Marine Pharmacology in 2019‐2021: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti‐Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

1. Introduction

The aim of the present review is to consolidate the 2019-2021 preclinical marine pharmacology literature, with a similar format to our previous 12 reviews of this series, which cover the period 1998-2018 [1,2,3,4,5,6,7,8,9,10,11,12]. The scientific electronic databases MarinLit, PubMed, PubChem, ScienceDirect, and Google Scholar were used to search and retrieve the peer-reviewed published literature. In contrast with our previous reviews, we have focused the current review only on structurally characterized marine chemicals, classified into six major chemical classes, namely, polyketides, terpenes, peptides, alkaloids, shikimates,and sugars, including compounds with mixed biogenetic origin, using a modification of Schmitz’s chemical classification [13]. Mechanism of action studies of marine chemicals demonstrating antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities are summarized in Table 1, and the corresponding structures are presented in Figure 1. Similarly, the mechanism of action studies with marine compounds with immune and nervous systems activities, as well as antidiabetic and anti-inflammatory bioactivities are listed in Table 2, with their respective structures consolidated in Figure 2. Finally, marine compounds with miscellaneous mechanisms of action shown to affect multiple cellular and molecular targets, but with no currently assigned pharmacological category, are presented in Table 3, with their structures depicted in Figure 3.

5.7 μM

2. Marine Compounds with Antibacterial, Antifungal, Antiprotozoal, Antituberculosis and Antiviral Activities

Table 1 presents 2019-2021 mechanism of action studies with 49 structurally characterized marine compounds (1–49) that demonstrated antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities and that are shown in Figure 1.

2.1. Antibacterial Activity

As shown in Table 1, and Figure 1, during 2019-2021, studies with 22 structurally characterized marine natural products (1-22) isolated from bacteria, fungi, sponges, worms, shrimp, ascidians, bryozoa, octopus, fish and algae, reported novel antibacterial mechanisms of pharmacological action targeting bacterial coenzyme-A biosynthesis, membrane disruption, quorum sensing, efflux pumps, cytoskeletal FTsZ protein, biofilm formation, production of reactive oxygen species, DNA damage, and penicillin-binding protein (PBP)2a.

Gomez Rodriguez and colleagues identified the polyketide adipostatin E (1), discovered in the marine Streptomyces blancoensis strain 20733-1, as a potent inhibitor of Streptococcus pneumoniae coenzyme-A biosynthesis, by targeting phosphopantothenoylcysteine synthetase (PPCS), which was considered “an effective drug target” [14]. Elliott and colleagues investigated an amphipathic peptide arenicin-3 (2), found in the marine polychaete lugworm Arenicola marina, that induced a “potent and rapid antimicrobial activity in vitro against various multidrug-resistant Gram-negative bacteria and extensively drug-resistant pathogenic Gram-negative bacteria” by a mechanism of action that resulted from “bacterial membrane binding and disruption of membrane integrity” as well as ATP release [15]. Paderog and colleagues reported that the anthracycline polyketide bisanhydroaklavinone (3), isolated from Philippine marine-sediment derived Steptomyces griseorubens strain DSD069, was shown to cause cell membrane damage to multidrug-resistant Staphylococcus aureus by “leakage and loss of vital cell constituents…and increase membrane permeability” [16]. Wang and colleagues discovered the polyketide cladodionen (4), purified from the marine fungus Cladosporium sp. Z148, that was shown to be a novel quorum sensing inhibitor by a mechanism involving inhibition of quorum sensing-related gene expression as well as biofilm formation [17]. Gowrishankar and colleagues characterized the cyclic dipeptide cyclo(L-leucyl-L-prolyl) (5), isolated from the mangrove rhizosphere bacterium Bacillus amyloliquefaciens, that inhibited the uropathogen Serratia marcesens by a mechanism that involved inhibition of quorum sensing, as revealed by dose-dependent decrease in prodigiosin secretion at sub-minimum inhibitory concentrations, thus this study is “the first …to uncover the potent antibiofilm efficacy of (5) against a Gram-negative pathogen…” [18]. Silva de Figueiredo and colleagues showed that a known marine alga Canistrocarpus cervicornis-derived diterpene (6), decreased the minimum inhibitory activity of tetracycline against methicillin resistant S. aureus by 8-fold, suggesting this seaweed diterpene might be a “potential source(s) of antibiotic adjuvant, acting as (a) potential inhibitor of efflux pump” [19]. Davison and Bewley identified a new polyketide chrysophaentin analog (7), purified from laboratory cultures of the marine microalga Chrysophaeum taylorii NIED-1699, that demonstrated bacterial Gram-positive activity by competitive inhibition of the bacterial cytoskeletal FTsZ protein, a “promising target for novel antibiotic development” [20]. Wang and colleagues investigated the peptide crustin (8), uncovered in the deep-sea hydrothermal vent shrimp Rimicaris sp., that was lethal to Gram-positive bacteria by a mechanism that involved membrane disruption and depolarization [21]. Campana and colleagues reported that the marine bisindole alkaloid 2,2-bis(6-bromo-3-indolyl)ethylamine (9), discovered in the California marine tunicate Didemnum candidum and the New Caledonian marine sponge Orina spp., showed high antimicrobial activity against E. coli, S. aureus and K. pneumoniae by a mechanism that involved both biofilm formation inhibition and disaggregation, highlighting the “potential of (9) as antimicrobial and anti-biofilm agent” [22]. Liang and colleagues discovered that the peptide-polyketide doscadenamide A (10), found in the marine cyanobacterium Moorea bouillonii, modulated quorum sensing in the Gram-negative bacterium P. aeruginosa, by a mechanism that involved binding to intracellular receptor proteins, thus affecting a process that plays a critical role in bacterial pathogenesis [23]. Jabila and colleagues characterized the polyketide kalafungin (11), found in a marine Streptomyces in Staphylococcus aureus-infected zebrafish, that demonstrated beta-lactamase inhibition by a noncompetitive inhibition mechanism that resulted in “destruction of cell membrane” [24]. Maynard and colleagues showed that the known polyketide antibiotic korormicin A (12), isolated from the marine bacterium Pseudoalteromonas sp. J010, killed Gram negative bacteria that express the Na+-pumping NADH:quinone oxidoreductase by production of reactive oxygen species, “that cause damage to cells” [25]. Chung and colleagues determined that the polyketide lactoquinomycin A (13), purified from the marine bacterium Streptomyces bacillaris strain MBTC38, had potent activity against Gram-positive bacteria by damaging DNA by intercalation and “switch(ed) from the supercoiled to relaxed form” [26]. Jayathilaka and colleagues reported that the peptide octominin (14), derived from a Korean marine Octopus minor defense protein, demonstrated bactericidal activity against multidrug resistant Gram-positive bacterium Streptococcus parauberis, by causing “cytoplasmic membrane damage and permeability alterations…possible DNA binding” [27]. Yu and colleagues identified a cyclic dipeptide cyclo(_L-Tyr-_L-Pro) (15), isolated from the marine fungus Penicillium chrysogenum DXY-1, that decreased bacterial quorum sensing-mediated pathogenicity by competitively binding to the receptor protein active pocket, thus becoming “a potential pro-drug for treating drug-resistant P. aeruginosa infections” [28]. Pan and colleagues investigated the peptide piscidin 5 (16), discovered in the marine bass Morone chrysops, and determined that it damaged bacterial membranes by a mechanism involving pathogen-associated molecular patterns, and in addition “could interact with bacterial genome DNA” [29]. Kim and colleagues reported that the terpenoids phorbaketal B and C (17, 18), derived from the marine sponge Phorbas sp., and determined by transcriptional analysis that their bacterial antibiofilm activity resulted from the inhibition of the “expression of the biofilm-related hemolysin gen hla and the nuclease gene nuc1” [30]. Kizhakkekalam and colleagues purified an aryl-enclosed macrocyclic polyketide (19), found in the intertidal marine red macroalga Hypnea valentiae-associated heterotrophic bacterium Shewanella algae, that demonstrated both antibacterial and antioxidant bioactivity which correlated with docking “with the active site of target protein, penicillin-binding protein (PBP)2a” [31]. Chakraborty and colleagues similarly discovered a macrocyclic polyketide (20), isolated from the marine red macroalga Hypnea valentia-associated heterotropic bacterium Shewanella algae, with siderophore mode of action which correlated with docking “with the binding site of PBP2a”[32]. Hansen and colleagues characterized the alkaloid securamine H (21), purified from the Arctic marine bryozoan Securiflustra securifrons, which potently inhibited Staphylococcus aureus by a reduction of metabolic activity that did not appear to involve cell membrane disruption nor “interfere(nce) with DNA replication, transcription or translation” [33]. Hansen and colleagues reported the isolation and characterization of a cysteine-rich peptide turgencin A (22) from the Arctic marine colonial ascidian Synoicum turgens, which displayed potent Gram-negative and Gram-positive antimicrobial activity via a dose- and time-dependent mechanism that caused immediate loss of “ membrane integrity” resulting in a “rapid effect on cell viability” [34]. Reina and colleagues described a tyramine (23) from the Gram-negative marine bacterium Vibrio alginolyticus, and demonstrated that this quorum-sensing compound inhibited pyoverdine production and motility in P. aeruginosa, providing insight into “the use of naturally produced quorum-sensing inhibitors as a possible strategy to combat bacterial infections” [35].

2.2. Antifungal Activity

As shown in Table 1, and Figure 1, during 2019-2021, 7 studies with structurally characterized marine natural products (24-30), isolated from bacteria, fungi and sponges, reported novel pharmacological mechanisms of action targeting ergosterol-containing membranes, the fungal cell wall, 3-hydroxy-3-methylglutaryl CoA synthase, conversion of phytosphingosine to phytoceramide, echinocandin (CAS)-responding gene-induction, and fungal genes involved in filament formation and cell adhesion.

Elsadek and colleagues characterized a novel polyhydroxylated macrolide amantelide A (24), discovered in the marine cyanobacterium Lyngbya majuscula, and demonstrated that its mechanism of action is similar to polyene antifungals, as “it binds to ergosterol-containing membranes”, leading to cell death [36]. Yang and colleagues described the new dolabellane-type diterpenoid atranone Q (25), derived from the marine-derived fungus Stachybotrys chartarum, observing that at high in vitro concentrations it had a “destructive effect on the cell wall and cell membrane of C. albicans” [37]. Tang and colleagues identified a novel β-lactone fusarilactone A (26), found in the mangrove sediment-derived fungus Fusarium solani H915, that inhibited 3-hydroxy-3-methylglutaryl CoA synthase, an enzyme present in eukaryotes that when inhibited “as shown potential for antiviral, antibacterial and cardiovascular protection”[38]. Kim and colleagues investigated the known alkaloid 2-n-heptyl-4-hydroxyquinoline (27), isolated from a marine actinomycete Streptomyces sp. MBTG13, that affected the fungus C. albicans filamentous growth induction by inhibiting mRNAs “related to the cAMP-Efg1 (signaling) pathway” [39]. Dalisay and colleagues reported that the polyketide oceanapiside (28), purified from the marine sponge Oceanapia phillipensis, inhibited C. glabrata sphingolipid metabolism by targeting “the step converting phytosphingosine to phytoceramide” [40]. Tripathi and colleagues showed that the marine sesquiterpene quinone puupehenone (29), uncovered in the marine sponge Hyrtios sp., potentiated the clinically used antifungal echinocandin (CAS) against CAS-insensitive Candida neoformans, by inhibiting CAS-responding gene-induction that is required for fungal cell wall repair [41]. Meng and colleague characterized the shikimate 3-methyl-N-(2′-phenethyl)-butyrylamide (30), discovered in the marine bacterium Streptomyces olivaceus, that exhibited excellent activity against C. albicans by regulating expression of several genes “associated with filament formation and cell adhesion” [42].

2.3. Antiprotozoal and Antituberculosis Activity

As shown in Table 1, and Figure 1, in 2019-2021, 13 antiprotozoal (antimalarial, antileishmanial and antitrypanosomal) and antituberculosis studies with structurally characterized marine natural products (31-43), isolated from bacteria, sponges, ascidians, zoanthids, hydroids, fish and algae reported novel pharmacological mechanisms of action targeting Plasmodium falciparum (P. falciparum) lysyl-tRNA synthetase, P. falciparum proteins actin and sortilin, P. falciparum liver-stage parasite, P. falciparum transition ring to early trophozoite transition, amoebae Acanthamoeba castellani programmed cell death induction mechanisms, Trichomonas vaginalis membrane disruption, Trypanosoma cruzi trypomastigote and amastigotes plasma membrane integrity, Trypanosoma cruzi cysteine protease cruzain, and Schistosoma mansoni parasite egg-production.

Malaria, is a global disease in humans caused by protozoans of the genus Plasmodium (P. falciparum, P. ovale, P. vivax and P. malariae), which as described in the World Health Organization (WHO) website (https://www.who.int/news-room/fact-sheets/detail/malaria), currently affects several million people worldwide. Alhadrami and colleagues characterized the anthraquinone capillasterquinone B (31), discovered in a coculture of the Red Sea sponge-derived actinobacteria Actinokineospora spheciospongiae strain EG-49 and Rhodococcus sp. UR59, that showed antimalarial activity by binding to Plasmodium falciparum lysyl-tRNA synthetase at “several amino acids inside the enzyme’s active site” [43]. Sweeney-Jones and colleagues described a new cyclic peptide kakeromamide B (32), derived from the Fijian marine cyanobacterium Moorea producens, that was predicted to bind to Plasmodium falciparum proteins actin and sortilin, thus suggesting “possible interference with parasite invasion of host cells” [44]. Knestrick and colleagues identified a highly modified linear hexapeptide friomaramide (33), found in the Antarctic marine sponge Inflatella coelosphaeroide, that inhibited Plasmodium falciparum liver-stage parasite development showing “similar inhibitory activity to the known liver-stage antimalarial drug primaquine” [45]. Wright and colleagues communicated that the known terpene nitenin (34), isolated from the deep-water marine sponge Spongia lamella, potently inhibited Plasmodium falciparum chloroquine-resistant strain Dd2 by targeting the parasite’s early transition “from ring to early trophozoite”, a novel property for an antimalarial [46]. Rodríguez-Expósito and collaborators investigated the terpenoid 4-epi-arbusculin A (35), purified from the Canary Islands indigenous marine zoanthid Palythoa aff. clavata, that affected the life cycle of the free-living amoebae Acanthamoeba castellani Neff by several programmed cell death induction mechanisms [47]. Huang and colleagues reported that the antimicrobial peptide epinecidin-1 (36) uncovered in the marine grouper Epinephelus coloides was reported to decrease the metronidazole-resistant protozoan parasite Trichomonas vaginalis multiplication both in vitro and in vivo, with mechanism of action involving “membrane disruption” [48]. Lima and colleagues showed that the terpenoid isololiolide (37), discovered in the marine hydroid Macrorhynchia philippina, inhibited both trypomastigote and intracellular amastigotes of Trypanosoma cruzi by causing disruption “of the plasma membrane integrity and a strong depolarization of the mitochondrial membrane potential” [49]. Lorenzo-Morales and colleagues characterized the oxasqualenoid terpenoid dehydrothyrsiferol (38), derived from the marine red alga Laurencia viridis, which demonstrated cysticidal activity against Acanthamoeba castellanii trophozoites inducing chromatin condensation, mitochondrial dysfunction and increased membrane permeability [50]. Boudreau and colleagues determined that the peptide gallinamide A (39), originally reported from the Panamanian marine cyanobacterium Schizothrix sp., was cytotoxic to the intracellular amastigote stage of the Chagas disease-causative agent Trypanosoma cruzi, by potently inhibiting the ”validated drug target” cysteine protease cruzain, thus representing “a new candidate for the treatment of Chagas disease [51]. Cartuche and colleagues identified the indolocarbazole alkaloid 7-oxostaurosporine (40), found in cultures of the Ecuadorian mangrove-derived Streptomyces sanyensis PBLC04, inhibited anti-Acanthamoeba spp., an agent affecting “millions of people worldwide”, by a mechanism that resulted in “chromatin condensation”, as well as, “affecting membrane permeability and causing mitochondrial damage” [52]. Casertano and colleagues investigated the novel alkaloid polyaurine A (41), isolated from the Indonesian marine ascidian Polycarpa aurata, which while not cytotoxic to mammalian cells, affected blood-dwelling Schistosoma mansoni parasite egg-production, observed as being “smaller, deformed, and/or fragmented”[53].

Tuberculosis, is a disease caused by Mycobacterium tuberculosis in both human and animals, and as noted in the WHO’s website (https://www.who.int/news-room/fact-sheets/detail/tuberculosis), remains a global health challenge affecting millions of people worldwide, a fact that continues to stimulate ongoing search for novel marine-derived metabolites as potential therapeutic leads. As shown in Table 1 and Figure 1, during 2019-2021, two antituberculosis studies with structurally characterized marine natural products (42,43) reported novel mechanisms of pharmacological action.

Liu and colleagues reported a new bioactive polyketide polypropionate fiscpropionate A (42), isolated from a deep-sea-derived fungus Aspergillus fischeri FS452, that inhibited Mycobacterium. tuberculosis protein tyrosine phosphatase B by a noncompetitive inhibition mechanism [54]. Sudomova and colleagues determined that marine brown algal carotenoid terpenoid fucoxanthin (43), was bacteriostatic to all clinical Mycobacterium tuberculosis strains tested, by potently and competitively binding to “crucial drug targets” mycobacterial cell wall biosynthesis enzymes UDP-galactopyranose mutase and arylamine-N-acetyltransferase, thus demonstrating “great therapeutic value for the treatment of tuberculosis” [55].

2.4. Antiviral Activity

As shown in Table 1 and Figure 1, during 2019-2021, 3 antiviral studies with structurally characterized marine chemicals (44-49), isolated from bacteria, fungi, and dinoflagellates reported novel mechanisms of pharmacological action targeting zika virus, hepatitis C virus, Venezuelan and Eastern equine encephalitis viruses, and human immunodeficiency virus type 1 (HIV-1).

Liu and colleagues reported a new phenylspirodrimane-type dimer alkaloid chartarlactam Q (44), isolated from the fermentation broth of a marine sponge-derived fungus Stachybotrys chartarum WGC-25 C-6, that inhibited Zika virus African-lineage MR766 strain by affecting the in vitro accumulation of viral proteins NS5 and E “in a dose-dependent manner” [56]. Li and colleagues described two novel sesquiterpene-based analogues harzianoic acids A and B (45, 46), discovered in the marine sponge-associated fungus Trichoderma harzianum, that inhibited hepatitis C virus (HCV) life cycle in vitro by binding to both the HCV viral envelope E1/E2 glycoproteins as well as the host cells key protein CD81, thus suggesting “potential for development as HCV inhibitors” [57]. Lin and colleagues characterized the polyketide homoseongomycin (47), found in the marine actinomycete bacterium K3-1, that potently inhibited Venezuelan and Eastern equine encephalitis viruses, by affecting both the early and late stages (assembly and budding) of the viral life cycle, with concomitant low toxicity [58]. Tan and colleagues determined that a natural xanthone dimer polyketide penicillixanthone A (48), isolated from a marine jellyfish-derived fungus Aspergillus fumigates, potently inhibited HIV-1 by binding to white blood cell membrane receptors C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 4 (CCR4), thus suggesting that this new type of CCR5/CXCR4 dual-coreceptor antagonist has potential “ for the development of anti-HIV therapeutics”[59]. Izumida and colleages identified the spirocyclic imine polyketide portimine (49), purified from the benthic marine dinoflagellate Vulcanodinium rugosum, that exhibited significant inhibition of HIV-1 replication at the nM range, by targeting both the HIV-1 Gag or Pol protein as well as reverse transcriptase directly, and thus was proposed as “a potent lead compound for development of novel anti-HIV-1 drugs” [60].

3. Marine Compounds with Antidiabetic and Anti-Inflammatory Activity, and Affecting the Immune and Nervous System

Table 2 presents the 2019-2021 mechanism of action studies with structurally characterized marine compounds (50-124) shown in Figure 2, that demonstrated antidiabetic or anti-inflammatory activity as well as affected the immune or nervous system.

3.1. Antidiabetic Activity

Diabetes is a disease that is characterized by high glucose blood levels that may lead to cardiovascular disease, as well as, kidney and nerve damage (https://www.niddk.nih.gov/health-information/diabetes). As shown in Table 2, and Figure 2, during 2019-2021, studies with 8 structurally characterized marine natural products (43, 50-56) isolated from fungi, algae and mangrove, reported novel antidiabetic mechanism of pharmacological action targeting α-amylase and α-glucosidase, insulin signaling pathways, oxidative stress, glucose transporter 4, and tyrosine phosphatase 1B.

Das and colleagues contributed the limonoid terpenoid xyloccensin-1 (50), discovered in the mangrove Xylocarpus granatum, that demonstrated significant antidiabetic activity resulting from potent in vitro inhibition of α-amylase and α-glucosidase, observations confirmed with α-glucosidase enzyme molecular docking binding studies [61]. Luo and colleagues described a synthetic derivative of shikimate bromophenol CYC27 (51), derived from the marine red alga Rhodomela confervoides, which induced hypoglycemia in diabetic mice by increased phosphorylation of insulin receptors, enhancement of insulin signaling pathways and “most regulated phosphoproteins (were) related to RNA splicing, mRNA processing and RNA processing” [62]. Zaharudin and colleagues determined that the terpene fucoxanthin (43), found in the marine brown edible alga Undaria pinnatifida, strongly inhibited yeast α-glucosidase enzyme with mixed-type inhibition kinetics, commenting that “a compound that inhibits yeast α-glucosidase activity will not necessary inhibit mammalian α-glucosidase activity” [63]. Interestingly, Arthiya and colleages demonstrated that fucoxanthin (43), isolated from the marine microalga P. tricornutum, inhibited rat intestinal α-glucosidase enzyme by noncompetitive inhibition [64]. Hudlikar and colleagues evaluated the protective effect of fucoxanthin (43) on high glucose-induced oxidative stress in mouse kidney mesangial cells in vitro, observing that fucoxanthin modified epigenomic and transcriptomic biomarkers thus protecting mesangial cells “from high glucose-induced oxidative stress and damage”[65]. Chakraborty and Antony identified the terpenoid abeo-oleanene (52), purified from the intertidal marine red alga Gracilaria salicornia, and assessed potent in vitro antioxidant and antidiabetic potential with dual inhibition of starch digestive enzymes α-amylase and α-glucosidase, further confirmed by in silico molecular modelling studies, thus proposing this compound might “ constitute prospective anti-hyperglycemic pharmaceutical candidate” [66]. Yang and colleagues investigated the polyketide ishophloroglucin A (53), uncovered in the marine brown edible seaweed Ishige okamurae, demonstrating it affected glucose homeostasis in pancreas and muscle of high fat diet-fed (HFD) mice by targeting the glucose transporter 4 in the muscles, thus considering the compound a “a functional food for the prevention of diabetes” [67]. Paudel and colleagues reported the anti-diabetic potential of a shikimate bis-(2,3,6-tribromo-4,5-dihydroxybenzylmethyl ether) (54), discovered in the marine alga Symphyocladia latiuscula, and determined by both enzyme kinetics and in silico molecular modeling potent tyrosine phosphatase 1B and α-glucosidase inhibition, as well as, enhancement of both insulin sensitivity and glucose uptake, thus (54) “may represent a novel class of anti-diabetic drugs” [68]. Seong and colleagues showed that the fatty acid (Z)-hexadec-12-enoic acid (55), derived from the edible marine brown seaweed Hizikia fusiformis, by detailed enzyme kinetics and molecular docking studies was a potent tyrosine phosphatase 1B and α-glucosidase inhibitor [69]. Lopez and colleagues characterized the fatty acid tripalmitin (56), found in a mangrove-associated fungus Zasmidium sp. strain EM5-10, as a mixed inhibitor of α-glucosidase as determined by enzyme kinetic studies, with potential to bind the human intestinal α-glucosidase, and “the first report on α-glucosidase inhibitory activity of triglycerides” [70]

3.2. Anti-Inflammatory Activity

As shown in Table 2 and Figure 2, during 2019-2021, studies with 28 structurally characterized marine natural products (43, 57-83) isolated from bacteria, fungi, sponges, sea hare, dinoflagellates, diatoms, algae and mangrove reported novel anti-inflammatory pharmacological mechanisms of action that targeted NF-kB activation, pro-inflammatory cytokine production, and reactive oxygen species generation.

Several marine-derived natural products investigated mechanistically during 2019-2021 demonstrated significant anti-inflammatory functions by targeting signal transduction pathways, leading to NF-kB activation and pro-inflammatory cytokine production. The anti-inflammatory activity of the terpenoid xanthophyll fucoxanthin (43) was reported in several papers: Su and colleagues reported that the terpenoid fucoxanthin (43), discovered in the marine diatom Conticribra weissflogii ND-8, prophylactically attenuated LPS-induced sepsis in a whole animal mouse model, by blocking NF-kB activation and the production of pro-inflammatory cytokines [81]. Zheng and colleagues showed that edible brown seaweed-derived terpenoid fucoxanthin (43), demonstrated protective effects in an in vivo model of alcohol-induced liver damage by activation of the Nrf2-sginaling pathway and decreasing NF-kB activation [82]. Ha and colleagues further characterized the terpenoid fucoxanthin (43), and observed that in osteoclast-like RAW264.7 cells in vitro, fucoxanthin increased Nrf2 activation, decreased the expression of osteoclast-specific markers, as well as “osteoclast differentiation and bone resorption ability” [83]. Li and colleagues determined that the terpenoid fucoxanthin (43), protected against LPS-induced murine lung inflammation in vivo, by decreasing cellular infiltration and both lung tissue COX-2 and iNOS expression. Interestingly, molecular docking simulations demonstrated that fucoxanthin (43) blocked LPS-induced signaling by binding to the TLR4 pocket that is required for LPS stimulation [84]. Together, these findings indicate that fucoxanthin (43) from both marine diatoms and seaweed has the potential to attenuate inflammation in vitro and in vivo.

Wen and colleagues identified the polyketide phenolic aglycone (58), derived from the marine fungus Aspergillus sp., and showed that it decreased LPS-induced NO production and NF-kB-regulated cytokines such as IL-1β and IL-6 [72]. Keeler and colleagues investigated the polyketide brevenal (59), isolated from the marine dinoflagellate Karenia brevis, showing that in the context of lung inflammation, it blocked NF-kB activation and development of fully activated macrophages in vitro, which are critical players that promote lung inflammation [73]. Alvariño and colleagues reported the polyketide caniferolide A (60), found in the marine actinomycete Streptomyces caniferus, which blocked NF-kB, p38, JNK, and MAPK activation with a concomitant increase in NRf2 that promoted the survival of BV2 microglial cells, suggesting that (60) may target “many pathological markers of Alzheimer’s disease” [74]. Ding and colleagues showed that the polyketide/shikimate curdepsidone C (63), obtained from the marine fungus Curvularia sp. IFB-Z10, blocked bacterial-induced THP-1 cell IL-1β production as well as activation of MAPK signaling pathways, presumably through direct interactions with the TLR1/2 receptor [76]. Ku and colleagues characterized the alkaloid collismycin C (64), isolated from the marine red alga-associated Streptomyces sp. strain MC025, and determined that in vitro it decreased NF-kB phosphorylation of p38 and TNF-α production, as well as was protective in a PolyP model of murine sepsis in mice [77]. Oh and colleagues contributed the polyketide dieckol (65), purified from brown seaweed Ecklonia cava, and showed that it attenuated the development of nonalcoholic fatty liver disease by decreasing NLRP3 inflammasome formation and pyroptosis in a mouse high-fat diet model [78]. Kim and colleagues evaluated the terpenoid epiloliolide (67), uncovered in the marine brown alga Sargassum horneri, on human periodontal ligament cells in vitro in the presence of P. gingivalis lipopolysaccharide (LPS), and observed a decreased production of inflammatory mediators TNF-α, IL-6, IL-1β, and promotion of cell growth and proliferation via “regulation of PKA/CREB signaling” [80]. Li and colleagues determined that the terpenoid fucoxanthinol (68), discovered in the marine diatom Nitschia laevis, was able to block the LPS-induced inflammatory response by microglia in vitro by increasing Nrf2 with a subsequent loss of the expression iNOS, COX-2, and pro-inflammatory cytokines TNF-α and IL-6, and PGE-2 [85]. Jan and colleagues identified the terpenoid hirsutanol A (69), derived from the marine red alga-derived fungus Chondrostereum sp. NTOU4196, that attenuated LPS-induced lung inflammation in vivo and behavioral changes in a mouse endotoxemia model by blocking LPS-induction of STAT3 and MMP-9 [86]. Chen and colleagues explored the polyketide 2-epi-jaspine B (70) analog, isolated from the marine sponges Pachastrissa sp. and Jaspis. sp., and in an in vivo rat model of complete Freund’s adjuvant rheumatoid arthritis (RA), showed it acted as a SphK1 inhibitor in vitro and significantly improved RA symptoms measured by decreased pro-inflammatory cytokines TNF-α, IL-6, IL-1β, swelling volume, and arthritis score [87]. Daskalaki and colleagues investigated the diterpenes (71,72), obtained from the red seaweed Laurencia glandulifera, that demonstrated the ability to decrease the production of pro-inflammatory mediators in vitro and suppress the development of dextran sulfate sodium-induced murine colitis in vivo [88]. Kim and colleagues reported the alkaloid O-demethylrenierone (75), purified from the marine sponge Haliclona sp., suppressed NF-kB nuclear translocation and subsequent expression of NO synthase, cyclooxygenase-2, with a subsequent increase in Nrf2 using human epithelial cell and monocyte cell lines [91]. Lee and colleagues showed that the terpenoid deacetylphylloketal (77), a novel derivative uncovered in the marine sponge Phyllospongia sp., inhibited LPS-induced NO, PGE₂, and pro-inflammatory cytokines TNF-α, IL-6, IL-1β production in human epithelial cells and PMA-differentiated macrophages by blocking NF-kB nuclear translocation and increasing HO-1 levels [93]. Kim and colleagues characterized the grasshopper terpenoid ketone (79), discovered in the marine brown alga Sargassum fulvellum, that attenuated LPS-induced nitric oxide production and pro-inflammatory cytokines IL-6, TNF-α and IL-1β by blocking multiple signaling pathways, including NF-kB [95]. Abdelfattah and colleagues contributed the alkaloids butylcycloprodigiosin and undecylprodigiosin (80, 81), derived from the red sea sponge Spheciospongia mastoidea, which attenuated gastric inflammation and gastric mucosal apoptosis in vivo by decreasing both NF-kB and iNOS expression and while increasing HO-1 expression, suggesting that prodigiosins “exerted gastroprotective effects” [96]. Hwang and colleagues described the bis(indole) alkaloid topsentin (82), found in the marine sponge Spongosorites genitrix, observing that it protected a human epidermal keratinocyte cell line in vitro from ultraviolet-induced inflammation, by suppressing AP-1 and MAPK signaling pathways [97].

Other marine-derived natural products investigated mechanistically during 2019-2021 demonstrated significant anti-inflammatory functions by targeting signaling pathways involved in reactive oxygen radicals, i.e., superoxide and nitric oxide generation: Pereira and colleagues determined that the steroidal endoperoxide terpenoid 5α,8α-epidioxycholest-6-en-3β-ol (57), isolated from the sea hare Aplysia depilans, blocked the induction of nitric oxide (NO) levels by decreasing the expression of iNOS and other pro-inflammatory markers [71]. Van Thanh and colleagues evaluated two novel terpenoids (61, 62), purified from the leaves of the Vietnamese mangrove Calophyllum inophyllum, and observed that they blocked LPS-induced NO production and the production of pro-inflammatory cytokines by blocking the induction of iNOS and NF-kB activation, respectively [75]. Hu and colleagues identified the meroterpenoid dysiarenone (66), isolated from the marine sponge Dysidea arenaria, that blocked LPS-induction of inflammatory cytokines and other mediators, such as ROS by increasing the production of HO-1 via a Nrf2-dependent mechanism [79]. Herath and colleagues investigated the terpenoid mojabanchromanol (73), a chromanol uncovered in the marine brown alga Sargassum horneri, that decreased ROS-mediated responses and TLR2/4/7 activation in a type II alveolar epithelial cell line, suggesting that mojobanchromanol may become a potential treatment against airway inflammation induced by particulate matter [89]. Ha and colleagues reported the polyketide neuchromenin (74), discovered in the Antarctic marine-derived fungal strain Penicillium glabrum SF-7123, that in an in vitro model of microglial and macrophage activation demonstrated suppression of LPS-induced NO-synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and downregulation of NF-kB and p38 pathways [90]. Chu and colleagues showed that the polyketide penicitrinone A (76), derived from the marine fungus Penicillium citrinum, decreased neutrophil activation and agonist-induced superoxide generation putatively “through Bcl-2, Bax and caspase 3 signaling cascades” [92]. Liu and colleagues contributed the polyketide sclerketide C (78), found in the marine coral-derived fungus Penicillium sclerotiorin, that inhibited NO production in LPS-induced macrophages, by binding to the active site of the iNOS enzyme and blocking its activity [94]. Kim and colleagues described the polyketide/terpenoid tuberatolide B (83), isolated from the marine brown alga Sargassum macrocarpum, that had both in vitro anti-inflammatory properties by attenuating LPS-induced NF-kB and MAPK phosphorylation, while in vivo, using a zebrafish model, (83) blocked the induction iNOS and subsequent NO production [98]. Taken together, these studies demonstrate the importance and potential of marine-derived compounds as therapeutic options in the treatment of inflammatory diseases.

3.3. Marine Compounds with Activity on the Immune System

As shown in Table 2 and Figure 2, during 2019-2021, studies with 9 structurally characterized marine natural products (65, 84-91) isolated from fungi, sea anemones, soft corals, mollusks, sea urchins, diatoms, algae reported novel immune system pharmacological mechanisms of action that indicate that marine-derived compounds have the ability to influence the immune system both in vitro and in vivo and provide evidence that these compounds could have significant therapeutic impact upon further investigation.

As shown in Table 2 and Figure 2, the ability of marine-derived compounds to modulate dendritic cell function varied depending on the source of the compound. Two compounds had anti-inflammatory effects both in vitro and in vivo. Firstly, Yin and colleagues, extended the pharmacology of the carotenoid pigment terpenoid astaxanthin (84), found in “microalgae and seafood”, and demonstrated it altered murine dendritic cell activation and reduced the production of pro-inflammatory cytokines TNF-α, IL-6, and IL-10 in vitro by increasing HO-1 and Nrf2 levels [99]. Secondly, Lin and colleagues reported that the cembranoid terpenoid crassolide (85), isolated from the soft coral Sarcophyton crassocaule, also negatively impacted LPS-induced activation of dendritic cells and downstream T cell responses in vitro, and these effects therapeutically attenuated the development of autoantibodies and associated thrombosis in vivo [100]. In contrast, Laborde and colleagues showed that the large pore-forming proteins sticholysins I and II, purified from the marine anemone Stichodactyla helianthus, enhanced bone marrow-derived dendritic cell maturation through a TLR4-specific manner that resulted in enhanced activation of CD8+ cytotoxic T cells [109]. Finally, Manzo and colleagues characterized an “unprecedented” polyketide phosphatidylmonogalactosyldiacylglycerol pool (91), uncovered in the marine diatom Thalassiosira weissflogii, which was also immunostimulatory to dendritic cells by acting directly as a TLR4 agonist that increased the ability of these cells to activate CD8+ T cells [110]. Taken together, the immunomodulatory effects of these molecules deserve further insight and investigation.

During this time period, three studies investigated the effect on immune function of the dark polyketide echinochrome A (87), isolated from sea urchins: Park and colleagues determined that echinochrome A (87) promoted the expansion of CD34+ hematopoietic precursors from the blood by decreasing p38-MAPK/JNK phosphorylation and ROS generation and subsequently enhancing activation of the p110δ/PI3K/Akt pathway in vitro [103]. Oh and colleagues reported that echinochrome A (87) attenuated experimental colitis in a mouse model of inflammatory bowel disease through the generation of regulatory T cells in vivo, “that modulate the inflammatory response and immune homeostasis” [104]. Finally, Park and colleagues described in another inflammatory autoimmune disease, that echinochrome A (87) alleviated bleomycin-induced scleroderma in vivo by decreasing the number of activated myofibroblasts and the number of pro-inflammatory macrophages and cytokine levels [105].

Additional studies during 2019-2021 demonstrated a significant impact of marine natural products on immune cell function both in vitro and in vivo. Li and colleagues contributed a novel pentadecapeptide (86), isolated from a marine cultured bivalve mollusk Cyclina sinensis, which showed enhanced activation of murine macrophage RAW 246.7 cells in vitro by increasing NF-kB and NLRP3, resulting in elevated release of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β [101]. Yang and colleagues identified a terpenoid cembranoid (90), purified from the South China sea soft coral Sinularia scabra, which attenuated the mitogenic responses of both T cells and B cells in vitro, suggesting that upon further study could become a “new class of potential immunosuppressive agents” [108]. Oh and colleagues investigated purified polyketide dieckol (65), obtained from marine brown alga Ecklonia cava, in an in vivo rat model of spontaneous hypertension, and observed that it attenuated endothelial dysfunction in both the gut and aorta by modulating the Treg/Th17 axis towards Tregs that are immunoprotective [102]. Han and colleagues studied the polyketide eckol (88), discovered in the marine brown alga Ecklonia cava, noting that it attenuated IgE-mediated mast cell activation and cytokine production in vitro and IgE-mediated allergic murine ear swelling in vivo [106]. Tai and colleagues, reported for the first time that the polyketide/terpenoid phomaketide A (89), derived from the marine fungus Phoma sp. NTOU4195, decreased lymphatic endothelial cell lymphangiogenesis in vitro by decreasing VEGFR-3 phosphorylation and eNOS. Additional studies demonstrated the in vivo significance of these effects in that (89) blocked the development of lymphatic vessels and tumor growth in a mouse tumor model, suggesting “this natural product could potentially treat cancer metastasis” [107].

3.4. Marine Compounds Affecting the Nervous System

As shown in Table 2 and Figure 2, in 2019-2021 studies with 38 structurally characterized marine natural compounds (43, 54, 84, 87, 88, 92-124) isolated from bacteria, fungi, sponges, soft corals, sea anemones, worms, cone snails, shrimp, sea urchins, sea cucumbers, dinoflagellates and algae reported novel nervous system mechanisms of action pharmacology that affected ion channels and membrane potential, increasing the antioxidant response pathway reducing reactive oxygen species (ROS), increasing survival factors and decreasing apoptotic factors.

Four compounds (92-95) were shown to reduce seizurogenic activity. Wang and colleagues reported the terpenoid alternarin A (92), discovered in the South China Sea soft coral Lobophytum crissum-derived fungus Alternaria sp., suppressed seizurogenic 4-aminopyridine (4-AP) induced hyperactive spontaneous calcium oscillations in murine neocortical cultures [111]. Andrud and colleagues showed that the alkaloid anabaseine (93), derived from the Pacific Ocean marine worm Paranemertes peregina, demonstrated in vitro binding to α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) that are commonly expressed in the brain, and caused depolarization in tsA201 cells expressing the human α4β2 nAChR [112]. Copmans and colleagues studied the alkaloids TMC-120A (94) and TMC-120B (95), found in the marine fungus Aspergillus insuetus, ameliorated epileptiform discharges in a pentylenetetrazole (PTZ)-induced seizure model in zebrafish and reduced seizure duration in a mouse psychomotor seizure model induced by corneal electrical stimulation [113].

Four compounds (84, 96-98) were observed to be neuroprotective and inform the development of novel Alzheimer’s Disease (AD) therapeutics. Yang and colleagues extended the pharmacology of the fatty acids arachidonic acid (Ara, 96) and eicosatrienoic acid (EtRA, 97), purified from the Pacific Ocean edible seaweed Hizika fusiforme, by showing them to be noncompetitive inhibitors of acetylcholine esterase (AChE) with a modified Ellman’s method, and also displayed antioxidant properties and anti-neuroinflammatory properties. Thus, these compounds indicate putative anti-AD properties by reducing acetylcholine breakdown, which is diminished in AD, as well as the antioxidant properties potentially reducing amyloid β (Aβ) and tau tangles which are caused by oxidative damage [114]. Han and colleagues contributed findings with the terpenoid astaxanthin (84), present in the red-orange pigment Asteroidea, salmon, trout, and the shells of crustaceans, that protected against memory impairment in a murine model of AD via binding to signal transducer and activator of transcription 3 (STAT3) and inhibiting phosphorylation and activation, resulting in reduced Aβ levels and β-secretase (BACE1) activity [115]. Taksima and colleagues determined that the terpenoid astaxanthin (84) decreased reactive oxygen species (ROS) that may contribute to oxidative damage and protein aggregation and decreased Aβ levels, thus improving cognitive dysfunction in a rat model of AD assessed using the Morris water maze, novel object recognition, and novel object location tests [116]. Lee and Jun described the polyketide 8,8’-bieckol (98), discovered in the edible brown seaweed Ecklonia cava, was a competitive inhibitor of AChE and a noncompetitive inhibitor BACE1, and thus should enhance cholinergic activity as well as decreasing Aβ protein aggregation [117].

Three compounds (99-101) were shown to affect ion channel flux. Konoki and colleagues investigated the polyketide brevetoxin (99), a voltage-gated sodium channel (VGSC) activator produced by the marine dinoflagellate Karenia brevis, showing that it binds to the VGSC at neurotoxin receptor 5 in Na_v1.2 (brain isoform) and Na_v1.4 (skeletal muscle isoform), shifting the voltage-dependence more negative and slowing inactivation in vitro using TsA-201 cells [118]. Jin and colleagues identified the novel peptides conorfamides As1a (100) and As2a (101), derived from the Mexican cone snail Conus austini, that inhibited neuronal α7 nAChR, resulting in an inhibition of calcium ion flow into the intracellular space in SH-SY5Y human neuroblastoma cell line [119].

Four compounds (102-104) demonstrated effects on pain perception. Niu and colleagues reported that a novel terpenoid conosteroid (102), found in the cone snail Conus geographus, was a negative allosteric modulator (NAM) of type-a γ-aminobutyric acid receptor (GABA_AR), resulting in murine pain inhibition using the hot plate model, but did not display anesthetic properties via the von Frey test, or effects on inflammatory pain with the formalin test [120]. Guo and colleagues showed that the peptide α-conotoxin Lv1F (103), isolated from the sea snail Conus lividus, competitively bound and inhibited α3β2 nAChR, resulting in a voltage-dependent blockade in Xenopus oocytes expressing rat α3β2 nAChR, which are normally expressed in the dorsal-root ganglion (DRG) of the spinal cord and are involved in pain and sensory perception [121,122]. Similarly, Qiang and colleagues studied the α-conotoxin Lv1d, from the same species, observing that it showed analgesic effects in both the murine hotplate test and the formalin test, suggesting it was also effective for inflammatory pain [121,122]. Liu and colleagues communicated that a helical conantokin peptide Con-T[M8Q] (104), purified from the genus Conus, was an antagonist of the GluN2B subunit of the N-methyl-D-aspartate receptor (NMDAR), which showed inhibition of physiological and psychological morphine dependence and attenuated withdrawal symptoms, as examined by naloxone-induced jumping and conditioned place preference tests in a murine model of morphine addiction [123].

Two compounds (105, 87) showed neuroprotective effects post-stroke. Wu and colleagues described that the terpenoid dictyol C (105), uncovered in the marine brown alga Dictyota sp., demonstrated neuroprotection of cerebral ischemia-reperfusion injury (CIRI) when given to rats two hours prior to middle cerebral artery occlusion (MCAO). Moreover, analysis in PC12 cells suggested that cryprotection resulted form an increase in nuclear factor erythroid 2–related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway as examined with H₂O₂-induced oxidative damage [124]. Kim and colleagues determined that polyketide echinochrome A (87), discovered in sea urchins, mitigated cerebral ischemic injury in rat MCAO when given after reperfusion as demonstrated in improved performance in the forced swim test as well as in histological preparations showing reduced brain infarct volume and reduced edema. Further analyses demonstrated increased cell growth and survival factors brain-derived neurotrophic factor (BDNF), B-cell leukemia/lymphoma 2 protein (Bcl-2), phospho-extracellular signal-regulated kinase (pERK), and phospho-protein kinase B (pAKT) expression and decreased pro-apoptotic factors caspase-3 and Bcl2 associated X (BAX) [125].

Twelve compounds (43, 54, 88, 106-114) showed promising effects for various neurodegenerative disorders. Paudel and colleagues evaluated the polyketide eckol (88), derived from the brown alga Ecklonia stolonifera, as an agonist of dopamine receptor 3 (D3) and dopamine receptor 4 (D4), that reduced Gα_i/o-mediated G-protein coupled receptor (GPCR) signaling resulting reduction in adenylyl cyclase in chinese hamster ovary (CHO) cells stably transfected and expressing human dopamine receptors [126]. Silva and colleagues identified the terpenoid eleganolone (106), found in the brown seaweed Bifurcaria bifurcata, as an inhibitor of 6-hydroxydopamine (6-OHDA) toxicity in SH-SY5Y cells, by increasing catalase activity which protects from ROS damage, decreasing ROS levels, and reducing depolarization of mitochondrial membrane potential. Additionally, it decreased pro-apoptotic factor caspase 3, and increased cytoplasmic localization of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a key regulator of apoptotic/inflammatory events [127]. Chalorak and colleagues reported that the terpenoid frondoside A (107), isolated from the sea cucumber Cucumaria frondosa, inhibited dopaminergic neuronal degeneration via an increase in the free-radical scavenging gene superoxide dismutase (SOD-3), an increase in genes associated with the protein degradation pathway, a reduction of the α-synuclein accumulation, and a decrease in apoptotic genes in a Caenorhabditis elegans model of PD [128]. Gan and colleagues showed that the terpenoid fucosterol (108), purified from brown alga, reduced intracellular levels of Aβ via a decrease in amyloid precursor protein mRNA and increased the mRNA levels anti-apoptotic factor neuroglobin (Ngb) [129]. Additionally, Hannan and colleagues studied fucosterol (108) with in silico analysis to identify binding affinity to tropomyosin receptor kinase B (TrkB), which is involved in neuronal growth and survival and BACE1, the enzyme involved in the production of Aβ in the brain [130]. Chen and colleagues contributed observations that the terpenoid fucoxanthin (43), extracted from a brown seaweed, reduced corneal denervation in a rat UVB-induced photokeratitis model by increasing Nrf2 expression and reduced intracellular ROS, as well as decreased symptoms of inflammatory pain (eye wipe behavior) and decreased transient receptor potential cation channel subfamily V member 1 (TRVP1) signaling that contributes to hyperalgesia [131]. Moreover, Wu and colleagues showed that fucoxanthin (43) binds to Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 inhibitor and sensor of oxidative stress, at the same binding site as Nrf2 thus enhancing Nrf2/ARE signaling in PC12 cells [132]. Kalina and colleagues described the APETx-like peptides Hcr 1b-2, Hcr 1b-3, and Hcr 1b-4 (109-111), discovered in the sea anemone Heteractis crispa, that inhibited rat acid-sensing ion channel (rASIC) 1a that is highly expressed in the central nervous system. Rat ASIC1a was expressed in Xenopus laevis oocytes and Hcr 1b-3 and -4 (109-110) reversibly inhibited the channel in a dose-dependent manner, indicating therapeutic potential for pathological conditions associated with prolonged acidosis including PD, multiple sclerosis, epilepsy, and ischemic stroke [133]. Tangrodchanapong and colleagues determined that the polyketide 2-butoxytetrahydrofuran (112), derived from the sea cucumber Holothuria scabra, inhibited Aβ-induced paralysis in C. elegans by suppression of Aβ oligomer formation and deposition via upregulation of autophagy genes important for clearing misfolded and abnormally aggregated proteins and a decrease in ROS levels that contribute to oxidative damage and protein degradation [134]. Fan and colleagues explored a novel terpenoid/shikimate neo-debromoaplysiatoxins E (113) and F (114), found in the marine cyanobacterium Lyngbya sp., that exhibited potent blocking activity against potassium channel 1.5 (Kv1.5), an ion channel expressed in neurons and smooth muscle cells and is important for cellular repolarization [135].

Three compounds (115-117) were reported to show neurotoxic effects. Jiao and colleagues reported that exposure to the polyketide okadaic acid (115), a marine shellfish toxin, resulted in neural tube defects in chicken (Gallus gallus) embryos via inhibition of the Nrf2 signaling pathway and increased ROS levels, as well as increasing cellular proliferation, decreasing neuronal differentiation, and decreasing pro-apoptotic factor caspase-3 [136]. Benoit and colleagues showed that the polyketide pinnatoxins (PnTXs) A (116) and G (117), isolated from the marine dinoflagellate Vulcanodinium rugosum, blocked synaptic transmission at the neuromuscular junction by competitive antagonism of muscle-type nAChR in mice, consistent with death via muscle paralysis and respiratory depression in vivo [137].

Two compounds (118-119) were shown to modulate neurotransmitter signaling. Seong and colleagues studied the polyketide phlorofucofuroeckol-A (PFF-A, 118), obtained from the brown alga Ecklonia stolonifera, noting that it was a noncompetitive inhibitor of human monoamine oxidase (MAO) -A and -B which prevented the breakdown of dopamine and other neurotransmitters. Additionally, PFF-A (118) was a D3 and D4 receptor agonist which stimulated Ga_i/o-mediated-GPCR signaling resulting in inhibition of adenylyl cyclase, as well as an antagonist to D1, serotonin 1a receptor (5HT1A), and neurokinin-1 (NK₁) indicating multifactorial effects on the dopaminergic and serotonergic systems that may be important for treating depression and/or PD [138]. Lee and colleagues characterized the terpenoid sargachromanol (119) compounds, purified from the brown alga Sargassum siliquastrum, potently inhibited AChE via a mixed reversible inhibition, suggesting that it binds to both an active site and a non-catalytic site of AChE, suggesting potential therapeutic development for the treatment of AD [139].

Two compounds (120-121) demonstrated important effects on reducing misfolded proteins. Chen and colleagues contributed the alkaloid santacruzamate A (120), discovered in a marine cyanobacterium, that increased KDEL, a receptor known for regulation the endoplasmic reticulum retrieval system important for regulating misfolded proteins both in vitro in PC12 and SH-SY5Y cells and in vivo in mouse brain tissue. It also increased mitochondrial space assembly protein 40 (Mia40) an augmenter of liver regeneration (ALR), potentially suppressing mitochondrial fission and apoptosis pathways. Notably, it improved behavioral results in a mouse model of AD, indicating that KDEL receptor played a role in improved memory impairment [140]. Jiang and colleagues described the novel terpenoid cembranoid (121), derived from the soft coral Sinularia sp., that bound to the c-terminal of Aβ monomers and inhibited Aβ aggregation, indicating a new source for novel therapeutics for AD [141].

Four compounds (54, 122-124) demonstrated neuroprotective effects. Paudel and colleagues determined that the shikimate bromophenol (54), found in the red alga Symphyocladia latiuscula was a human dopamine D4 receptor agonist, which may provide a novel therapeutic for treating cognitive deficits associated with schizophrenia. It also demonstrated lesser human dopamine D3 receptor agonist activity, potentially as a novel therapeutic for PD management [142]. [143]. Paudel and colleagues additionally evaluated the bromophenol (54), as a mixed-type inhibitor of AChE, a competitive inhibitor of butyrylcholinesterase (BChE), as well as noncompetitive inhibition of BACE1 in vitro, indicating therapeutic potential for AD management [144]. Liu and colleagues identified the sugar glucuronomannan GM2 (122), isolated from the brown seaweed Saccharina japonica, that improved cell viability by inhibiting lactate dehydrogenase (LDH) release, reduced ROS levels in PC12 cells, improved the ratio of anti-apoptotic Bcl-2 and pro-apoptotic Bax, and reduced caspases 3 and 9, attenuating apoptosis. Feng and colleagues investigated the terpenoid stellettin B (123), purified from the marine sponge Jaspis stellifera, that increased Nrf2/ARE signaling, decreased ROS-positive cells, and decreased caspase-3 signaling in SH-SY5Y cells. Additionally, reversed zebrafish locomotion deficits in a 6-OHDA-induced model of PD, suggesting therapeutic potential [145]. Sheng and colleagues demonstrated that the terpenoid 5α-androst-3β, 5α, 6β-triol (124), discovered in the soft coral Nepthea brassica, demonstrated protection of retinal ganglion cells in a mouse model of retinal ischemic injury via negative regulation of Keap1 resulting in an upregulation of Nrf-2/ARE signaling [146].

4. Marine Compounds with Miscellaneous Mechanisms of Action

As reported in the 2019-2021 peer-reviewed literature, Table 3 presents 55 marine compounds (43, 65, 88, 118, 125-170) with miscellaneous mechanisms of action shown to affect multiple cellular and molecular targets, but with no currently assigned pharmacological category, and that have been isolated from marine bacteria, cyanobacteria, seahorses, sharks, crinoids, octopuses, mussels, oysters, sponges, fungi, and algae, with their corresponding structures shown in Figure 3: marine cyanobacterium Okeania sp.-derived linear peptide amantamide (125) that selectively stimulated C-X-C chemokine receptor type 7 and increased extracellular signal-regulated kinase 1 phosphorylation [147]; marine octopus Amphioctopus neglectus-derived macrocyclic lactone (126) with radical-scavenging capacity and anti-hypertensive activity against angiotensin converting enzyme [148]; marine edible shellfish Arca subcrenata-derived peptides D2-G1S-1 and G2-G1S-2 (127, 128) that demonstrated potent radical scavenging activities and extended worm Caenorhabditis elegans lifespan, thus suggesting “applications in functional cosmetics additives” [149]; marine fugal strain Aspergillus sp. F452-derived polyketide aspermytin A (129) that inhibited Staphylococcus aureus-derived sortase A by a reversible mixed inhibitor mechanism that affected “bacterial adherence to fibronectin-coated surfaces” [150]; marine sponge-derived terpenoid avarol (130) that reduced synthesis of cholesteryl ester by potent inhibition of sterol O-acyltransferase and concomitant reduction in lipid droplet accumulation in CHO-K1 cells [151]; marine brown alga Ecklonia cava-derived polyketide pyrogallol-phloroglucinol-6,6-bieckol (131) that decreased murine hypertension resulting from a high-fat diet by affecting aortic endothelial to mesenchymal transition as well as LOX-1 and MMP-9 gene expression [152]; marine red algae-derived shikimate 3-bromo-4,5-dihydroxybenzaldehyde (132) that enhanced antioxidant enzyme HO-1 expression and increased Nrf2 expression, phosphorylation and nuclear translocation [153]; marine oyster Crassostrea gigas-derived novel peptide (133) that promoted MC3T3-E1 osteoblast-like cells proliferation by binding to the α5β1 integrin [154]; an additional marine oyster Crassostrea gigas-derived peptide (134) which inhibited thrombin by a competitive inhibition mechanism [155]; marine sponge Dysidea herbacea-derived polyketide diphenyl ether (135) that inhibited bacterial α-_D-galactosidase by irreversibly inactivating the active-site of the enzyme [156]; marine brown alga Ecklonia cava-derived shikimate dieckol (65) that reduced oxidative stress-exposed porcine oocytes by increasing the level of glutathione and antioxidant enzymes [157], and suppressed ultraviolet radiation-induced skin damage in human dermal fibroblasts by increasing collagen synthesis and reducing proinflammatory cytokines and metalloproteinases [158]; marine brown alga Ishige okamurae-derived polyketide diphlorethohydroxycarmalol (DPHC) (136) that dose-dependently reduced high-fat diet-induced obesity in mice by reducing critical adipogenic-specific, lipogenic enzyme expression, and exerted vasodilatory effects via calcium signaling [159,160,161]; marine brown alga Ecklonia stolonifera-derived phlorotannin (137) with potential antioxidant and tyrosinase inhibitory activity [162]; marine alga Ecklonia cava-derived polyketide eckol (88) that reduced ROS generation in particulate matter 2.5-induced skin damage to keratinocytes by inhibiting MAPK signaling [163]; marine fungus Streptomyces nitrosporeus YBH10-5-derived polyketide farnesylquinone (138) observed to have fat-reducing effects by enhancing mitochondrial β-oxidation rate and modifying energy metabolism genes’ transcription [164]; marine brown alga Eisenia bicyclis polyketide fucofuroeckol-A (139) that suppressed melanogenesis in murine B16 melanoma cells by down regulation of tyrosinase-related protein-2 activity suggesting it might be beneficial as a “melanin control drug for hyperpigmentation disorders” [165]; marine brown alga Sargassum wightii-derived terpenoid fucoxanthin (43) that inhibited angiotensin 1-converting enzyme by a non-competitive mechanism and binding to the active site of the enzyme [166], and alleviated oxidative stress in glomerular mesangial cells by stimulating Akt/Sirt1/FoxO3 α signaling [167]; marine fungal strain Aspergillus sp. SF-5929-derived polyketide funalenone (140) that dose-dependently inhibited PTP1B enzyme by a non-competitive mechanism targeting “ a site that is distinct from the catalytic site of PTP1B” [168]; deep-sea-derived actinomycete Streptomyces lusitanus SCSIOLR32 polyketide grincamycin B (142) that targeted isocitrate dehydrogenase 1 and might become a “potential target for hematological malignancies intervention in the future” [169]; mangrove endophytic fungus Tilachlidium sp.-derived novel thiodiketopiperazine alkaloid GQQ-792 (141) shown to be a non-ATP competitive inhibitor of phosphoglycerate kinase 1 [170]; marine edible seahorse Hippocampus abdominalis-derived peptides HGSH and KGPSW (143,144) that protected against H₂O₂-induced oxidative damage in human umbilical vein endothelial cells by activating the nuclear transcription factor-erythroid 2-related factor signaling pathway, suggesting these peptides as a “ promising agent for oxidative stress-related cardiovascular diseases” [171]; marine brown alga Sargassum horneri-derived monoterpene (-)-loliolide (145) that suppressed both lipid accumulation in 3T3-L11 adipocytes and expression of adipogenic and lipogenic proteins, thus might be a “lipid-lowering agent in the management of patients who suffer from obesity” [172]; marine sponge Monanchora pulchra-derived alkaloid monanchomycalin B (146) observed to be a “slow-binding irreversible” inhibitor of α-galactosidase from marine γ-proteobacterium Pseudoalteromonas sp. KMM 701 targeting two alkaloid binding sites on the molecule [173]; marine sponge Clathria frondifera associated fungus Monascus sp. NMK7-derived polyketide monacolin X (147) that suppressed angiogenesis by downregulation of the VEGFR2 signaling pathway [174]; marine sponge Diacarnus erythraeanus-derived norterpene peroxide (-)-muqubilin A (148) found to be a retinoic acid receptor α positive allosteric modulator and retinoic acid signaling enhancer [175]; marine sponge Mycale aff. nullarosette-derived polyketide mycalolide A (149) that inhibited cytokinesis by disruption of F-actin and binucleation induction [176]; marine blue mussel Mytilus edulis-derived dodecapeptide (150) that promoted growth of osteoblasts, bone loss reduction in ovariectomized mice and interacted with integrins 1L5G and 3V14 [177]; tilapia Oreochromis niloticus-derived oligopeptide (151) shown to be protective of angiotensin II-induced hypertensive endothelial injury by affecting Nrf2 and NF-kB signaling pathways [178]; marine fungus Penicillium sp. KFD28-derived indole-terpenoid penerpene A (152) that potently inhibited protein tyrosine phosphatase B by binding to the active site pocket [179]; mangrove endophytic fungus Penicillium janthinellum-derived alkaloid penicisulfuranol A (153) discovered as a novel Hsp90 C-terminus inhibitor at “cysteine residues near amino acid region responsible for dimerization of Hsp90” [180]; marine endophytic fungal strain Pestalotiopsis neglecta SCSIO41403 polyketide pestalotioquinoside C (154) that acted as a putative liver X receptor alpha agonist as demonstrated by the upregulation of downstream gene ABCA1 [181]; marine sponge-derived fungal strain Aspergillus sp. 151304 cyclohexapeptide petrosamide C (155) that dose-dependently inhibited pancreatic lipase by a non-competitive mechanism [182]; marine sponge Phakellia fusca-derived cycloheptapeptide phakefustantin A (156) that inhibited the PI3K/Akt signaling pathway by regulating the transcriptional function of retinoic X receptor-α [183]; marine brown alga Ecklonia cava-derived phlorotannin shikimate 2-phloroeckol (157) that inhibited tyrosinase by a slow-binding competitive inhibition of the active site of the enzyme [184]; marine brown alga Ecklonia cava-derived functional polyphenol polyketide phlorofucofuroeckol A (118) shown to modulate human tracheal fibroblast collagen type 1 protein expression by downregulation of MAPKs and SMAD 2/3 signaling pathways [185], and enhance bone marrow osteoblastogenesis [186]; marine fungus Penicillium polonicum-derived diketopiperazine alkaloid polonimide analog (158) with inhibitory activity against agricultural insect pest Ostrinia furnacalis GH18 chitinase OfChi-h supported by docking studies with the enzyme [187]; marine red alga Polysiphonia morrowii shikimate 5-bromo-3,4-dihydroxybenzaldehyde (132) that inhibited adipogenesis in 3T3-L1 adipocytes by regulation of adipogenic transcription factors as well as activation of the AMP-activated protein kinase pathway [188]; marine fungus Penicillium sp. SF-5497-derived meroterpenoid preaustinoid A6 (159) which inhibited protein tyrosine phosphatase B in a noncompetitive manner [189]; marine red alga Pyropia yezoensis-derived peptide (160) assessed as protective against synthetic glucocorticoid dexamethasone-induced myotube atrophy [190]; crinoid Himerometra magnipinna-derived anthraquinone polyketide rhodoptilometrin (161) that significantly increased wound healing and cell migration as well as increased FAK, fibronectin and type 1 collagen protein and gene expression in human hGF-1 gingival fibroblasts [191]; marine alga Sargassum serratifolium-derived terpenoid sargahydroquinoic acid (162) that stimulated beige-like adipocytes by lipid catabolic pathway activation [192]; shark-derived marine bile terpenoid 5β-scymnol (163) demonstrated to be a novel agonist of the TGR5 receptor by causing sustained intracellular Ca²⁺ release, thus “showing therapeutic potential for treating atherosclerosis [193]; fungus Aspergillus quadrilineatus FJJ093-derived epipolythiodioxopiperazine alkaloid secoemestrin C (164) determined to be an uncompetitive inhibitor of isocitrate lyase (ICL) in the glyoxylate cycle of Candida albicans and also inhibit ICL mRNA expression [194]; marine ascidian Didemnum proliferum-derived alkaloid shishijimicin A (165) noted to bind to double-stranded DNA’s minor groove with its β-carboline moiety playing a role “in the binding through intercalation” [195]; marine green alga Codium cylindricum Holmes-derived terpenoid siphonaxanthin (166) that induced transcription factor Nrf2 protein expression and signaling in HepG2 cells [196]; marine alga Symphyocladia latiuscula-derived bromophenol polyketide (54) that competitively inhibited both melanin and tyrosinase in melanoma cells [197]; marine bacterium Saccharothrix sp. 10-10-derived polyketide tetracenomycin X (167) that induced cell cycle arrest by downregulating cyclin D1 as a result of proteosomal degradation [198]; cyanobacterium Schizothrix sp.-derived cyclodepsipeptide tutuilamide A (168) that demonstrated as a potent and reversible inhibitor of the pancreatic serine protease elastase [199]; marine brown edible alga Undaria pinnatifida peptide KNFL (169) that inhibited angiotensin-1 converting enzyme via a non-competitive inhibition mechanism and binding to the ACE non-active site via hydrogen bonds, suggesting it could become a “functional food ingredient(s) against hypertension” [200]; marine Dunaliella salina microalga-derived terpenoid zeaxanthin heneicosylate (170) that ameliorated age-associated rat cardiac dysfunction by stimulation of retinoid receptors [201].

5. Reviews on Marine Pharmacology and Pharmaceuticals

In 2019-2021 a large number of reviews were published that covered general and/or specific areas of marine preclinical pharmacology: (a) marine pharmacology and marine pharmaceuticals: marine natural products and their relevant biological activities published in 2019, 2020 and 2021 [202]; advances in marine natural products therapeutic potential [203]; polar marine terpenoids and their potential for drug discovery [204,205,206]; bioactive properties of marine phenolics [207]; chemistry and biological activities of marine flavonoids [208]; marine-derived spirotetronates and potential pharmaceutical applications [209]; bioactivities of marine-derived hydroperoxides [210]; marine-derived macrocyclic alkaloids as a potential source of drugs [211]; pharmacology of thiazole-based marine-derived peptides [212]; marine meroterpenoids and cembranoids biological activities [213,214]; marine-derived macrolides chemical and biological diversity [215]; pharmacology of cyanobacterial-derived natural products [216,217,218,219,220,221]; marine natural products from microalgae: an -omics overview [222,223]; pharmacological potential of macroalgae natural products [224,225,226,227,228,229,230,231]; bioactive compounds from Bryozoa and Cnidaria [232,233,234,235]; genus Didemnum secondary metabolites pharmacological properties [236]; marine fungi-derived bioactive compounds [237,238,239]; pharmacological significance of marine microbial natural compounds [240,241,242,243,244]; marine sponge-derived pharmacological activity [245,246]; pharmacological activity of mangrove-derived natural products [247,248,249]; bioactive marine natural products from Indonesia (1970-2017) and the Red Sea [250,251]; marine-derived bioactive compounds in China (2009-2018) [252]; marine bioactive natural products from the Yucatan Peninsula [253]; marine natural products as source of new drugs: a patent review and productivity (2015-2018) [254,255]; natural product based antibody drug conjugates: clinical status as of November 9, 2020 [256]; the global marine pharmaceutical pipeline: approved marine-derived compounds and in Phase I, II and III of clinical development https://www.marinepharmacology.org/; (b) antimicrobial, antifungal and antiviral marine pharmacology: marine bacteria-derived antimicrobial natural products [257,258,259,260]; marine bacteria as source of quorum sensing inhibitors [261,262,263,264]; marine natural products targeting multidrug-resistant bacteria [265,266,267]; ascidian-derived marine antimicrobial natural products [268]; epinecidin-1, and other marine antimicrobial peptides [269,270]; marine fungi-derived antimicrobial natural products [271,272]; marine macrolides with antibacterial and/or antifungal activity [273]; antimicrobial lipids from marine organisms [274]; marine tryptophan-derived antimicrobial alkaloids [275]; recent advances on marine-based antifungals [276]; marine natural products for RNA virus infections including SARS-CoV-2 [277,278,279]; natural products targeting hepatitis C and respiratory viruses [280,281]; marine algae-derived compounds as antivirals [282,283,284]; (c) antiprotozoal and antimalarial marine pharmacology: antiprotozoal activities of marine polyether triterpenoids [285]; recent advances in novel antiprotozoal agents [286,287]; marine drugs as new drug lead for trypanosomatids and malaria [288,289]; marine-sponge-derived antimalarial metabolites [290]; antituberculosis marine natural products [291]; marine natural products and latent tuberculosis drug resistance [292]; d) immuno- and anti-inflammatory marine pharmacology: anti-inflammatory marine natural products [293]; marine-derived compounds for rheumatoid arthritis treatment [294]; marine anti-inflammatory alkaloids [295]; anti-inflammatory compounds from marine fungi [296]; anti-inflammatory prostaglandins and peptides in marine organisms [297,298]; marine polypeptides as inhibitors of neutrophil elastase [299]; anti-inflammatory marine n-3 polyunsaturated fatty acids [300,301,302]; anti-inflammatory pharmacology of fucoxanthin [303]; antioxidant properties of marine algae [304]; Sargassum seaweed as a source of anti-inflammatory natural products [305]; microalgae with immunomodulatory activities [306]; immunodulation by marine invertebrate-derived natural products [307,308]; marine-derived vaccine adjuvants [309] (e) cardiovascular and antidiabetic marine pharmacology: marine-derived anti-atherosclerotic and lipid-lowering compounds [310,311]; marine-derived anti-thrombotics and patents [312,313]; marine-derived sulfated polysaccharides as antithrombotics [314]; microalgae-derived bioactive compounds for cardiovascular pharmacology and inflammation [315]; anti-obesity and anti-diabetic effect of marine algae [316,317,318,319]; antidiabetic properties of Indian mangroves [320]; anti-obesity and anti-diabetic benefits of the carotenoids astaxanthin and fucoxanthin [321,322]; brown seaweeds for management of metabolic syndrome [323,324]; (f) nervous system marine pharmacology: neuroprotective potential of marine natural products [325,326]; marine omega-3 phospholipids and brain health [327]; pharmacological diversity of conotoxins [328,329]; biological activities and pharmacological applications of conopeptides [329]; marine toxins and gastrointestinal visceral pain therapeutics [330]; marine algae anti-inflammatory and neuroprotective pharmacology [331,332,333]; marine compounds for Alzheimer’s therapeutics [334,335,336,337,338]; cyanobacterial bioactive compounds for Alzheimer’s disease [339]; marine natural products for Parkinson’s Disease [340]; neuroprotective pharmacology of astaxanthin [341,342,343]; cnidarian peptide neurotoxins as modulators in central nervous system diseases [344]; marine toxins targeting mammalian voltage-gated potassium channels [345]; marine excitatory amino acids [346] ; marine natural products with monoamine oxidase inhibitory activity [347]; (g) miscellaneous molecular targets, methodologies and uses: marine natural product databases [348,349]; metabolomic tools used in marine natural product drug discovery [350]; chemical genetics approach for biologically active marine natural products discovery [351]; marine-derived cellular signal transduction inhibitors [352]; seaweed-derived signal transduction pathway modulators [353]; astaxanthin modulation of autophagy signal transduction pathways and ocular diseases [354,355]; marine natural product protein kinase inhibitors [356]; marine natural products as ATP-competitive mTOR kinase inhibitors [357]; drug potential of the marine-derived protein kinase C modulators bryostatins [358,359]; natural products as eukaryotic protein secretion modulators [360]; marine natural products targeting eukaryotic cell membranes and cytoskeleton [361,362]; marine natural products as pregnane X receptor ligands [363]; ubiquitin-proteasome system modulation by marine natural products [364]; intracellular calcium signal modulation by marine natural products [365]; cyanobacterial natural products for skin protection and cosmetic applications [366,367,368]; seaweed bioactive compounds as nutraceuticals and cosmeceuticals [369,370,371].

6. Conclusions

This review covering the peer-reviewed marine pharmacology literature published in 2019-2021 is the 12th contribution to the marine preclinical pharmacology pipeline review series that was initiated by AMSM in 1998 [1,2,3,4,5,6,7,8,9,10,11], with the purpose of presenting a consolidated and systematic overview of selected peer-reviewed preclinical marine pharmacological literature published during 2019-2021. Global preclinical marine pharmacology mechanism of action research involved chemists and pharmacologists from 41 countries, namely, Australia, Belgium, Brazil, Canada, Chile, China, Costa Rica, Cuba, Czech Republic, Denmark, Egypt, Ecuador, France, Germany, Greece, Hungary, India, Indonesia, Iran, Ireland, Italy, Japan, Jordan, Malaysia, Mexico, the Netherlands, Norway, Panama, Portugal, Romania, Russian Federation, Saudi Arabia, Singapore, South Korea, Spain, Switzerland, Thailand, Taiwan, the Philippines; United Kingdom, Vietnam, and the United States. Thus, during 2019-2021 the marine preclinical pharmaceutical pipeline continued to generate novel marine chemical leads for the active marine clinical pharmaceutical pipeline. As currently shown on the marine pharmaceutical pipeline website https://www.marinepharmacology.org/ (May 2024) there are 15 marine-derived pharmaceuticals approved by either the U.S. Food and Drug Administration, Australia, Japan and/or China, and 33 compounds in either Phase I, II and III of clinical pharmaceutical development.