compounds were identified from a pool of over 52,000 molecules in the marine database. To improve binding affinity and reduce potential toxicity, scaffold hopping was employed to modify the 17 compounds, resulting in the generation of 1070 new compounds. These new compounds were further evaluated through docking and ADMET analysis, leading to the identification of three compounds—39713a, 34346a, and 34419a—with superior predicted activity and drug-like properties compared to the original 17 compounds. Further analysis showed that the binding free energy values of the three candidate compounds were less than −12.200 kcal/mol, which was similar to or better than −12.377 kcal/mol of the known positive compound VU6015929, and the drug-like properties were better than those of the positive compounds. Molecular dynamics simulations were then conducted on these three candidate compounds, confirming their stable interactions with the target protein. In conclusion, compounds 39713a, 34346a, and 34419a show promise as potential DDR1 inhibitors for the treatment of ulcerative colitis. [ABSTRACT FROM AUTHOR]

Marine natural products have long been recognized as a vast and diverse source of bioactive compounds with potential therapeutic applications, particularly in oncology. This review provides an updated overview of the significant advances made in the discovery and development of marine-derived anticancer drugs between 2019 and 2023. With a focus on recent research findings, the review explores the rich biodiversity of marine organisms, including sponges, corals, algae, and microorganisms, which have yielded numerous compounds exhibiting promising anticancer properties. Emphasizing the multifaceted mechanisms of action, the review discusses the molecular targets and pathways targeted by these compounds, such as cell cycle regulation, apoptosis induction, angiogenesis inhibition, and modulation of signaling pathways. Additionally, the review highlights the innovative strategies employed in the isolation, structural elucidation, and chemical modification of marine natural products to enhance their potency, selectivity, and pharmacological properties. Furthermore, it addresses the challenges and opportunities associated with the development of marine-derived anticancer drugs, including issues related to supply, sustainability, synthesis, and clinical translation. Finally, the review underscores the immense potential of marine natural products as a valuable reservoir of novel anticancer agents and advocates for continued exploration and exploitation of the marine environment to address the unmet medical needs in cancer therapy [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of cell cycle progression and represent important therapeutic targets in breast cancer. This study employs a comprehensive computational approach to identify novel CDK4/6 inhibitors from marine natural products. We utilized structure-based virtual screening of the CMNPD database and MNP library, followed by rigorous filtering based on drug-likeness criteria, PAINS filter, ADME properties, and toxicity profiles. From an initial hit of 9,497 compounds, 2,344 passed drug-likeness and PAINS filters. Further ADME filtering yielded 50 compounds, of which 25 exhibited non-toxic profiles. These 25 candidates underwent consensus molecular docking using seven distinct algorithms: AutoDockTools 4.2, idock, LeDock, Qvina 2, Smina, AutoDock Vina 1.2.0, PLANTS, and rDock. Based on these results, six top-scoring compounds were selected for comprehensive 500 nanosecond all-atom molecular dynamics simulations to evaluate their structural stability and interactions with CDK4/6. Our analysis revealed that compounds CMNPD11585 and CMNPD2744 demonstrated superior stability in their interactions with CDK4/6, exhibiting lower RMSD and RMSF values, more favorable binding free energies, and persistent hydrogen bonding patterns. These compounds also showed lower Solvent Accessible Surface Area values, indicating better compatibility with the CDK4/6 active site. Subsequent in-vitro studies using MTT assays on MCF-7 breast cancer cells confirmed the cytotoxic effects of these compounds, with CMNPD11585 showing the highest potency, followed by CMNPD2744. [ABSTRACT FROM AUTHOR]

Pro-inflammatory cytokines, like interleukin-1 beta and interferon gamma, are known to activate signalling pathways causing pancreatic beta cell death and dysfunction, contributing to the onset of diabetes. Targeting cytokine signalling pathways offers a potential strategy to slow or even halt disease progression, reducing reliance on exogenous insulin and improving glucose regulation. This study explores the protective and proliferative effects of breitfussin C (BfC), a natural compound isolated from the Arctic marine hydrozoan Thuiaria breitfussi, on pancreatic beta cells exposed to pro-inflammatory cytokines. Using the beta cell line RIN-M5F, we assessed the protective effects of BfC through a MTS assay for cell viability, caspase 3/7 activity for apoptosis, and EdU incorporation and cell cycle distribution for proliferation. Additionally, we investigated BfC's inhibitory effects on the DYRK family of kinases using kinase activity and binding assays, western blotting, and docking simulations. Our findings reveal that BfC treatment effectively increases beta cell proliferation and counteracts cytokine-induced decrease in proliferation. The proliferative effect is associated with inhibition of DYRK kinases and a subsequent decrease in the cell cycle inhibitor p27KIP. These results suggest that BfC mediates beta cell-protective effect by promoting proliferation through DYRK inhibition, highlighting its potential as a molecular starting point for the development of a therapeutic agent against diabetes. [ABSTRACT FROM AUTHOR]

The structural diversity of marine natural products is considered a potential resource for the pharmaceutical industry. In our study of marine-derived compounds, one bacterium Bacillus licheniformis S-1 was discovered to have the ability to produce bioactive natural products. After a further chemistry investigation, one novel 4-aminopyridinium derivative, 4-(dimethylamino)-1-(2S-((4hydroxybenzoyl)oxy)propyl)pyridin-1-ium (1), along with 15 known cyclic dipeptides (2–16) were isolated from the bacterium B. licheniformis S-1 derived from a shallow sea sediment. The structures of compounds 1–16 were elucidated through comprehensive NMR spectroscopic and specific optical rotation (OR) data analyses. Compound 6 showed antibacterial activity against Pseudomonas fulva with an MIC value of 50 µg/mL. This is the first study to discover a pyridinium derivative and cyclic dipeptides from B. licheniformis. [ABSTRACT FROM AUTHOR]

Background/Objectives: Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by colorectal immune infiltration and significant microbiota compositional changes. Gut microbiota homeostasis is necessary to maintain the healthy state of humans. MR2938, a quinazolin-4(3H)-one derivative derived from the marine natural product penipanoid C, alleviated DSS-induced colitis in a dose-dependent manner. Herein, we aimed to investigate the impact of MR2938 on the gut microbiota in dextran sodium sulfate (DSS)-induced colitis in mice and to elucidate the role of the gut microbiota in the therapeutic mechanism of MR2938 for alleviating colitis. Methods: Acute colitis was induced with DSS in mice. Mice were administered with 100 mg/kg or 50 mg/kg of MR2938. Cecal content was also preserved in liquid nitrogen and subsequently analyzed following 16S RNA sequencing. Antibiotic cocktail-induced microbiome depletion was performed to further investigate the relationship between MR2938 and gut microbiota. The inflammatory factor levels were performed by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Alcian blue staining and immunofluorescence were used to estimate the intestinal barrier. Results: The 16S rRNA sequencing revealed microbiota modulation by MR2938. Compared with the model group, the 100 mg/kg MR2938 group was associated with higher abundances of Entercoccus and a lower abundance of Staphylococcus, while the 50 mg/kg MR2938 group was associated with higher abundances of Lactobacillus and a lower abundance of Staphylococcus. The antibiotic-mediated microbiota depletion experiments demonstrated that the gut microbiota primarily contributed to barrier function protection, with little impact on inflammatory factor levels during the MR2938 treatment. Conclusions: These findings suggest that intestinal flora play a crucial role in MR2938's therapeutic mechanism for alleviating colitis. [ABSTRACT FROM AUTHOR]

Neuroinflammation and neuronal cell death are leading causes of death in the elderly and underlie various neurodegenerative diseases. These diseases involve complex pathophysiological mechanisms, including inflammatory responses, oxidative stress, and ferroptosis. Compounds derived from deep-sea fungi exhibit low toxicity and potent neuroprotective effects, offering a promising source for drug development. In this study, we isolated 44 natural products from deep-sea-derived fungi and identified isobisvertinol (17) as a compound with anti-inflammatory and ferroptosis-inhibiting effects. Using LPS-induced microglial inflammation and RSL3-induced neuronal ferroptosis models, we found that 17 targets TLR4 to provide neuroprotection. Molecular docking studies revealed that 17 inhibits TLR4 activation by occupying the hydrophobic pocket at the TLR4-MD2 binding site. Additionally, 17 suppresses TLR4, reducing p38 MAPK phosphorylation, and inhibits ferroptosis by decreasing lipid peroxidation and modulating mitochondrial membrane potential. Metabolomic analysis showed that 17 rescues alterations in multiple metabolic pathways induced by RSL3 and increases levels of antioxidant metabolites, including glutamine, glutamate, and glutathione. In summary, our results indicate that isobisvertinol (17) targets TLR4 in neural cells to reduce inflammation and inhibit p38 MAPK phosphorylation, while regulating metabolic pathways, mainly GSH synthesis, to provide antioxidant effects and prevent ferroptosis in neurons. [ABSTRACT FROM AUTHOR]

Matteson homologation, a successive extension of chiral boronic esters, is perfectly suited for the synthesis of complex molecular structures containing several stereogenic centers. The "classical version" allows the introduction of various functional groups in a 1,2-anti-configuration. The absolute configuration is determined by the choice of the chiral auxiliary, which can be used to introduce several stereogenic centers. In contrast, in Aggarwal's lithiation-borylation strategy, new chiral auxiliary reagents must be used in each reaction step, which on the other hand allows the individual insertion of the desired stereogenic centers. Both methods have their individual advantages and disadvantages and are well suited for the synthesis of marine natural products. [ABSTRACT FROM AUTHOR]

The waters around the western Antarctic Peninsula are experiencing fast warming due to global change, being among the most affected regions on the planet. This polar area is home to a large and rich community of benthic marine invertebrates, such as sponges, tunicates, corals, and many other animals. Among the sponges, the bright yellow Dendrilla antarctica is commonly known for using secondary diterpenoids as a defensive mechanism against local potential predators. From the dichloromethane extract of sponge samples from Deception Island collected in January 2023, we isolated a novel derivative with an unusual β-lactone diterpene skeleton here named dendrillolactone (1), along with seven previously described diterpenes, including deceptionin (2), a gracilane norditerpene (3), cadlinolide C (4), a glaciolane norditerpene (5), membranolide (6), aplysulphurin (7), and tetrahydroaplysulphurine-1 (8). Here, we also report our studies on the changes in the chemical arsenal of this sponge by slow temperature increase in aquaria experiments. Despite being a species capable of inhabiting volcanically active areas, with frequent water temperature fluctuations due to the existing fumaroles, the results show that diterpenes such as deceptionin, cadlinolide C, membranolide, and tetrahydroaplysulphurin-1 seem to be susceptible to the temperature increase, resulting in a trend to higher concentrations. However, temperatures above 4 °C severely affected sponge metabolism, causing its death much earlier than expected. Further research on the roles of these natural products in D. antarctica and their relationship to the sponge's resilience to environmental changes should help to better understand the defensive mechanisms of Antarctic marine benthos in the context of global change. [ABSTRACT FROM AUTHOR]

Abstract Marine natural products have long been recognized as a vast and diverse source of bioactive compounds with potential therapeutic applications, particularly in oncology. This review provides an updated overview of the significant advances made in the discovery and development of marine-derived anticancer drugs between 2019 and 2023. With a focus on recent research findings, the review explores the rich biodiversity of marine organisms, including sponges, corals, algae, and microorganisms, which have yielded numerous compounds exhibiting promising anticancer properties. Emphasizing the multifaceted mechanisms of action, the review discusses the molecular targets and pathways targeted by these compounds, such as cell cycle regulation, apoptosis induction, angiogenesis inhibition, and modulation of signaling pathways. Additionally, the review highlights the innovative strategies employed in the isolation, structural elucidation, and chemical modification of marine natural products to enhance their potency, selectivity, and pharmacological properties. Furthermore, it addresses the challenges and opportunities associated with the development of marine-derived anticancer drugs, including issues related to supply, sustainability, synthesis, and clinical translation. Finally, the review underscores the immense potential of marine natural products as a valuable reservoir of novel anticancer agents and advocates for continued exploration and exploitation of the marine environment to address the unmet medical needs in cancer therapy Graphical Abstract

Abstract Drug discovery and development is a challenging and time-consuming process. Laboratory experiments conducted on Vidarabine showed IC50 6.97 µg∕mL, 25.78 µg∕mL, and ˃ 100 µg∕mL against non-small Lung cancer (A-549), Human Melanoma (A-375), and Human epidermoid Skin carcinoma (skin/epidermis) (A-431) respectively. To address these challenges, this paper presents an Artificial Intelligence (AI) model that combines the capabilities of Deep Learning (DL) to identify potential new drug candidates, Fuzzy Rough Set (FRS) theory to determine the most important chemical compound features, Explainable Artificial Intelligence (XAI) to explain the features’ importance in the last layer, and medicinal chemistry to rediscover anticancer drugs based on natural products like Vidarabine. The proposed model aims to identify potential new drug candidates. By analyzing the results from laboratory experiments on Vidarabine, the model identifies Sulfur and magnesium oxide (MgO) as new potential anticancer agents. The proposed model selected Sulfur and MgO based on Interpreting their promising features, and further laboratory experiments were conducted to validate the model’s predictions. The results demonstrated that, while Vidarabine was inactive against the A-431 cell line (IC50 ˃ 100 µg∕mL), Sulfur and MgO exhibited significant anticancer activity (IC50 4.55 and 17.29 µg/ml respectively). Sulfur displayed strong activity against A-549 and A-375 cell lines (IC50 3.06 and 1.86 µg/ml respectively) better than Vidarabine (IC50 6.97 and 25.78 µg/ml respectively). However, MgO showed weaker activity against these two cell lines. This paper emphasizes the importance of uncovering hidden chemical features that may not be discernible without the assistance of AI. This highlights the ability of AI to discover novel compounds with therapeutic potential, which can significantly impact the field of drug discovery. The promising anticancer activity exhibited by Sulfur and MgO warrants further preclinical studies.

The screening of novel antiviral agents from marine microorganisms is an important strategy for new drug development. Our previous study found that polyether K-41A and its analog K-41Am, derived from a marine Streptomyces strain, exhibit anti-HIV activity by suppressing the activities of HIV-1 reverse transcriptase (RT) and its integrase (IN). Among the K-41A derivatives, two disaccharide-bearing polyethers—K-41B and K-41Bm—were found to have potent anti-HIV-1IIIB activity in vitro. This study aimed to clarify whether K-41B and K-41Bm have inhibitory effects on different HIV-1 strains or whether these two derivatives have mechanisms of action different from that of their precursor, K-41A. An anti-HIV-1 assay indicated that K-41B and K-41Bm have potent anti-HIV-1BaL activity, with low 50% inhibitory concentrations (IC50s) (0.076 and 0.208 μM, respectively) and high selective indexes (SIs) (58.829 and 31.938, respectively) in the peripheral blood mononuclear cell (PBMC)-HIV-1BaL system. The time-of-addition (TOA) assay indicated that K-41B and K-41Bm may exert antiviral effects by activating multiple stages of HIV-1 replication. A cell protection assay indicated that the pretreatment of cells with K-41B or K-41Bm has almost no inhibitory effect on HIV-1 infection. A virus inactivation assay indicated that pretreatment of the virus with K-41B or K-41Bm inhibits HIV-1 infection by 60%. A cell–cell fusion assay showed that K-41B and K-41Bm blocked the cell fusion mediated by viral envelope proteins. The HIV-1 key enzyme experiment also indicated that both compounds have certain inhibitory effects on HIV-1 IN. Furthermore, molecular docking showed that K-41B and K-41Bm interact with several viral and host proteins, including HIV-1 IN, an envelope protein (gp120), a transmembrane protein (gp41), and cell surface receptors (CD4, CCR5, and CXCR4). Overall, in addition to having a similar anti-HIV-1 mechanism of inhibiting HIV-1 IN like the precursor polyether K-41A, the disaccharide-bearing polyether derivatives K-41B and K-41Bm may also inhibit viral entry. This suggests that they display anti-HIV-1 mechanisms that are different from those of their precursor polyethers.

Marine fungal natural products (MFNPs) are a vital source of pharmaceuticals, primarily synthesized by relevant biosynthetic gene clusters (BGCs). However, many of these BGCs remain silent under standard laboratory culture conditions, delaying the development of novel drugs from MFNPs to some extent. This review highlights recent efforts in genome mining and biosynthetic pathways of bioactive natural products from marine fungi, focusing on methods such as bioinformatics analysis, gene knockout, and heterologous expression to identify relevant BGCs and elucidate the biosynthetic pathways and enzyme functions of MFNPs. The research efforts presented in this review provide essential insights for future gene-guided mining and biosynthetic pathway analysis in MFNPs. [ABSTRACT FROM AUTHOR]

Sphingoid bases are important bioactive lipids found in a variety of organisms, serving as the backbone of sphingolipids, which regulate essential physiological processes. Here we describe the total synthesis and structure revision of halisphingosine A, a sphingoid base initially isolated from marine sponges. To address inconsistencies in the NMR interpretation of this natural product, we developed a synthetic route involving a late‐stage enantioselective Henry reaction that allows access to multiple stereoisomers of the proposed halisphingosine A core structure. Our library of 32 fully characterized synthetic stereoisomers enabled us to rectify the structure of halisphingosine A as (2R,3R,8R,Z)‐2‐aminooctadec‐9‐ene‐1,3,8‐triol, and to pursue further structure–activity relation (SAR) studies regarding their antimicrobial and cytotoxic potential. In summary, our study offers a yet unreported compound library along with validated analytical datasets of marine sphingoid base derivatives, which significantly affects future ecometabolomic marine research and will facilitate the identification of inhibitors of sphingolipid metabolism or antagonists of sphingolipid base‐sensing receptors. [ABSTRACT FROM AUTHOR]

In this study, we leveraged a sophisticated active learning model to enhance virtual screening for SQLE inhibitors. The model's improved predictive accuracy identified compounds with significant advantages in binding affinity and thermodynamic stability. Detailed analyses, including molecular dynamics simulations and ADMET profiling, were conducted, particularly focusing on compounds CMNPD11566 and its derivative HCJ007. CMNPD11566 showed stable interactions with SQLE, while HCJ007 exhibited improved binding stability and more frequent interactions with key residues, indicating enhanced dynamic adaptability and overall binding effectiveness. ADMET data comparison highlighted HCJ007s superior profile in terms of lower toxicity and better drug-likeness. Our findings suggest HCJ007 as a promising candidate for SQLE inhibition, with significant improvements over CMNPD11566 in various pharmacokinetic and safety parameters. The study underscores the efficacy of computational models in drug discovery and the importance of comprehensive preclinical evaluations. [ABSTRACT FROM AUTHOR]

The cosmetics industry is experiencing continuous growth and the search for dermoactive metabolites continues to increase, positioning natural marine products as an essential element in this market. The genus Sargassum , a cosmopolitan brown alga, stands out for its diversified arsenal of metabolites with biological properties of great interest for the cosmetic sector. This study presents an updated review of the dermocosmetic properties of 17 Sargassum species published between 2020 and 2024, emphasizing increasing interest in its antioxidant and photoprotective properties. Furthermore, the review highlights the crucial role of green extraction methodologies, such as ultrassom-assisted extraction (EAU), enzyme-assisted extraction (EAE) and microwave-assisted extraction (MAE). It is also provided a conceptual outline of the spectrometric analytical techniques used for characterization of extracts and identification of active composts, such as polysaccharides (alginate and fucoidane), phenolic composts (phlorotannins and phenylpropanóids) and terpenoids (diterpenoids, saponins and norisoprenóids). In addition to addressing bioprospecting and the potential of the biorefinery in the cosmetics sector, this review analyzes challenges related to quality control of raw materials, seasonal fluctuations of seaweed and regulations governing the collection and use of seaweed. To provide a detailed update on the dermocosmetic potential of these algae, the review aims to support future research and encourage bioprospection of this biomass as a sustainable and promising source for the development of new bioproducts. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) affects over 77 million adults in India, with cases expected to reach 134 million by 2045. Current treatments, including sulfonylureas and thiazolidinediones, are inadequate, underscoring the need for novel therapeutic strategies. This study investigates marine natural products (MNPs) as alternative therapeutic agents targeting SIK2, a key enzyme involved in DM. The structural stability of the predicted SIK2 model was validated using computational methods and subsequently employed for structure-based virtual screening (SBVS) of over 38,000 MNPs. This approach identified five promising candidates: CMNPD21753 and CMNPD13370 from the Comprehensive Marine Natural Product Database, MNPD10685 from the Marine Natural Products Database, and SWMDRR053 and SWMDRR052 from the Seaweed Metabolite Database. The identified compounds demonstrated docking scores ranging from −7.64 to −11.95 kcal/mol and MMGBSA binding scores between −33.29 and −68.29 kcal/mol, with favourable predicted pharmacokinetic and toxicity profiles. Molecular dynamics simulations (MDS) revealed stronger predicted binding affinity for these compounds compared to ARN-3236, a known SIK2 inhibitor. Principal component (PC)-based free energy landscape (FEL) analysis further supported the stable binding of these compounds to SIK2. These computational findings highlight the potential of these leads as novel SIK2 inhibitors, warranting future in vitro and in vivo validation. [ABSTRACT FROM AUTHOR]

Genomic and chemical analysis has revealed that numerous species of filamentous cyanobacteria harbor complex secondary metabolisms tailored to their particular ecological niche. The metabolomic analysis of strains and environmental samples from benthic cyanobacterial mats (BCMs) from coral reefs has the potential to expand the library of marine cyanobacteria-derived natural products. In this study, cyanobacterial strains were obtained from phytobenthos collected from coral reefs in Abrolhos, Brazil and Ishigaki, Japan. Phylogenetic analysis of isolates shows high similarity to previously described members of benthic mats and also suggests the geographic expansion of the Adonisia lineage. Chemical analysis by untargeted liquid chromatography-high resolution mass spectrometry and data processing via MZmine and FBMN-GNPS confirmed the presence of a wide diversity of secondary metabolites. In addition, similarity analysis applying the newly developed tool DBsimilarity indicated the broad coverage of various biosynthetic and chemical classes of compounds previously reported for cyanobacteria. This report is one of the first applications of untargeted metabolomics workflow and similarity network construction for groups of marine filamentous cyanobacteria isolated from benthic mats on corals reefs. [ABSTRACT FROM AUTHOR]

Propolis, a complex natural product that honey bees produce by mastication to protect and maintain their hive structures, comprises various bioactive constituents, including phenolic acids, flavonoids, diterpenes, sesquiterpenes, lignans, vitamins, minerals, etc. The objective of the current research was to extract crude propolis to enrich the total polyphenolic and flavonoid content, conduct preliminary phytochemical screening, and develop and evaluate dosage form to improve formulation characteristics and immunomodulatory potential. Total balsam, polyphenols, and flavonoids were found to be 46% w/w, 34.82 ± 0.078 mg equivalent of gallic acid/g, and 23.61 ± 0.045 mg equivalent of quercetin/g, respectively. DSC and FTIR studies demonstrated molecular dispersion of the propolis extract. Formulation was optimized with a 32 factorial design, and an optimized batch showed 92.20 ± 1.72% drug release in 1 h, an elevated hypersensitivity (DTH) response (p < 0.0001), increased phagocytic activity (p < 0.01), and a significantly (p < 0.001) higher total leukocyte count ((5.015 ± 0.19) × 103/mm3). The developed formulation showed significantly modulated immune modulatory potential compared with the propolis extract and conventional levamisole. This study can be further extended for clinical evaluations. [ABSTRACT FROM AUTHOR]

Marine natural products are increasingly utilized in nutrition, cosmetics, and medicine, garnering significant attention from researchers globally. With the expansion of marine resource exploration in recent years, the demand for marine natural products has risen, necessitating rapid and cost-effective activity evaluations using model organisms. Zebrafish, a valuable vertebrate model, has become an efficient tool for screening and identifying safe, active molecules from marine natural products. This review, based on nearly 10 years of literature, summarizes the current status and progress of zebrafish models in evaluating marine natural product bioactivity. It also highlights their potential in exploring marine resources with health benefits, offering a reference for the future development and utilization of marine biological resources. [ABSTRACT FROM AUTHOR]

Breast cancer remains a leading cause of mortality among women worldwide. Our current research focuses on identifying effective therapeutic agents by targeting the human aromatase enzyme. Aromatase inhibitors (AIs) have been effective in treating postmenopausal breast cancer but face challenges such as drug resistance and long-term side effects like cognitive decline and osteoporosis. Natural products, especially from marine organisms, are emerging as potential sources for new drug candidates due to their structural diversity and pharmacological properties. This study aims to discover marine natural products capable of inhibiting human aromatase by combining ligand-based and structure-based pharmacophore models for virtual screening against the Comprehensive Marine Natural Products Database. From the initial virtual screening of more than 31,000 compounds, 1,385 marine natural products were identified as possible candidates. Following initial molecular docking analysis, only four compounds managed to pass the criteria this research has introduced to confirm strong binding affinity to aromatase. All four compounds yielded acceptable binding affinities, with CMPND 27987 having the highest −10.1 kcal/mol. All four hits were subjected to molecular dynamics, and CMPND 27987 was further confirmed to be the most stable at the protein's active site, with an MM-GBSA free binding energy of −27.75 kcal/mol. Our in silico studies indicate that CMPND 27987 interacts effectively within the binding site of the human aromatase, maintaining high affinity and stability. Based on these findings, we propose that CMPND 27987 could hold significant potential for further lead optimization and drug development. [ABSTRACT FROM AUTHOR]

Human Adenovirus (HAdV) infections in immunocompromised patients can result in disseminated diseases with high morbidity and mortality rates due to the absence of available treatments for these infections. The sponge Ircinia felix was selected for the significant anti‐HAdV activity displayed by its organic extracts. Its chemical analysis yielded three novel sesterterpene lactams, ircinialactams J−L, along with three known sesterterpene furans which structures were established by a deep spectrometric analysis. Ircinialactam J displayed significant antiviral activity against HAdV without significant cytotoxicity, showing an effectiveness 11 times greater than that of the standard treatment, cidofovir®. Comparison of the antiviral evaluation results of the isolated compounds allowed us to deduce some structure‐activity relationships. Mechanistic assays suggest that ircinialactam J targets an early step of the HAdV replicative cycle before HAdV genome reaches the nucleus of the host cell. The first total synthesis of ircinialactam J was also accomplished to prove the structure and to provide access to analogues. Key steps are a regio‐ and stereoselective construction of the trisubstituted Z‐olefin at Δ7 by iron‐catalyzed carbometallation of a homopropargylic alcohol, a stereoselective methylation to generate the stereogenic center at C18, and the formation of the (Z)‐Δ20 by stereoselective aldol condensation to introduce the tetronic acid unit. Ircinialactam J is a promising chemical lead to new potent antiviral drugs against HAdV infections. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM), a major global health concern, is a chronic metabolic disorder. Bioactive compounds sourced from numerous marine natural products recently have drawn attention as novel therapeutic approaches. Considering these chemicals and their role in cellular redox modulation by involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway, the current study attempts to highlight their anti-diabetic effects and the molecular mechanisms involved. Reactive oxygen species (ROS)-mediated oxidative stress, inflammation, and cellular damage are linked to most human pathologies specifically DM. The Nrf2/HO-1 pathway is a key defense mechanism developed by the cells to combat ROS burst. Marine natural compounds have strong pharmacological potential in triggering cellular antioxidant defense mechanisms by declining oxidative damage and inflammation linked to DM. How marine natural products potentially alleviate DM specifically type 2 diabetes (T2D) and its related issues is especially focused on. The literature was thoroughly analyzed to open a discussion about specific marine compounds and their well-established anti-diabetic effects to elucidate possible therapeutic applications. Furthermore, opportunities and the pros and cons of using these marine bioactive compounds as complementary treatment for DM are also discussed. The diverse characteristics of marine natural products, specifically with regard to redox control, offer promising opportunities for drug discovery and therapeutic interventions in clinical trials. [ABSTRACT FROM AUTHOR]

Marine fungi represent a treasure trove of bioactive secondary metabolites, with benzopyran compounds emerging as a significant class of these natural products. This review delves into the structural diversity, biological activities, and sources of benzopyran compounds, highlighting their isolation from marine fungi inhabiting diverse environments such as sponges, marine sediments, algae, mangroves, and corals. Our literature search, conducted from 2000 to 2023, has identified a wealth of benzopyran compounds, showcasing their potential as lead compounds in drug development. The characteristics of benzopyran from marine fungi are explored, encompassing various subclasses such as chromones, isocoumarins, citrinins, and other related compounds. These compounds exhibit a remarkable chemical diversity, which is crucial for their diverse biological activities. The potential of benzopyran compounds in drug development is also discussed, emphasizing their roles in anti-tumor, antibacterial, anti-inflammatory, and enzyme inhibitory activities. In recent years, a remarkable 210 bioactive benzopyran compounds have been isolated from the secondary metabolites of marine fungi. These findings underscore the importance of marine fungi as a source of novel bioactive compounds, offering a plethora of potential lead compounds for the development of marine-derived drugs. This review aims to provide a comprehensive overview of the current state of research on benzopyran compounds, setting the stage for future advancements in the field of marine natural products. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and Down syndrome (DS) share a common therapeutic target, the dual-specificity, tyrosine phosphorylation activated kinase 1A (DYRK1A). Abnormally active DYRK1A is responsible for cognitive disorders (memory, learning, spatial localization) observed in both conditions. In DS, DYRK1A is overexpressed due to the presence of the DYRK1A gene on chromosome 21. In AD, calcium-activated calpains cleave full-length DYRK1A (FL-DYRK1A) into a more stable and more active, low molecular weight, kinase (LMW-DYRK1A). Genetic and pharmacological experiments carried out with animal models of AD and DS strongly support the idea that pharmacological inhibitors of DYRK1A might be able to correct memory/learning disorders in people with AD and DS. Starting from a marine sponge natural product, Leucettamine B, Perha Pharmaceuticals has optimized, through classical medicinal chemistry, and extensively characterized a small molecule drug candidate, Leucettinib-21. Regulatory preclinical safety studies in rats and minipigs have been completed and formulation of Leucettinib-21 has been optimized as immediate-release tablets. Leucettinib-21 is now undergoing a phase 1 clinical trial (120 participants, including 12 adults with DS and 12 patients with AD). The therapeutic potential of DYRK1A inhibitors in AD and DS is presented. [ABSTRACT FROM AUTHOR]

Background/aim: Tuberculosis (TB) has become the world's deadliest disease. The lack of an effective therapeutic drug to treat it is one of the obstacle for doctors. Today, multidrug-resistant TB cases are increasing. Investigating these new drug should be given intensive and careful consideration. Marine invertebrates are valuable since they produce a large number of active compounds, and screening of these active compounds is very important. Materials and methods: Anti-TB screening of compounds derived from marine invertebrates was performed via the in silico method. Three-dimensional structures of pantothenate kinase (MtPanK type 1, PDB ID: 4BFT), Mycobacterium tuberculosis InhA (PDB ID: 2X23), protein kinase B (PDB ID: 5U94), and ß-ketoacyl acyl carrier protein synthase I (MtKasA, PDB ID: 2WGE) were used as the protein targeted receptors. Results: The molecular docking analysis showed that the potential candidate compounds with the lowest docking score were 19-hydroxypsammaplysin Q, 19-hydroxypsammaplysin S, psammaplysin L, and psammaplysin K dimethoxy acetal. Several compounds, such as molamide C and the manzamine group, are also potential anti-TB compounds. Conclusion: This study showed that psammaplysin groups have potential as anti-TB compounds. Further laboratory experiments should be done to confirm the in silico data. [ABSTRACT FROM AUTHOR]

Marine natural products offer a promising source in the development of new antibiotic drugs. Two previously undescribed compounds, including one sulfur-bearing alkaloid named quinosumycin (1) along with one chromone derivative namely chromycone (2), were discovered from an ethyl acetate (EtOAc) extract of marine Streptomyces diastaticus NBU2966 through a bioactivity-guided isolation prioritized for antimicrobial potential. The analysis of nuclear magnetic resonance spectroscopy (NMR), high resolution electrospray ionization mass spectroscopy (HRESIMS) data, and electronic circular dichroism (ECD) calculations enabled the elucidation of their structures and the determination of their absolute configurations. Quinosumycin (1) is the first heterodimer scaffold incorporating quinolinone and quinazolinone motifs coupled by a thioether bond. Interestingly, Compound 1 exhibited a relatively selective growth inhibition against methicillin-resistant Staphylococcus aureus (MRSA) with the minimal inhibitory concentration (MIC) value of 8 µg/mL. [ABSTRACT FROM AUTHOR]

Marine products have gained attention for their potential benefits in the treatment of breast cancer, offering an alternative or supplementary approach to traditional therapies. While they are not intended to replace established medical treatments like chemotherapy or surgery, marine natural products have shown promise in providing symptom relief, enhancing the quality of life, and potentially improving treatment success for breast cancer patients. Studies have explored the use of marine products in conjunction with chemotherapy for their palliative care benefits and as adjuvants to conventional therapies. Marinederived compounds have been investigated for their anticancer properties, including apoptosis induction, anti-proliferative effects, and modulation of signaling pathways involved in breast cancer progression. These natural products offer a complementary avenue for managing breast cancer, potentially enhancing treatment outcomes, and addressing therapeutic challenges. The utilization of marine products in breast cancer therapy dates back to ancient times when various cultures recognized the therapeutic benefits of plants, herbs, and marine resources. The purpose of this study is to visually map and guide future research on supplementary marine products and chemotherapy in breast cancer based on bibliometric analysis. [ABSTRACT FROM AUTHOR]

Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound 8a , a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound 11a (IC 50 = 0.24 μmol/L). Furthermore, 11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 in vitro for anti-HBV activity. Treatment with 11a in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies. A new CpAM was screened by HTS system (Huh7-LTCH). Under the bioactivity-driven synthesis, we designed the best compound 11a , which can effectively inhibit HBV DNA in vitro and in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]