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The marine natural product fucoxanthin has been reported previously to produce anti-Alzheimer's disease (AD) neuroprotective effects in vitro and in vivo. Fucoxanthin was also demonstrated to be safe in preclinical and small population clinical studies, but the low bioavailability of fucoxanthin in the central nervous system (CNS) has limited its clinical applications. To overcome this, poly lactic-co-glycolic acid-block-polyethylene glycol loaded fucoxanthin (PLGA-PEG-Fuc) nanoparticles with diameter at around 200 nm and negative charge were synthesized and suggested to penetrate into the CNS. Loaded fucoxanthin could be liberated from PLGA-PEG nanoparticles by sustained released in the physiological environment. PLGA-PEG-Fuc nanoparticles were shown to significantly inhibit the formation of Aβ fibrils and oligomers. Moreover, these nanoparticles were taken up by both neurons and microglia, leading to the reduction of Aβ oligomers-induced neurotoxicity in vitro. Most importantly, intravenous injection of PLGA-PEG-Fuc nanoparticles prevented cognitive impairments in Aβ oligomers-induced AD mice with greater efficacy than free fucoxanthin, possibly via acting on Nrf2 and NF-κB signaling pathways. These results altogether suggest that PLGA-PEG nanoparticles can enhance the bioavailability of fucoxanthin and potentiate its efficacy for the treatment of AD, thus potentially enabling its future use for AD therapy.

Tau hyperphosphorylation and aggregation is considered as a main pathological mechanism underlying Alzheimer's disease (AD). Rose Bengal (RB) is a synthetic dye used for disease diagnosis, which was reported to inhibit tau toxicity via inhibiting tau aggregation in Drosophila. However, it was unknown if RB could produce anti-AD effects in rodents.The research aimed to investigate if and how RB could prevent β-amyloid (Aβ) oligomers-induced tau hyperphosphorylation in rodents.RB was tested in vitro (0.3-1 μM) and prevented Aβ oligomers-induced tau hyperphosphorylation in PC12 cells. Moreover, RB (10-30 mg/kg, i.p.) effectively attenuated cognitive impairments induced by Aβ oligomers in mice. Western blotting analysis demonstrated that RB significantly increased the expression of pSer473-Akt, pSer9-glycogen synthase kinase-3β (GSK3β) and reduced the expression of cyclin-dependent kinase 5 (CDK5) both in vitro and in vivo. Molecular docking analysis suggested that RB might directly interact with GSK3β and CDK5 by acting on ATP binding sites. Gene Ontology enrichment analysis indicated that RB might act on protein phosphorylation pathways to inhibit tau hyperphosphorylation.RB was shown to inhibit tau neurotoxicity at least partially via inhibiting the activity of GSK3β and CDK5, which is a novel neuroprotective mechanism besides the inhibition of tau aggregation. As tau hyperphosphorylation is an important target for AD therapy, this study also provided support for investigating the drug repurposing of RB as an anti-AD drug candidate.

The designing of drugs that can simultaneously affect different protein targets is one novel and promising way to treat complex diseases. Multitarget drugs act on multiple protein receptors each implicated in the same disease state, and may be considered to be more beneficial than conventional drug therapies. For example, these drugs can have improved therapeutic potency due to synergistic effects on multiple targets, as well as improved safety and resistance profiles due to the combined regulation of potential primary therapeutic targets and compensatory elements and lower dosage typically required. This review analyzes in-silico methods that facilitate multitarget drug design that facilitate the discovery and development of novel therapeutic agents. Here presented is a summary of the progress in structure-based drug discovery techniques that study the process of molecular recognition of targets and ligands, moving from static molecular docking to improved molecular dynamics approaches in multitarget drug design, and the advantages and limitations of each.

In following up on observed in vitro anti-inflammatory activity of the organic extract of the marine sponge-derived fungus Aspergillus tamarii MCCF102, two new dipyrrolobenzoquinones, terreusinone B and C (1 and 2), were discovered along with the known analogue, terreusinone (3). The structures of 1–3 were determined by spectroscopic and spectrometric analyses, along with chemical inter-conversion. In vitro testing on lipopolysaccharide (LPS) stimulated RAW 264.7 murine macrophage cells revealed that 1–3 exhibit anti-inflammatory activity by inhibiting nitric oxide production in a dose-dependent manner (IC50

Mesophotic coral ecosystems (MCEs) represent an underexplored source of intriguing natural products. Efforts to discover bioactive metabolites from sponge-associated fungi in MCEs identified a new steroid, acremocholone (1) and its three known analogs (2-4), from Acremonium sp. NBUF150. The Acremonium sp. NBUF150 was isolated from a Ciocalypta sponge located 70 m deep within the South China Sea. The planar structures and absolute configuration of 1-4 were determined from NMR-derived spectroscopic data, HR-ESI-MS, and X-ray crystallography. Compound 1 exhibited antimicrobial inhibition against Vibrio scophthalmi, V. shilonii and V. brasiliensis at minimum inhibitory concentrations of 8 μg/mL; compound 2 inhibited V. shilonii and V. brasiliensis at 8 and 32 μg/mL, respectively, and compound 4 inhibited growth of V. brasiliensis at 16 μg/mL. Sponge associated fungi from MCEs represent a promising resource of anti-Vibrio drug leads for aquaculture use.

The identity and biological activity of most metabolites still remain unknown. A key bottleneck in the full exploration of this tremendous source of new structures and pharmaceutical activities is the compound purification needed for bioactivity assignments of individual compounds and downstream structure elucidation. To enable bioactivity-focused compound identification from complex mixtures, we developed a scalable native metabolomics approach that integrates non-targeted liquid chromatography tandem mass spectrometry, and simultaneous detection of protein binding via native mass spectrometry. While screening for new protease inhibitors from an environmental cyanobacteria community, native metabolomics revealed 30 cyclodepsipeptides as chymotrypsin binders. Mass spectrometry-guided purification then allowed for the full structure elucidation of four new specialized metabolites via tandem mass spectrometry, chemical derivatization, and nuclear magnetic resonance spectroscopy. Together with the evaluation of biological activities, our results identified the rivulariapeptolides as a family of serine protease inhibitors with nanomolar potency, highlighting native metabolomics as promising approach for drug discovery, chemical ecology, and chemical biology studies.

The new phthalideisoquinoline hemiacetal alkaloids (2-7) and the known analogues (1 and 8) were isolated from the bulbs of Corydalis decumbens. The new compounds were characterized by analysis of their NMR spectroscopic data, chemical degradation syntheses, X-ray crystallography, and comparison of experimental and calculated ECD data. All the isolates were screened in vitro for inhibitory activity of spontaneous calcium oscillations in primary cultured neocortical neurons. Compounds 1-3 and 5-7 were found to be active in the suppression of spontaneous calcium oscillations with IC50 values of 6.8, 5.6, 11.6, 10.2, 8.3, and 3.1 μM, respectively. It was also observed that the presence of hydroxy, methoxy, and ethoxy groups at the remote stereogenic center C-7' of some isolated phthalideisoquinoline hemiacetal alkaloids could alter the preferred conformation and invert the sign of optical rotation, rather than this resulting from configurational isomerism at C-1 or C-9, and that the 3J1,9 coupling constants of these analogues varied accordingly. For example, compounds 1 and 6 are levorotatory, despite these molecules having the same carbon skeleton and absolute configuration as (+)-egenine. This emphasizes the potential risk of incorrectly assigning absolute configuration based only on observed coupling constants or optical rotation when comparing the data of new compounds with literature values for known analogues, especially within this class of molecules.

Metabolomics can be used to study complex mixtures of natural products, or secondary metabolites, for many different purposes. One productive application of metabolomics that has emerged in recent years is the guiding direction for isolating molecules with structural novelty through analysis of untargeted LC-MS/MS data. The metabolomics-driven investigation and bioassay-guided fractionation of a biomass assemblage from the South China Sea dominated by a marine filamentous cyanobacteria, cf. Neolyngbya sp., has led to the discovery of a natural product in this study, wenchangamide A (1). Wenchangamide A was found to concentration-dependently cause fast-onset apoptosis in HCT116 human colon cancer cells in vitro (24 h IC50 = 38 μM). Untargeted metabolomics, by way of MS/MS molecular networking, was used further to generate a structural proposal for a new natural product analogue of 1, here coined wenchangamide B, which was present in the organic extract and bioactive sub-fractions of the biomass examined. The wenchangamides are of interest for anticancer drug discovery, and the characterization of these molecules will facilitate the future discovery of related natural products and development of synthetic analogues.

Fucoxanthin, one of the most abundant carotenoids from edible brown seaweeds, for years has been used as a bioactive dietary supplement and functional food ingredient. Recently, fucoxanthin was reported to penetrate the blood-brain barrier, and was superior to other carotenoids to exert anti-neurodegenerative disorder effects via acting on multiple targets, including amyloid protein aggregation, oxidative stress, neuroinflammation, neuronal loss, neurotransmission dysregulation and gut microbiota disorder. However, the concentration of fucoxanthin required for in vivo neuroprotective effects is somewhat high, and the poor bioavailability of this molecule might prevent its clinical use. As such, new strategies have been introduced to overcome these obstacles, and may help to develop fucoxanthin as a novel lead for neurodegenerative disorders. Moreover, it has been shown that some metabolites of fucoxanthin may produce potent in vivo neuroprotective effects. Altogether, these studies suggest the possibility for future development of fucoxanthin as a one-compound-multiple-target or pro-drug type pharmaceutical or nutraceutical treatment for neurodegenerative disorders.Trial registration: ClinicalTrials.gov identifier: NCT03625284.Trial registration: ClinicalTrials.gov identifier: NCT02875392.Trial registration: ClinicalTrials.gov identifier: NCT03613740.Trial registration: ClinicalTrials.gov identifier: NCT04761406.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that has multiple causes. Therefore, multiple-target-directed ligands (MTDLs), which act on multiple targets, have been developed as a novel strategy for AD therapy. In this study, novel drug candidates were designed and synthesized by the covalent linkings of tacrine, a previously used anti-AD acetylcholinesterase (AChE) inhibitor, and dipicolylamine, an β-amyloid (Aβ) aggregation inhibitor. Most tacrine-dipicolylamine dimers potently inhibited AChE and Aβ1-42 aggregation in vitro, and 13a exhibited nanomolar level inhibition. Molecular docking analysis suggested that 13a could interact with the catalytic active sites and the peripheral anion site of AChE, and bind to Aβ1-42 pentamers. Moreover, 13a effectively attenuated Aβ1-42 oligomers-induced cognitive dysfunction in mice by activating the cAMP-response element binding protein/brain-derived neurotrophic factor signaling pathway, decreasing tau phosphorylation, preventing synaptic toxicity, and inhibiting neuroinflammation. The safety profile of 13a in mice was demonstrated by acute toxicity experiments. All these results suggested that novel tacrine-dipicolylamine dimers, especially 13a, have multi-target neuroprotective and cognitive-enhancing potentials, and therefore might be developed as MTDLs to combat AD.

Two new polyketide natural products, globosuxanthone F (1), and 2′-hydroxy bisdechlorogeodin (2), were isolated from the fungus Pleosporales sp. NBUF144, which was derived from a 62 m deep Chalinidae family sponge together with four known metabolites, 3,4-dihydroglobosuxanthone A (3), 8-hydroxy-3-methylxanthone-1-carboxylate (4), crosphaeropsone C (5), and 4-megastigmen-3,9-dione (6). The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR and high-resolution electrospray ionization mass spectra (HRESIMS) data. The absolute configuration of 1 was further established by single-crystal X-ray diffraction studies. Compounds 1-5 were evaluated for cytotoxicity towards CCRF-CEM human acute lymphatic leukemia cells, and it was found that 1 had an IC50 value of 0.46 µM.

Eukaryotic elongation factor 2 kinase (eEF2K or Ca2+/calmodulin-dependent protein kinase, CAMKIII) is a new member of an atypical α-kinase family different from conventional protein kinases that is now considered as a potential target for the treatment of cancer. This protein regulates the phosphorylation of eukaryotic elongation factor 2 (eEF2) to restrain activity and inhibit the elongation stage of protein synthesis. Mounting evidence shows that eEF2K regulates the cell cycle, autophagy, apoptosis, angiogenesis, invasion, and metastasis in several types of cancers. The expression of eEF2K promotes survival of cancer cells, and the level of this protein is increased in many cancer cells to adapt them to the microenvironment conditions including hypoxia, nutrient depletion, and acidosis. The physiological function of eEF2K and its role in the development and progression of cancer are here reviewed in detail. In addition, a summary of progress for in vitro eEF2K inhibitors from anti-cancer drug discovery research in recent years, along with their structure–activity relationships (SARs) and synthetic routes or natural sources, is also described. Special attention is given to those inhibitors that have been already validated in vivo, with the overall aim to provide reference context for the further development of new first-in-class anti-cancer drugs that target eEF2K.

Antibody-drug conjugates (ADCs) represent a new dimension of anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based proteasome inhibitors. These proteasome active agents are an emerging class of anticancer drug that possesses ultra-potent cytotoxicity to some cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.

The in situ application of iChip cultivation in mangrove sediment from Hainan province, China, led to the isolation of a novel bacterial species Gallaecimonas mangrovi HK-28. The extract of G. mangrovi HK-28 exhibited antibiotic activity against the aquatic pathogen Vibrio harveyi, and its chemical constituents were further investigated by bioactivity-guided isolation. Three new diketopiperazines, gallaecimonamides A-C, were accordingly isolated from the AcOEt extract of the fermentation broth of G. mangrovi HK-28. The planar structures of gallaecimonamides A-C were determined using HR-ESI-MS together with 1D- and 2D-NMR. The absolute configurations of gallaecimonamides A-C were assigned by optical rotation, NOESY experiment and TDDFT ECD calculations. The in vitro antibacterial and antimalarial activities of gallaecimonamides A-C were assessed. Gallaecimonamide A was found to display antibacterial activity against V. harveyi with a MIC value of 50 μm. However, gallaecimonamides B and C showed no antibacterial activity against V. harveyi (MIC >300 μm). In addition, all the isolates did not exhibit any inhibitory activities against V. parahaemolyticus (MIC>300 μm) and Plasmodium falciparum W2 (EC50 >100 μg/mL).

Four new steroids, dendronecholones A-D (1–4), and two known analogues, 12β,16β,20-trihydroxycholesta-1,4-dien-3-one 16-acetate (5) and nanjiol A (6), were isolated from Dendronephthya soft coral collected in waters off Zhejiang Province, China. The structures were elucidated by extensive spectrometric and spectroscopic analyses involving 1D and 2D NMRexperiments, high-resolution electrospray ionization mass spectrometry (HRESIMS), and single-crystal X-ray diffraction. Bioassay of the six compounds was performed on thirteen pathogenic Vibrio spp., nine of which were directly isolated from the gut of a half-smooth tongue sole (Cynoglossus semilaevis) and black scraper (Navodon septentrionalis) after its death from bacterial infection. These anti-Vibrio tests indicated that compounds 3 and 6 displayed inhibition towards Vibrio parahaemolyticus with minimum inhibitory concentrations (MIC) of 8 μg/mL, compounds 1–6 exhibited inhibition against V. scophthalmi, with minimum inhibitory concentrations (MIC) ranging from 8 to 32 μg/mL, compounds 1, 2 and 6 also inhibited the growth of V. harveyi, with values of 32, 8 and 8 μg/mL. . Dendronephthya soft corals are an unexplored biological resource for the development of these and other new anti-Vibrio lead compounds and potential aquaculture treatments.

Bioassay-guided phytochemical investigation of a commercially available maqui berry (Aristotelia chilensis) extract used in botanical dietary supplement products led to the isolation of 16 compounds, including one phenolic molecule, 1, discovered for the first time from a natural source, along with several known compounds, 2–16, including three substances not reported previously in A. chilensis, 2, 14, and 15. Each isolate was characterized by detailed analysis of NMR spectroscopic and HRESIMS data, and tested for their in vitro hydroxyl radical scavenging and quinone-reductase inducing biological activities. A sensitive and accurate LC-DAD-MS method for the quantitative determination of the occurrence of six bioactive compounds, 6, 7, 10–12, and 14, was developed and validated using maqui berry isolates purified in the course of this study as authentic standards. The method presented can be utilized for dereplication efforts in future natural product research projects, or to evaluate chemical markers for quality assurance and batch-to-batch standardization of this botanical dietary supplement component.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an important class of natural products that contain antibiotics and a variety of other bioactive compounds. The existing methods for discovery of RiPPs by combining genome mining and computational mass spectrometry are limited to discovering specific classes of RiPPs from small datasets, and these methods fail to handle unknown post-translational modifications. Here, we present MetaMiner, a software tool for addressing these challenges that is compatible with large-scale screening platforms for natural product discovery. After searching millions of spectra in the Global Natural Products Social (GNPS) molecular networking infrastructure against just eight genomic and metagenomic datasets, MetaMiner discovered 31 known and seven unknown RiPPs from diverse microbial communities, including human microbiome and lichen microbiome, and microorganisms isolated from the International Space Station.

The new phthalideisoquinoline hemiacetal alkaloids (

Protein kinases are validated drug targets for a number of therapeutic areas, as kinase deregulation is known to play an essential role in many disease states. Many investigated protein kinase inhibitors are natural product small molecules or their derivatives. Many marine-derived natural products from various marine sources, such as bacteria and cyanobacteria, fungi, animals, algae, soft corals, sponges, etc. have been found to have potent kinase inhibitory activity, or desirable pharmacophores for further development. This review covers the new compounds reported from the beginning of 2014 through the middle of 2019 as having been isolated from marine organisms and having potential therapeutic applications due to kinase inhibitory and associated bioactivities. Moreover, some existing clinical drugs based on marine-derived natural product scaffolds are also discussed.

Schefflera kwangsiensis Merr. ex H.L. Li (Araliaceae) is a widely used traditional Chinese medicine for pain management in the clinic. In the present study, we isolated a previously undescribed lupane saponin, designated as schekwanglupaside C (Sch C) from the ethanolic extract of S. kwangsiensis. The structure of Sch C was determined by comprehensive spectroscopic and spectrometric analyses and chemical degradation. In primary cultured cortical neurons, Sch C altered the pattern of spontaneous Ca

Lingaoamide (1), a new cyclic heptapeptide natural product, was isolated from a freshwater Oscillatoria cyanobacterium. The producing organism was collected in Chinese water spinach paddy farm fields in Lingao County, Hainan, China. The structure of 1 was determined by conventional mass spectrometry, NMR spectroscopy, and chemical degradation studies. Lingaoamide concentration-dependently up-regulates the biogenesis of pro-pathogenic melanin pigments (melanogenesis) in the rice blast fungus, Magnaporthe grisea, when tested in vitro. This molecule also exhibits weak in vitro inhibition (MIC 32 μg/mL) of Gram-negative Pseudomonas aeruginosa and Gram-positive Bacillus pumilus, and does not appear to impact plant growth or immune response in vivo using the model organism, Arabidopsis thaliana.

Two new compounds, including a para-benzoquinone ring-containing abietane (1), a para-benzoquinone ring-containing 7,8-seco-abietane (2), and 14 other known highly oxidized abietane diterpenoids (3-16), were isolated from an extract prepared from the cones of Taxodium distichum, collected in central Ohio. The active subfraction from which all compounds isolated in this study were purified was tested in vivo using Leishmania donovani-infected mice, and was found to dose-dependently reduce the parasite burden in the murine livers after iv administration of this crude mixture at 5.6 and 11.1 mg/kg. The structures of 1 and 2 were established by detailed 1D- and 2D-NMR experiments, HRESIMS data, and electronic circular dichroism studies. Compounds 3 and 4 were each fully characterized spectroscopically and also isolated from a natural source for the first time. Compounds 2-16 were tested in vitro against L. donovani promastigotes and L. amazonensis intracellular amastigotes. Compound 2 was the most active against L. amazonensis amastigotes (IC50 = 1.4 μM), and 10 was the most potent against L. donovani promastigotes (IC50 = 1.6 μM). These compounds may be suggested for further studies such as in vivo experimentation either alone or in combination with other Taxodium isolates.

Two new γ-lactones, aspergilactones A (1) and B (2), were discovered along with two known compounds, annularin A (3) and pericoterpenoid A (4), from a culture of the sponge-associated fungus Aspergillus sp. LS45. The planar structures of 1–4 were characterized using comprehensive spectroscopic methods and comparison with literature data. The absolute configurations of 1 and 2 were determined by comparison of electronic circular dichroism (ECD) spectroscopic and optical rotation data with those of known analogues as well as calculated ECD analysis. Compounds 1–4 were tested in a variety of bioassays, and both 1 and 4 exhibited significant inhibition against the lateral root growth of Arabidopsis thaliana Columbia-0 at a concentration of 100 μM. In addition, the in vitro cytotoxic activities of 1–4 against six human cancer cell lines CCRF-CEM, K562, BGC823, AGS, HCT-116 and MDA-MB-231 were evaluated. Compound 4 showed moderate inhibitory effects on CCRF-CEM and K562 cancer cell lines with IC50 values of 13.8 ± 1.6 and 12.9 ± 2.5 μM, respectively. However, compounds 1–4 did not show any notable AChE inhibitory activity in vitro.

25C-NBOMe is a designer substituted phenethylamine and a high-potency psychedelic that acts on the 5-HT2A receptor. Although 25C-NBOMe overdoses have been related to several deaths in the USA and Europe, very limited data exists on the in vitro neurotoxicity of 25C-NBOMe. In this study, we found that 25C-NBOMe potently reduced cell viability of SH-SY5Y, PC12, and SN4741 cells, with IC50 values of 89, 78, and 62 μM, respectively. Methamphetamine decreased the cell viability of these cells with IC50 values at millimolar range in the same tests, indicating that 25C-NBOMe is > 50 times more potent than methamphetamine in its ability to reduce viability of SH-SY5Y cells. The neurotoxicity of 25C-NBOMe on SH-SY5Y cells was further confirmed by using fluorescein diacetate/propidium iodide double staining. 25C-NBOMe elevated the expression of phosphorylated extracellular signal-regulated kinase (pERK), but decreased the expression of phosphorylated Akt and phosphorylated Ser9- glycogen synthase kinase 3β (GSK3β) in time- and concentration-dependent manners. Interestingly, either specific GSK3β inhibitors or specific mitogen-activated protein kinase kinase (MEK) inhibitors significantly prevented 25C-NBOMe-induced neurotoxicity in SH-SY5Y cells. These results suggest that 25C-NBOMe unexpectedly produced more potent neurotoxicity than methamphetamine and that the inhibition of the Akt pathway and activation of the ERK cascade might be involved in 25C-NBOMe-induced neurotoxicity. Most importantly, these findings further inform the toxicity of 25C-NBOMe abuse to the central nervous system for public health.

Alzheimer's disease is a progressive neurodegenerative disorder that mainly affects the elderly. Soluble β-amyloid oligomer, which can induce neurotoxicity, is generally regarded as the main neurotoxin in Alzheimer's disease. Here we report that eckmaxol, a phlorotannin extracted from the brown alga Ecklonia maxima, could produce neuroprotective effects in SH-SY5Y cells. Eckmaxol effectively prevented but did not rescue β-amyloid oligomer-induced neuronal apoptosis and increase of intracellular reactive oxygen species. Eckmaxol also significantly reversed the decreased expression of phospho-Ser9-glycogen synthase kinase 3β and increased expression of phospho-extracellular signal-regulated kinase, which was induced by Aβ oligomer. Moreover, both glycogen synthase kinase 3β and mitogen activated protein kinase inhibitors produced neuroprotective effects in SH-SY5Y cells. Furthermore, eckmaxol showed favorable interaction in the ATP binding site of glycogen synthase kinase 3β and mitogen activated protein kinase. These results suggested that eckmaxol might produce neuroprotective effects via concurrent inhibition of glycogen synthase kinase 3β and extracellular signal-regulated kinase pathways, possibly via directly acting on glycogen synthase kinase 3β and mitogen activated protein kinase. Based on the central role that β-amyloid oligomers play in the pathogenesis of Alzheimer's disease and the high annual production of Ecklonia maxima for alginate and other nutritional ingredients, this report represents a new candidate for the treatment of Alzheimer's disease, and also expands the potential application of Ecklonia maxima and its constituents in the field of pharmacology.