Marine natural products with anti-inflammation effects

The ocean possesses a complex setting with high pressure,high salinity,oligotrophy,low temperature and weak illumination conditions.To survive and evolve in such harsh surroundings,marine organisms metabolize a series of chemicals known as secondary metabolites which indicate structural and functional diversity to adapt interspecific survival competition.During recent decades,the anti-inflammatory property of marine natural products has come under scrutiny as inflammation involves in the vast majority of diseases.Correspondingly,a myriad of marine bioactive molecules including terpenes,polypeptides,polysaccharides,sterols and many others may bring a new insight into inflammation therapies with multifarious sources and minimal side effects.And a better understanding of their mechanisms of anti-inflammation may lead to better treatments for numerous diseases.Herein,the research progress of marine-derived anti-inflammation compounds and the relevant mechanisms were reviewed,to provide a basis for the research and development of anti-inflammatory marine drugs.

Research progress of anti-plant virus agents based on marine natural products

Plant virus diseases are a serious threat to food crops,vegetables,and cash crops,their prevention and control are extremely difficult,known as‘plant cancer’,and effective prevention and control agents are extremely short.Environmentally friendly natural antiviral active substances are key resources for the development of anti-plant virus drugs.Marine natural products are the most active field of new drugs and lead compounds discovery.However,there are few studies on their pesticide activities,especially their anti-plant virus activities.In the present manuscript,the latest research on anti-plant virus activity,structure-activity relationship,and mode of action of marine natural products were reviewed.It is hoped that this review will provide a useful reference for the research of anti-plant virus drugs.

Role of marine natural products in the development of antiviral agents against SARS‑CoV‑2:potential and prospects

A novel coronavirus,known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has surfaced and caused global concern owing to its ferocity.SARS-CoV-2 is the causative agent of coronavirus disease 2019;however,it was only discovered at the end of the year and was considered a pandemic by the World Health Organization.Therefore,the develop-ment of novel potent inhibitors against SARS-CoV-2 and future outbreaks is urgently required.Numerous naturally occurring bioactive substances have been studied in the clinical setting for diverse disorders.The intricate infection and replication mechanism of SARS-CoV-2 offers diverse therapeutic drug targets for developing antiviral medicines by employing natural products that are safer than synthetic compounds.Marine natural products(MNPs)have received increased attention in the development of novel drugs owing to their high diversity and availability.Therefore,this review article investigates the infection and replication mechanisms,including the function of the SARS-CoV-2 genome and structure.Furthermore,we highlighted anti-SARS-CoV-2 therapeutic intervention efforts utilizing MNPs and predicted SARS-CoV-2 inhibitor design.

An overview of the marine natural products in clinical trials and on the market

The first marine natural products that served as leads or scaffolds for medicines were discovered in the middle of last century:the arabinosyl glycosides from the marine sponge Tectitethya crypta.Synthesis and modifications of the natural molecules generated antiviral and antileukemic drugs developed in the 1970’s and in the following decades,including the first effective treatment against HIV infection.With the improvement of techniques for the elucidation of chemical structure of the molecules,as well as chemical synthesis,especially from the 1990’s,there was an increase in the number of bioactive natural products characterized from marine organisms.New chemical structures with high specificity towards molecular targets in cells allowed the development of new drugs with indication for the treatment of several illnesses,from cancer to new antibiotics,and even neurological disorders.Currently there are at least 13 molecules derived from marine natural products on advanced clinical trials,and nine were approved to be used as medicines.Considering that in the past eight years,more than 1000 new compounds from marine organisms were described,per year,the expectation is that many more drugs will be derived from marine natural products in a near future.

Potentials of marine natural products against malaria, leishmaniasis, and trypanosomiasis parasites: a review of recent articles

Background:Malaria and neglected communicable protozoa parasitic diseases,such as leishmaniasis,and trypanosomiasis,are among the otherwise called diseases for neglected communities,which are habitual in underprivileged populations in developing tropical and subtropical regions of Africa,Asia,and the Americas.Some of the currently available therapeutic drugs have some limitations such as toxicity and questionable efficacy and long treatment period,which have encouraged resistance.These have prompted many researchers to focus on fin ding new drugs that are safe,effective,and affordable from marine environ merits.The aim of this review was to show the diversity,structural scaffolds,in-vitro or in-vivo efficacy,and recent progress made in the discovery/isolation of marine natural products(MNPs)with potent bioactivity against malaria,leishmaniasis,and trypanosomiasis.Main text:We searched PubMed and Google scholar using Boolean Operators(AND,OR,and NOT)and the combination of related terms for articles on marine natural products(MNPs)discovery published only in English language from January 2016 to June 2020.Twenty nine articles reported the isolation,identification and antiparasitic activity of the isolated compounds from marine environment.A total of 125 compounds were reported to have been isolated,out of which 45 were newly isolated compounds.These compounds were all isolated from bacteria,a fungus,sponges,algae,a bryozoan,cnidarians and soft corals.In recent years,great progress is being made on anti-malarial drug discovery from marine organisms with the isolation of these potent compounds.Comparably,some of these promising antikinetoplastid MNPs have potency better or similar to conventional drugs and could be developed as both antileishmanial and antitrypanosomal drugs.However,very few of these MNPs have a pharmaceutical destiny due to lack of the following:sustainable production of the bioactive compounds,stan da rd efficient screening methods,knowledge of the mechanism of action,partnerships between researchers and pharmaceutical industries.Conclusions:It is crystal clear that marine organisms are a rich source of antiparasitic compounds,such as alkaloids,terpenoids,peptides,polyketides,terpene,coumarins,steroids,fatty acid derivatives,and lactones.The current and future technological innovation in natural products drug discovery will bolster the drug armamentarium for malaria and neglected tropical diseases.

Identification of marine natural product Pretrichodermamide B as a STAT3 inhibitor for efficient anticancer therapy

The Janus kinase(JAK)/signal transducer and activator of transcription 3(STAT3)regulates the expression of various critical mediators of cancer and is considered as one of the central communication nodes in cell growth and survival.Marine natural products(MNP)represent great resources for discovery of bioactive lead compounds,especially anti-cancer agents.Through the medium-throughput screening of our in-house MNP library,Pretrichodermamide B,an epidithiodiketopiperazine,was identified as a JAK/STAT3 signaling inhibitor.Further studies identified that Pretrichodermamide B directly binds to STAT3,preventing phosphorylation and thus inhibiting JAK/STAT3 signaling.Moreover,it suppressed cancer cell growth,in vitro,at low micromolar concentrations and demonstrated efficacy in vivo by decreasing tumor growth in a xenograft mouse model.In addition,it was shown that Pretrichodermamide B was able to induce cell cycle arrest and promote cell apoptosis.This study demonstrated that Pretrichodermamide B is a novel STAT3 inhibitor,which should be considered for further exploration as a promising anti-cancer therapy.

Developing natural marine products for treating liver diseases

In recent years,marine-derived bioactive compounds have gained increasing attention because of their higher biodiversity vs land-derived compounds.A number of marine-derived compounds are proven to improve lipid metabolism,modulate the gut microbiota,and possess anti-inflammatory,antioxidant,antibacterial,antiviral,and antitumor activities.With the increasing understanding of the molecular landscape underlying the pathogenesis of chronic liver diseases,interest has spiked in developing new therapeutic drugs and medicine food homology from marine sources for the prevention and treatment of liver diseases.

Quinosumycin,a novel anti-MRSA thioether-linked quinolinone-quinazolinone heterodimer from a marine actinomycete Streptomyces diastaticus NBU2966

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(NMR)spectroscopy,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 8μg/mL.

Heterologous expression facilitates the discovery and characterization of marine microbial natural products

Microbial natural products and their derivatives have been developed as a considerable part of clinical drugs and agricultural chemicals.Marine microbial natural products exhibit diverse chemical structures and bioactivities with substantial potential for the development of novel pharmaceuticals.However,discovering compounds with new skeletons from marine microbes remains challenging.In recent decades,multiple approaches have been de-veloped to discover novel marine microbial natural products,among which heterologous expression has proven to be an effective method.Facilitated by large DNA cloning and comparative metabolomic technologies,a few novel bioactive natural products from marine microorganisms have been identified by the expression of their biosynthetic gene clusters(BGCs)in heterologous hosts.Heterologous expression is advantageous for character-izing gene functions and elucidating the biosynthetic mechanisms of natural products.This review provides an overview of recent progress in heterologous expression-guided discovery,biosynthetic mechanism elucidation,and yield optimization of natural products from marine microorganisms and discusses the future directions of the heterologous expression strategy in facilitating novel natural product exploitation.

Antifouling Activities of Marine Bacteria Associated with Sponge (Sigmadocia sp.)

The present study aimed at assessing the antifouling activity of bacteria associated with marine sponges. A total of eight bacterial strains were isolated from the surface of sponge Sigmadocia sp., of them, SS02, SS05 and SS06 showed inhibitory activity against biofilm-forming bacteria. The extracts of these 3 strains considerably affected the extracellular polymeric substance producing ability and adhesion of biofilm-forming bacterial strains. In addition to disc diffusion assay, microalgal settlement assay was carried out with the extracts mixed with polyurethane wood polish and coated onto stainless steel coupons. The extract of strain SS05 showed strong microalgal settlement inhibitory activity. Strain SS05 was identified as Bacillus cereus based on its 16S rRNA gene. Metabolites of the bacterial strains associated with marine invertebrates promise to be developed into environment-friendly antifouling agents.

The biologically and ecologically important natural products from the Chinese sea hare Bursatella leachii:structures,stereochemistry and beyond

A novel amide alkaloid,bursatamide A(1),featuring an unprecedented propyl-hexahydronaphthalene carbon frame-work,was isolated from the infrequently studied sea hare Bursatella leachi,alongside a new 3-phenoxypropanenitrile alkaloid,bursatellin B(2),and twelve known compounds.The structures of 1 and 2 were elucidated through comprehensive spectroscopic data analyses,while their relative and absolute configurations(ACs)were established through total synthesis and a series of quantum chem-ical calculations,including calculated electronic circular dichroism(ECD)spectra,optical rotatory dispersion(ORD)methods,and DP4^(+) probability analyses.Bursatamide A(1)demonstrated inhibitory effects against the human pathogenic bacteria Listeria monocyt-ogenes and Vibrio cholerae.Erythro-bursatellin B(21),a diastereoisomer of 2,exhibited notable antibacterial activity against the fish pathogenic bacterium Streptococcus parauberis FP KSP28,with an MIC90 value of 0.0472 μg·mL^(-1).

Chemical and biological diversity of new natural products from marine sponges:a review(2009–2018)

Marine sponges are productive sources of bioactive secondary metabolites with over 200 new compounds isolated each year,contributing 23%of approved marine drugs so far.This review describes statistical research,structural diversity,and pharmacological activity of sponge derived new natural products from 2009 to 2018.Approximately 2762 new metabolites have been reported from 180 genera of sponges this decade,of which the main structural types are alkaloids and terpenoids,accounting for 50%of the total.More than half of new molecules showed biological activities including cytotoxic,antibacterial,antifungal,antiviral,anti-inflammatory,antioxidant,enzyme inhibition,and antimalarial activities.As summarized in this review,macrolides and peptides had higher proportions of new bioactive compounds in new compounds than other chemical classes.Every chemical class displayed cytotoxicity as the dominant activity.Alkaloids were the major contributors to antibacterial,antifungal,and antioxidant activities while steroids were primarily responsible for pest resistance activity.Alkaloids,terpenoids,and steroids displayed the most diverse biological activities.The statistic research of new compounds by published year,chemical class,sponge taxonomy,and biological activity are presented.Structural novelty and significant bioactivities of some representative compounds are highlighted.Marine sponges are rich sources of novel bioactive compounds and serve as animal hosts for microorganisms,highlighting the undisputed potential of sponges in the marine drugs research and development.

Crystal Structure of 2-(2-Carboxy-4-hydroxy-6-methoxyphenoxy)-3,5-dichloro-6-hydroxy-4-methylbenzoic Acid 1-Methyl Ester

The title compound, neogeodin hydrate （C17H14C1208, CAS： 94540-50-8）, was derived from marine fungus Aspergilhts terreus CRIM301. It was unequivocally characterized by IR, NMR spectroscopies, and single-crystal X-ray crystallography and tested for various biological activities. Neogeodin hydrate crystallizes in the triclinic space group P1 with a = 8.1159（5） A, b = 8.2472（4） A, c= 14.1278（7） A, a = 81.448（2）°, β = 84.860（2）°, γ= 70.400（2）°, V = 880.13（8） A3; Z = 2. It comprises a diphenyl ether, asterric acid skeleton and dichloro substituents. The methoxyphenoxy rings of the inversely related molecules form a ribbon-like structure that is stabilized by O-H...O hydrogen bonds through the doubly disordered carboxyl groups and by C-H...O interactions, generating the same R22（8） ring motif. The chlorinated methylbenzoate rings, making mostly a right angle, link the parallel upper and lower ribbons via bifurcated O-H...O and C-H...O hydrogen bonds, yielding endless channels. The channels formed are further sustained by C-H...O and π...π interactions Neogeodin hydrate exhibits inhibition against superoxide anion radical formation in the xanthine/xanthine oxidase （XXO） assay, but has no aromatase inhibitory activity.

In vitro antimicrobial and synergistic effect of essential oil from the red macroalgae Centroceras clavulatum (C. Agardh) Montagne with conventional antibiotics

Objective:To study the chemical profile,antimicrobial properties,and synergistic effect with known antibiotics of essential oil extracted from the marine red macroalgae Centroceras clavulatum(C.Agardh)Montagne,collected in Morocco.Methods:The chemical composition of the oil was analyzed by gas chromatography-mass spectrometry.The oil was evaluated for antibacterial(Pseudomonas aeruginosa,Escherichia coli,Bacillus subtilis,Micrococcus luteus,Staphylococcus aureus,and Klebsiella pneumoniae),and antifungal activity(Candida albicans,Candida glabrata,Candida krusei,and Candida parapsilosis),by the disc diffusion method.The minimum inhibitory and minimum microbicidal concentrations of the oil were determined,as well as the synergistic effects of its application combined with the antibiotics ciprofloxacin and fluconazole,by the checkerboard method.Results:Thirty molecules were identified in the essential oil,comprising 96.27%of the total oil composition.Monoterpenes such as carvacrol(36.06%)were the most abundant compounds,followed by caryophyllene(14.67%),endo-borneol(9.04%),pyroterebic acid(3.23%)and caryophyllene oxide(3.13%).The oil exhibited a moderate antimicrobial activity with inhibition zone diameters ranging from 9.0 to 15.0 mm.The minimum inhibitory concentration values varied between 0.9 and 14.7 mg/mL,and Bacillus subtilis and Escherichia coli were the more sensitive bacteria with 0.9 and 1.9 mg/mL,respectively.The minimum microbicidal concentration values ranged from 0.4 to 14.7 mg/mL.A significant synergic action was observed when the oil was applied in combination with ciprofloxacin and fluconazole,with fractional inhibitory concentration index values ranging from 0.31 to 0.50.Synergy was found in 80%of the combinations and a 2 to 16-fold reduction of antibiotics MIC was observed.Conclusions:Our findings suggest that the essential oil of Centroceras clavulatum should be further appraised for its potential use in the management of multi-drug resistant microorganisms,with the purpose to restore the activity of standard antimicrobial drugs.

A new chloro-azaphilone derivative with pro-angiogenesis activity from the hadal trench-derived fungus Chaetomium globosum YP-106

A new chloro-azaphilone derivative chaetoviridin L(1)along with four known analogues,namely,chaetomugilin A(2),chaetoviridin E(3),chaetomugilin O(4),and chaephilone D(5),is isolated and identified from the culture extract of Chaetomium globosum YP-106,a deep-sea derived fungus obtained from the hadal zone seawater collected in the Yap Trench.Their structures were determined based on detailed interpretation of nuclear magnetic resonance(NMR)spectroscopic,mass spectrometry(MS)data analysis and comparison with the reported literature.The absolute configuration of the new compound was established by quantum chemical calculations of electronic circular dichroism(ECD).All the isolated compounds were evaluated for pro-angiogenesis activity using zebra fish model.Compounds 1,2,and 5significantly promoted the angiogenesis in a dose-dependent manner and thus,these compounds might be used as promising molecules for the treatment of cardiovascular disease.

Tubastraea coccinea: A Non-Indigenous Coral (Cnidaria, Scleractinia) Collected at Arvoredo Island, South of Brazil with Potential MRSA and VRE Antimicrobial Activity

Bacterial infection is considered to be one of the most critical health issues of the world. It is essential to overcome this problem by the development of new drugs. Marine organisms as corals, sponges, seaweeds, and other are an incredible source of novel pharmacologically active compounds. Herein, the antimicrobial activity (extract/fractions) of the invasive stony coralTubastraea coccinea was evaluated by the disk diffusion method against 21 microbial strains (ATCC and clinical strains). Micro broth dilution was used to determinate the MIC of the fractions that showed antimicrobial activity by the disk diffusion method. Bioautography assay was also performed. Our results showed that the n-butanol (BF) and aqueous fractions (AF) showed activity against ATCC strains Staphylococcus aureus (MIC 31.25 and 250 μg/mL),Salmonella typhimurium (MIC 125 and 500 μg/mL), Escherichia coli (MIC 62.5 and 500 μg/mL) and Pseudomonas aeruginosa (MIC 62.5 and 500 μg/mL), respectively. Moreover, BF fraction was also effective against the clinical strains S. aureus(MIC 62.5 μg/mL), Klebsiella pneumoniae Carbapenemase—KPC (MIC 125 μg/mL), Methicillin-Resistant Staphylococcus aureus—MRSA (MIC 125 μg/mL) and Vancomycin-Resistant Enterococcus faecalis—VRE (MIC 62.5 μg/mL). The ratio MBC/MIC reinforces the bactericidal profile of BF fraction. The bioautography assay of BF fraction showed the presence of antimicrobial components at Rf0.55.

Structure modification,antialgal,antiplasmodial,and toxic evaluations of a series of new marine-derived 14-membered resorcylic acid lactone derivatives

Marine natural products play critical roles in the chemical defense of many marine organisms and are essential,reputable sources of successful drug leads.Sixty-seven 14-membered resorcylic acid lactone derivatives 3–27 and 30–71 of the natural product zeaenol(1)isolated from the marine-derived fungus Cochliobolus lunatus were semisynthesized by chlorination,acylation,esterification,and acetalization in one to three steps.The structures of these new derivatives were established by HRESIMS and NMR techniques.All the compounds(1–71)were evaluated for their antialgal and antiplasmodial activities.Among them,14 compounds displayed antifouling activities against adhesion of the fouling diatoms.In particular,9 and 34 exhibited strong and selective inhibitory effects against the diatoms Navicula laevissima and Navicula exigua(EC50=6.67 and 8.55μmol/L),respectively,which were similar in efficacy to those of the positive control SeaNine 211(EC50=2.90 and 9.74μmol/L).More importantly,38,39,and 69–71 showed potent antiplasmodial activities against Plasmodium falciparum with IC50 values ranging from 3.54 to 9.72μmol/L.Very interestingly,the five antiplasmodial derivatives displayed non-toxicity in the cytotoxicity assays and the zebrafish embryos model,thus,representing potential promising antiplasmodial drug agents.The preliminary structure–activity relationships indicated that biphenyl substituent at C-2,acetonide at positions C-5′and C-6′,and tri-or tetra-substituted of acyl groups increased the antiplasmodial activity.Therefore,combining evaluation of chemical ecology with pharmacological models will be implemented as a systematic strategy,not only for environmentally friendly antifoulants but also for structurally novel drugs.

Evaluation of fermentation conditions triggering increased antibacterial activity from a near-shore marine intertidal environment-associated Streptomyces species

A near-shore marine intertidal environment-associated Streptomyces isolate(USC-633)from the Sunshine Coast Region of Queensland,Australia,cultivated under a range of chemically defined and complex media to determine optimal parameters resulting in the secretion of diverse array of secondary metabolites with antimicrobial properties against various antibiotic resistant bacteria.Following extraction,fractioning and re-testing of active metabolites resulted in persistent antibacterial activity against Escherichia coli(Migula)(ATCC 13706)and subsequent Nuclear Magnetic Resonance(NMR)analysis of the active fractions confirmed the induction of metabolites different than the ones in fractions which did not display activity against the same bacterial species.Overall findings again confirmed the value of One StraineMany Compounds(OSMAC)approach that tests a wide range of growth parameters to trigger bioactive compound secretion increasing the likelihood of finding novel therapeutic agents.The isolate was found to be adaptable to both marine and terrestrial conditions corresponding to its original nearshore marine intertidal environment.Wide variations in its morphology,sporulation and diffusible pigment production were observed when different growth media were used.

Metabolites from marine invertebrates and their symbiotic microorganisms: molecular diversity discovery, mining, and application

Metabolites from marine organisms have proven to be a rich source for the discovery of multiple potent bioactive moleculeswith diverse structures. In recent years, we initiated a program to investigate the diversity of the secondary metabolites frommarine invertebrates and their symbiotic microorganisms collected from the South China Sea. In this review, representativecases are summarized focusing on molecular diversity, mining, and application of natural products from these marineorganisms. To provide a comprehensive introduction to the field of marine natural products, we highlight typical moleculesincluding their structures, chemical synthesis, bioactivities and mechanisms, structure-activity relationships as well as biogenesis. The mining of marine-derived microorganisms to produce novel secondary metabolites is also discussed through theOSMAC strategy and via partial chemical epigenetic modification. A broad prospectus has revealed a plethora of bioactivenatural products with novel structures from marine organisms, especially from soft corals, gorgonians, sponges, and theirsymbiotic fungi and bacteria.

Dysideanones F—G and dysiherbols D—E,unusual sesquiterpene quinones with rearranged skeletons from the marine sponge Dysidea avara

Four new sesquiterpene quinone meroterpenoids,dysideanones F—G(1—2)and dysiherbols D—E(3—4),were isolated from the marine sponge Dysidea avara collected from the South China Sea.The new structures were elucidated by extensive analysis of spectroscopic data including HR-MS and 1D and 2D NMR spectra,and their absolute configurations were assigned by single-crystal X-ray diffraction and ECD calculations.Anti-inflammatory evaluation showed that dysiherbols D—E(3—4)exhibited moderate inhibitory activity on TNF-α-induced NF-κB activation in human HEK-293T cells with IC_(50)values of 10.2 and 8.6μmol·L^(-1),respectively.