Marine Pharmacology in 2016–2017: 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

The review of the 2016–2017 marine pharmacology literature was prepared in a manner similar as the 10 prior reviews of this series. Preclinical marine pharmacology research during 2016–2017 assessed 313 marine compounds with novel pharmacology reported by a growing number of investigators from 54 countries. The peer-reviewed literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 123 marine natural products, 111 marine compounds with antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 79 marine compounds displayed miscellaneous mechanisms of action which upon further investigation may contribute to several pharmacological classes. Therefore, in 2016–2017, the preclinical marine natural product pharmacology pipeline generated both novel pharmacology as well as potentially new lead compounds for the growing clinical marine pharmaceutical pipeline, and thus sustained with its contributions the global research for novel and effective therapeutic strategies for multiple disease categories.


Introduction
The present review aims to consolidate the 2016-2017 preclinical marine pharmacology literature, with a format similar to our previous 10 reviews of this series which cover the period 1998-2015 [1][2][3][4][5][6][7][8][9][10]. All peer-reviewed articles were retrieved from the following databases: MarinLit, PubMed, Chemical Abstracts ® , ISI Web of Knowledge, and Google Scholar. As in our previous reviews we have decided to limit the review to the bioactivity and/or pharmacology of structurally characterized marine chemicals, which we have classified using a modification of Schmitz's chemical classification [11] into six major chemical classes, namely, polyketides, terpenes, peptides, alkaloids, shikimates, and sugars. The preclinical antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacology of marine chemicals is reported in Table 1, with the structures, shown in Figure 1. Marine compounds that showed immune and nervous systems activities, as well as antidiabetic and anti-inflammatory effects are exhibited in Table 2, with their respective structures consolidated in Figure 2. Finally, marine compounds affecting a variety of cellular and molecular targets are noted in Table 3, and their structures presented in Figure 3.
Several publications during 2016-2017 reported on several marine extracts or structurally uncharacterized compounds, with potentially novel preclinical and/or clinical pharmacology: In vitro antibacterial and antibiotic potentiating activities of tropical Mauritian marine sponge extracts [12]; a sterol-rich fraction with significant synergistic antiinflammatory activity isolated from the South Korean soft coral Dendronephthya gigantea [13]; two metabolites with anti-methicillin-resistant Staphylococcus aureus activity from an Indian marine sponge Clathria procera associated actinomycete S. pharmamarensis ICN40 with antimicrobial potential "after structure identification and clinical studies" are completed [14]; 49 of 251 bacterial isolates from sediments from several Red Sea harbor and lagoon environments with the potential to produce secondary metabolites with "antimicrobial activity" [15]; antibacterial activity in extracts from the marine bacterium Salinispora arenicola from the Gulf of California, Mexico [16]; activation by cyanobacterium Oscillatoria sp. lipopolysaccharide of rat microglia and murine B cells with concomitant Toll-like receptor 4 signaling in vitro [17,18]; and lipophilic fractions from the Icelandic marine sponge Halichondria sitiens that decrease dendritic cells' pro-inflammatory cytokine release [19].

Antibacterial Activity
During 2016-2017, 51 studies reported on antibacterial bioactivity in marine natural products (1-67) isolated from ascidians, bacteria, fungi, mussels, sea urchins, soft corals, and sponges, global research that contributed new preclinical pharmacology that may contribute to the ongoing search of novel therapeutics for multi-drug resistant bacterial infections.
As shown in Table 1, and Figure 1, eleven publications reported on the mode of action of marine-derived antibacterial compounds. Cheng and colleagues reported a new chlorinated quinolone, ageloline A (1) isolated from a Streptomyces sp. derived from the Mediterranean sponge Agelas oroides that inhibited growth of Chlamydia trachomatis inclusions resulting from a mechanism that "might be related to its antioxidant potential" [20]. Davison and colleagues discovered a new analog of the peptidyl nucleoside antibiotic blasticidin S (2) produced by the actinomycete Streptomyces griseochromogenes that demonstrated increased potency against both Gram-positive and Gram-negative bacteria, with the NorA multidrug transporter being a key factor involved in membrane permeability that "facilitates cellular entry of peptidyl nucleosides" [21]. Le Norcy and colleagues described the activity of dibromohemibastadin-1 (3), derived from natural bastadins discovered in the marine sponge Ianthella basta, and which prevented and disrupted Gram negative bacterial biofilms without toxicity by a mechanism that involved "regulation in the quorum sensing" which is a process considered important for "biofilm formation and organization" [22]. Wyche and colleagues demonstrated in a series of in vitro and in vivo studies that the polyether antibiotic ecteinamycin (4) isolated from a marine-derived bacterium Actinomadura sp., showed significant activity against the toxigenic strains of Clostridium difficile and proposed that the mechanism of action leading to detoxification and cell death likely involved "potassium transport dysregulation" [23]. Tseng and colleagues identified 5-episinuleptolide (5) isolated from the soft coral Sinularia leptoclados as an inhibitor of biofilm-associated Gram-negative bacterium Acinetobacter baumannii infections, shown to be of high incidence in immunocompromised individuals, by a mechanism that

Antibacterial Activity
During 2016-2017, 51 studies reported on antibacterial bioactivity in marine natural products (1-67) isolated from ascidians, bacteria, fungi, mussels, sea urchins, soft corals, and sponges, global research that contributed new preclinical pharmacology that may contribute to the ongoing search of novel therapeutics for multi-drug resistant bacterial infections.
As shown in Table 1, and Figure 1, eleven publications reported on the mode of action of marine-derived antibacterial compounds. Cheng and colleagues reported a new chlorinated quinolone, ageloline A (1) isolated from a Streptomyces sp. derived from the Mediterranean sponge Agelas oroides that inhibited growth of Chlamydia trachomatis inclusions resulting from a mechanism that "might be related to its antioxidant potential" [20]. Davison and colleagues discovered a new analog of the peptidyl nucleoside antibiotic blasticidin S (2) produced by the actinomycete Streptomyces griseochromogenes that demonstrated increased potency against both Gram-positive and Gram-negative bacteria, with the NorA multidrug transporter being a key factor involved in membrane permeability that "facilitates cellular entry of peptidyl nucleosides" [21]. Le Norcy and colleagues described the activity of dibromohemibastadin-1 (3), derived from natural bastadins discovered in the marine sponge Ianthella basta, and which prevented and disrupted Gram negative bacterial biofilms without toxicity by a mechanism that involved "regulation in the quorum sensing" which is a process considered important for "biofilm formation and organization" [22]. Wyche and colleagues demonstrated in a series of in vitro and in vivo studies that the polyether antibiotic ecteinamycin (4) isolated from a marine-derived bacterium Actinomadura sp., showed significant activity against the toxigenic strains of Clostridium difficile and proposed that the mechanism of action leading to detoxification and cell death likely involved "potassium transport dysregulation" [23]. Tseng and colleagues identified 5-episinuleptolide (5) isolated from the soft coral Sinularia leptoclados as an inhibitor of biofilm-associated Gram-negative bacterium Acinetobacter baumannii infections, shown to be of high incidence in immunocompromised individuals, by a mechanism that correlated with a decreased production of the extracellular polysaccharide poly-β-(1,6)-N-acetylglucosamine [24]. Solstand and colleagues described two new antimicrobial peptides eecentrocin 1 and eestrongylocin 2 (6, 7) from the haemocytes of the edible sea urchin Echinus esculentus with potent antimicrobial activity against both Gram-positive and Gram-negative bacteria, concluding that "a genomic approach to discover homologues in other echinoderms for the discovery of novel antimicrobial peptides could be a beneficial venture" [25]. Sung and colleagues observed the increased production of the antibiotics granaticin and granatomycin D (8,9) from marine-derived Streptomyces PTY08712 isolated from the tunicate Styela canopus when co-cultured with several human bacterial pathogens, concluding that "utilization of co-culture experiments . . . may enhance metabolite production and further our understanding of . . . microbial interactions" [26]. Adnani and colleagues reported the isolation of new antibiotic anthracycline keyicin (10) from a coculture of marine bacteria Rhodococcus sp. and Micromonospora sp. derived from the ascidian Ecteinascidia turbinata and the sponge Chondrilla nucula, which was found to be selective for Gram-positive bacteria by a unique mechanism that "does not involve nucleic acid damage" [27]. Mokhlesi and colleagues discovered two new peptides microcionamides C and D (11,12) from the marine sponge Clathria basilana which inhibited Gram-positive bacterial growth with a mechanism that suggested "dissipation of the bacterial membrane potential", which is an electrical gradient across the bacterial cytoplasmatic membrane that is required for both ATP generation and active transport processes [28]. Leoni and colleagues reported that the novel peptide myticalin A5 (13) isolated from the mussel Mytilus galloprovincialis had antimicrobial activity against both Gram-positive and Gramnegative bacteria by a mode of action that appeared to involve inhibition of RNA synthesis but "remains to be elucidated" [29]. Costantino and colleagues isolated a new γ-lactone plakofuranolactone (14) from the extract of the marine sponge Plakortis cf. lita that inhibited the bacterial LasI/R quorum sensing system, a "mechanism of cell-cell communication and gene regulation in bacteria" [30]. Lee and colleagues studied the activity of psammaplin A (15), a marine natural product isolated from sponges, on Gram-negative bacterium Vibrio vulnificus infections noting that it suppressed cytotoxicity in vitro and prolonged both the survival and pathology of V. vulnificus-infected mice [31].

Antifungal Activity
Eleven studies during 2016-2017 reported on the antifungal activity of several marine natural products (68-79) isolated from marine bacteria, dinoflagellates, fungi and sponges, a slight increase from our last review [10], and previous reviews of this marine pharmacology series.
As shown in Table 1 and Figure 1, two reports investigated an antifungal marine compound with a novel mechanism of action. Espiritu investigated the polydroxy polyene antifungal amphidinol 3 (68) isolated from cultures of the marine dinoflagellate Amphidinium klebsii [72], observing that membrane integrity loss by direct interaction with membrane lipids showed "an absolute dependence on the presence of sterols". Furthermore, Iwamoto and colleagues, using atomic force microscopy, determined that amphidinol 3 formed "different types of sterol-aided polymorphic channels in a concentration dependent manner" [73].
As shown in Table 1 and Figure 1, 9 marine compounds (83, 89-96) isolated from bacteria, fungi, sponges were reported to possess bioactivity towards the so-called neglected protozoal diseases: Leishmaniasis, caused by the genus Leishmania (L.), amebiasis, trichomoniasis, as well as African sleeping sickness (caused by Trypanosoma (T.) brucei rhodesiense and T. brucei gambiense) and American sleeping sickness or Chagas disease (caused by T. cruzi).
Only one report described two antitrypanosomal marine chemicals as well as their mechanisms of action. Carballeira and colleagues examined the mode of action of novel very long-chain α-methoxylated fatty acids (89,90), isolated from the Caribbean sponge Asteropus niger, and demonstrated that they were toxic towards L. infantum amastigotes and free living promastigotes by inhibition of Leishmania topoisomerase 1B enzyme considered "an important therapeutic target against L. infantum" [90]. In addition, seven marine natural products (82, 91-96) exhibited antileishmanial and antiprotozoal activity, although their mechanisms of action remained undetermined: The cyclic depsipeptide dudawalamide D (82) from the Papua New Guinean cyanobacterium Moorea producens with potent against L. donovani. [84]; a new oxysterol (91), isolated from a Panamanian octocoral Gorgonia sp. that moderately reduced the multiplication of L. infantum promastigotes thus suggesting "antileishmanial efficacy against intracellular amastigotes" [91]; two linear furanosesterterpenoids ircinin-1 and -2 (92, 93) from the Turkish sponge Ircinia oros with moderate activity against L. donovani, suggesting the compounds' "bifuran terminus . . . positively influences the in vitro antiprotozoal activity" [92]; a new cyclic polyketide-peptide hybrid janadolide (94) from the Japanese marine cyanobaterium Okeania sp. which demonstrated very potent activity against T. brucei brucei, thus revealing potential for development as "new antitrypanosomal drugs" [93]; the cyclic pentapeptide malformin A1 (95) isolated from the Philippine marine seagrass-derived fungus Aspergillus tubingensis IFM 63452 highly active towards the parasite T. congolense and recommended as "an antiprotozoal agent" [94]; a novel azepino-diindole alkaloid rhodozepinone (96) isolated from a Red Sea marine sponge-derived bacterium Rhodococcus sp. UA13 s with moderate activity against T. brucei brucei TC221 and perhaps a "promising future contribution to drug discovery" [95].
The emergence of drug-resistant Mycobacterium tuberculosis has continued to stimulate an ongoing global search for novel therapeutic leads with novel mechanisms of action, and, as shown in Table 1 and Figure 1, during 2016-2017, 8 novel marine natural products (62, 97-103), isolated from bacteria, sponges and fungi, generated promising pharmacological activity and thus contributed to the search for novel antituberculosis agents. Arai and colleagues identified the alkaloid melophlin A (97) isolated from the Indonesian marine sponge Melophlus sp. that demonstrated strong inhibitory activity against dormant M. smegmatis by targeting the "BCG1083 protein of putative exopolyphosphatase and the BCG1321c protein of diadenosine 5 ,5"-P 1 ,P 4 -tetraphosphate phosphorylase" [96]. Rodrigues Felix and colleagues isolated the polyketide 15-α-methoxypuupehenol (98) from the marine sponge Petrosia sp. that demonstrated potent antibacterial activity against dormant M. tuberculosis, highlighting a mode of action in which bacterial killing "is observed only for dormant but not metabolically active bacteria" [97].
As shown in Table 1 and Figure 1, additional six marine natural products (99-103) exhibited antituberculosis activity, although their mechanisms of action remained undetermined: the alkaloid gliotoxin (99) derived from a deep-sea fungus Aspergillus sp. SCSIO Ind09F01 that strongly inhibited "at very low µM level" M. tuberculosis in vitro [98]; the polyketide proximicin B (100) isolated from the South China Sea sediments-derived Verrucosispora sp. MS100047 which demonstrated "a good anti-BCG activity" [99]; the hybrid peptide/polyketide smenothiazole A (101) isolated from a sponge consortium of Puerto Rican marine sponge Plakortis symbiotica-Xestospongia deweerdtae and identified as a "new lead compound with high activity" against M. tuberculosis H 37 Rv [100]; a new macrolide sporalactam B (62) isolated from Northeastern Pacific Canadian marine sediment-derived Micromonospora sp. RJA4480 reported to demonstrate "selective and potent inhibition of M. tuberculosis" [65]; an "unusual" alkaloid talaramide A (102) isolated from the mangrove endophytic fungus Talaromyces sp. HZ-YX1 that inhibited a mycobacterial protein kinase C required for localization of mycobacterial in macrophage [101], and a naphthoquinone dimer viomellein (103) produced by the Indonesian sponge-derived Aspergillus sp. that showed potent activity against dormant M. bovis BCG [102].

Antiviral Activity
As shown in Table 1  As shown in Table 1, 6 reports described antiviral marine chemicals and their mechanisms of action. O'Rourke and colleagues communicated that the alkaloid hymenialdisine (104), isolated from the Red Sea sponge Stylissa carteri inhibited HIV infection and while the retroviral reverse transcriptase was not inhibited, the investigators concluded that it could "serve as starting scaffold(s) for further investigation" [103]. Yamashita and colleagues discovered that the merosesquiterpene metachromin A (105) isolated from the marine sponge Dactylospongia metachromia significantly inhibited the production of hepatitis B virus (HBV) by affecting the activities of the viral core promoter and reducing the hepatic nuclear factor α protein, a mechanism that may contribute to "ameliorating HBV-related disorders in the liver" [104]. Ishikawa and colleagues reported that the carotenoid peridin (106) isolated from the Japanese coral Isis hippuris inhibited the proliferation and survival of HTLV-1-infected T-cell lines by a mechanism that involved "suppression of NF-κB and Akt signaling" suggesting the compound was a "promising drug for HTLV-1-associated diseases" [105]. Niu and colleagues determined that the phenolic lactone spiromastilactone D (107) isolated from a South Atlantic deep-sea (2869 m) sediment-derived fungus Spiromastix sp. MCCC 3A00308 demonstrated "broad anti-influenza spectrum" by a mechanism that targeted viral attachment and entry by affecting "hemagglutinin protein-sialic acid receptor interaction" and viral genome replication by "targeting the viral RNP complex" [106]. Kim and colleagues investigated the indolosesquiterpenoid xiamycin D (108) isolated from the Korean saltern-derived halophilic actinomycete Streptomyces sp. strain HK18 and observed it displayed potent inhibition of porcine epidemic diarrhea virus by inhibiting genes encoding several essential structural proteins required for PEDV replication, thus demonstrating novel and "promising skeletons against PEDV-related viruses" [107]. Cheng and colleagues isolated a new ecdysone terpenoid zoanthone A (109) from a Taiwanese sea anemone Zoanthus spp. that demonstrated good activity against dengue virus 2 by a mechanism that inhibited viral replication by blocking the C-terminal RNA-dependent RNA polymerase domain of NS5, the "largest and the most conserved (non-structural) protein" of the virus [108].

Antidiabetic Activity
As shown in Table 2 and Figure 2, twelve publications reported on the mode of action of marine-derived antidiabetic compounds (124-132) during 2016-2017. Yamazaki and colleagues contributed to the pharmacology of diabetes by noting that the diterpene marine alkaloid agelasine G (124) isolated from the Japanese marine sponge Agelas nakamurai selectively inhibited protein tyrosine phosphase B (PTP1B) and enhanced insulin-stimulated phosphorylation of serine/threonine protein kinase B or Akt in vitro, noting that further studies may "provide a candidate for anti-diabetes therapeutic agents" [151]. Xu and colleagues observed that a novel bromophenol bis (2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) (125) isolated from the red alga Odonthalia corymbifera, increased glucose uptake in vitro, decreased the expression of protein tyrosine phosphatase 1B, activated the insulin signaling pathway and in mice "significantly decreased the blood glucose", thus, suggesting

Antidiabetic Activity
As shown in Table 2 and Figure 2, twelve publications reported on the mode of action of marine-derived antidiabetic compounds (124-132) during 2016-2017. Yamazaki and colleagues contributed to the pharmacology of diabetes by noting that the diterpene marine alkaloid agelasine G (124) isolated from the Japanese marine sponge Agelas nakamurai selectively inhibited protein tyrosine phosphase B (PTP1B) and enhanced insulin-stimulated phosphorylation of serine/threonine protein kinase B or Akt in vitro, noting that further studies may "provide a candidate for anti-diabetes therapeutic agents" [151]. Xu and colleagues observed that a novel bromophenol bis (2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) (125) isolated from the red alga Odonthalia corymbifera, increased glucose uptake in vitro, decreased the expression of protein tyrosine phosphatase 1B, activated the insulin signaling pathway and in mice "significantly decreased the blood glucose", thus, suggesting BDDE might be a "treatment of type-2 diabetes" [152]. Kim and colleagues reported that the marine algal polyphenol dieckol (126), isolated from the marine brown alga Ecklonia cava attenuated blood glucose levels in the zebrafish model of hyperglycemia, an in vivo paradigm used to study chronic diseases, such as diabetes, by a mechanism that stimulated the protein kinase B (Akt) pathway, thus demonstrating the "anti-diabetic effect" of this compound [153]. Woo and colleagues showed that the novel polyoxygenated steroid gombasterol E (127) isolated from the Korean marine sponge Clathria gombawuiensis moderately enhanced both glucose uptake in adipocytes and phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase in mouse skeletal myoblasts [154]. Villa-Pérez and colleagues reported that the furanocembranolide diterpenoid leptolide (128) isolated from soft coral Leptogorgia alba improved insulin sensitivity by increasing intracellular insulin signaling in both liver and skeletal muscle tissues of a diet-induced obese mice model, a "preclinical model of insulin resistance", concluding that "furanocembranolides as a new therapeutic class to treat Type 2 diabetes" [155]. Cui and colleagues demonstrated that two new polyketides nectriacids B and C (129, 130) isolated from a South China Sea mangrove Sonneratia ovata-derived endophytic fungus Nectria sp. HN001 moderately inhibited αglucosidase, a significant finding because this enzyme prevents "breaking down complex carbohydrates for absorption" [156]. Lin and colleagues discovered a new sesquiterpene penicilliumin B (131) isolated from South China Sea deep sea (1300 m) sediment-derived Penicillium strain F00120 that potently inhibited kidney fibrogenic action of high glucose in vitro through oxidative stress disruption, thus, suggesting this compound had potential for "therapy of diabetic nephropathy" [157]. Chen and colleagues studied a polyketide wailupemycin I (132) isolated from a Chinese marine alga Enteromorpha prolifera-derived Streptomyces sp. OUCMDZ-3434 that moderately inhibited α-glucosidase by competitive inhibition of the enzyme [158].
Moreover, four marine natural products (133-136) listed in Table 2 and shown Figure 2, demonstrated antidiabetic activity during 2016-2017, but the mechanism of action of these compounds remained undetermined at the time of publication: a new polyketide asperentin B (133) isolated from a deep (2769 m) Mediterranean Sea sediment-derived Aspergillus sydowii which "strongly" inhibited human protein tyrosine phosphatase 1B, an important "target for the treatment of type 2 diabetes" [159]; a novel lactone lasiodiplactone (134) isolated from a South China Sea mangrove Acanthus ilicifolius-derived endophytic fungus Lasiodiplodia theobromae ZJ-HQ1 that exhibited α-glucosidase inhibitory activity that was better "than the clinical α-glucosidase inhibitor acarbose" [160]; a new de-O-methyllasiodiplodin (135) isolated from the co-cultivation of the Chinese mangrove Clerodendrum inerme-derived endophytic fungus Trichoderma sp. 307 and the aquatic pathogenic bacterium Acinetobacter johnsonii B2 that inhibited α-glucosidase better "than the positive control acarbose" [161]; and a known isocoumarin analogue sescandelin B (136) isolated form the Chinese Kandelia obovata-derived endophytic fungus Talaromyces amesolkiae, which showed moderate inhibition of α-glucosidase, "which was much better than acarbose" [162].

Anti-Inflammatory Activity
As shown in Table 2 and Figure 2, there was a remarkable increase in anti-inflammatory pharmacology of marine compounds (127, during 2016-2017. The molecular mechanism of action of anti-inflammatory marine natural products (127, was assessed in both in vitro and in vivo preclinical pharmacological studies in twenty one papers, which used several in vitro and in vivo models of inflammation. Zbakh and colleagues evaluated the anti-inflammatory properties of the meroterpene 11-hydroxy-1 -O-methylamentadione (AMT-E) (127) isolated from the brown alga Cystoseira usneoides in a murine model of experimental colitis, observing that the levels of myeloperoxidase, cytokines and the expression of the pro-inflammatory genes nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were reduced, concluding that AMG-W might be a candidate for "prevention/treatment of inflammatory bowel dis-ease" [163]. Jung and colleagues investigated three known diketopiperazines (138)(139)(140) isolated from a Korean marine sediment-derived bacteria Bacillus sp. HC001 and Piscicoccus sp. 12L081 and observed that they effectively inhibited LPS-induced release and expression of transforming growth factor β-induced protein in human endothelial cells, as well as protected against cecal ligation and puncture-induced lethality and organ damage in a murine model of experimental sepsis [164,165]. Ahmad and colleagues reported that the orally administered brominated indol 6-bromoisatin (141) isolated form the Australian marine gastropod mollusc Dicathais orbita inhibited inflammation in a murine model of lipopolysaccharide-induced acute lung injury by significantly reducing pro-inflammatory tumor necrosis-α (TNF-α) and interleukin-1 β (IL-1β) production and associated lung damage, thus, concluding this compound "provides a lead for the development of safer anti-inflammatory drugs" [166]. El-Desoky and colleagues studied a new nitrogenous diterpene ceylonamide A (142), isolated from the Indonesian marine sponge Spongia ceylonensis and determined that they exhibited moderate in vitro anti-inflammatory activity of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in RAW264 macrophages with structure-activity relationships studies. This revealed that the "position of the carbonyl group of the γ-lactam ring . . . at its nitrogen atom were important for inhibitory activity" [167]. Ngan and colleagues isolated a known polyketide citrinin H1 (143) from the Korean sand-derived bacterium Penicillium sp. SF-5629 and observed moderate inhibition E. coli LPS-activated BV-2 microglia in vitro nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) release with concomitant downregulation of the inducible enzymes nitric oxide synthase and cyclooxygenase-2 attributed to "inhibition of NF-κB and p38 MAPK signaling pathways" [168]. Manzoor and colleagues observed that 4-hydroxy-2,3-dimethyl-2-nonen-4-olide (144) extracted from Korean marine alga Ulva pertusa moderately inhibited pro-inflammatory cytokines IL-12 p40 and IL-6 release from bone marrow-derived dendritic cells, as well as signal transduction by inhibiting phosphorylation of nuclear factor -κB (NF-κB), and thus, warranted further study to evaluate its potential as a "therapeutic agent for inflammation-associated maladies" [169]. Aminin and colleagues assessed the anti-inflammatory pharmacology of the triterpene glycoside cucumarioside A 2 -2 (145) isolated from the Russian edible sea cucumber Cucumaria japonica by demonstrating that this compound potently interacted with P2X purinergic receptors, in particular P2X4, on mature macrophage membranes and enhanced reversible ATPdependent Ca 2+ signaling thus leading to "activation of cellular immunity" [170]. Ha and colleagues studied the anti-inflammatory effects of a known curvularin-type metabolite (146) derived from an Antarctic Ross Sea sponge-derived fungus Penicillium sp. SF-5850 that potently inhibited LPS-induced RAW264.7 macrophages production of pro-inflammatory NO and PGE 2 as well as the expression of iNOS and COX-2 by inhibition of the NF-κB, a "transcriptional factor(s) involved in inflammation-related disorders" [171]. Ciaglia and colleagues characterized the anti-inflammatory effects of the terpenoid 9,11-dihydrogracilin A (147) isolated from the Antarctic marine sponge Dendrilla membranosa and observed that, in human peripheral blood mononuclear cells, in vitro, it downregulated NF-κB as well as inhibition of IL-10, while in vivo it significantly attenuated mouse ear edema and inflammation, thus supporting the use of this compound "in inflammatory cutaneous diseases [172]. Jiao and colleagues investigated the "terpene-polyketide-pyridine hybrid" dysivillosin A (148) isolated from the South China Sea marine sponge Dysidea villosa that inhibited RBL-2H3 mast cell release of β-hexosaminidase, a marker of degranulation, as well as pro-inflammatory leukotriene B4 and IL-4 by suppressing the IgE/Syk signaling pathway, thus suggesting a "new chemotherapeutic scaffold targeting Syk-associated allergy" [173]. Su and colleagues extended the pharmacology of the known antimicrobial peptide epinecidin-1 (149) isolated from the orange-spotted grouper Epinephelus coioides by showing that its anti-inflamatory activity resulted from degradation of the Toll-like receptor signaling adaptor protein MyD88 in RAW 264.7 mouse macrophages and concomitant activation of the Smurf E3 ligase proteasome degradation pathway [174]. Lin and colleagues continued the evaluation of the terpenoid excavatolide (150) isolated from the Taiwanese gorgonia coral Briareum excavatum, observing that it inhibited LPS-induced osteoclast-like cell formation and tartrate-resistant acid phosphatase (TRAP) expression, in vitro, while also significantly reducing paw oedema and TRAP-positive multinucleated cell formation in two rat models of experimental arthritis [175]. Several studies extended the anti-inflammatory mechanisms of the marine carotenoid fucoxanthin (151) isolated from the edible brown alga Undaria pinnatifida: Choe and colleagues reported that fucoxanthin inhibited paw edema in an experimental in vivo model of inflammation by reducing activation of iNOS, COX-2 and NF-κB [176]; Grassa-López and colleagues observed that fucoxanthin ameliorated lipogenesis, decreased insulin resistance as well as biomarkers of both inflammation and cardiovascular disfunction in an experimental rat obesity model [177]; Sugiura and colleagues determined that in vitro fucoxanthin suppressed PLA 2 and COX-2 expression in a rat basophilic leukemia-2H3 cells, while in vivo inhibiting PLA 2 , COX-2 and hyaluronidase in several ICR mouse ear models of inflammation [178]; Taira and colleagues observed that concentration-dependent cytoprotection or apoptosis in RAW264.7 macrophage cells by the carotenoids fucoxanthinol and fucoxanthin resulted from activation of the Nrf2-ARE signaling pathway [179]. Sintsova and colleagues characterized a novel Kunitz-type peptide (152) isolated from the sea anemone Heteractis crispa that significantly decreased intracellular Ca 2+ in histamine-treated murine bone marrowderived macrophages thus suggesting the involvement of "H 1 -type histamine receptor blockage" in the anti-inflammatory mechanism of action of this peptide [180]. Hong and colleagues determined that the diterpenoid hipposponlachnin B (153) isolated from the South China Sea marine sponge Hippospongia lachne decreased production of β-hexosaminidase, a degranulation biomarker and pro-inflammatory mediators IL-4 and LTB4 by RBL-2H3 cells, suggesting a possible therapeutic use for "the treatment of allergy" [181]. Kozuma and colleagues isolated new cyclic peptides ogipeptins A-D (154)(155)(156)(157) from the culture broth of the Japanese marine Gram-negative bacterium Pseudoalteromonas sp. SANK 71903 that blocked the binding of LPS to the cluster of differentiation 14 (CD14) in vitro and decreased TNF-α release by human U937 monocytic cells, concluding that these peptides could be developed for use "as anti-LPS drugs against LPS-associated diseases" [182]. Kwon and colleagues reported a new anthranilic acid derivative oscarellin (158) isolated from a Philippine sponge Oscarella stillans that strongly inhibited LPS-induced TNF-αand IL-6 production in murine macrophage RAW 264.7 macrophages by a mechanism "associated with inactivation of c-Jun NH 2 -terminal kinase (JNK), extracellular signal-regulated kinase (ERK), activator protein-1 (AP-1), and NF-κB and activation of activating transcription factor-3 (ATF-3)" [183]. Kim and colleagues observed that the novel alkaloid pseudane-VII (159) isolated from the marine bacterium Pseudolateromonas sp. M2 modulated release of pro-inflammatory mediators (NO, IL-1β and IL-6) by LPS-treated RAW 264.7 murine macrophage cell line in vitro via inhibition of "MAPK phosphorylation and NF-κB translocation", while in vivo treatment with this compound suppressed production of IL-1β and iNOS expression, suggesting "pseudane VII has potential as treatment for inflammatory responses and diseases" [184].

Marine Compounds with Activity on the Immune System
In 2016-2017, the preclinical pharmacology of marine compounds that were reported to affect the immune system is shown in Table 2 and Figure 2. The molecular mechanism of action of marine natural products that affected the immune system (145,(193)(194)(195)(196)(197)(198)(199) was described in seven papers which used several in vitro and in vivo models. Pislyagin and colleagues reported that the triterpene glycoside cucumarioside A 2 -2 (145) isolated from the Far Eastern sea cucumber Cucumaria japonica caused changes in mouse spleen morphology, proliferative activity "predominantly in B-cells" and macrophage activation in mouse spleen, concomitant with increase in IL-1β, iNOs, ROS and NO production [210,211]. Sánchez and colleagues investigated three terpenoids gracillin A, H and L (193)(194)(195) isolated from the marine sponge Spongionella gracillis that inhibited human T lymphocyte IL-2 production, as well as CD147 expression by reducing calcineurin phosphatase activity, thus concluding that gracilins are a "valuable option for synthetic drug development" [212,213]. Kicha and colleagues determined the immunomodulatory effects of the mycosporine-like amino acids (MAA) shinorine and porphyra-334 (196,197) isolated from the red alga Porphyra sp. and reported they both induced NF-κB activity and moderated tryptophan metabolism in human myelomonocytic cell line THP-1, thus recommending "a more detailed risk-benefit assessment" before MAA are used "in daily care products" [214]. Chung and colleagues studied the cembrane-type diterpenoid sinulariolide (198), isolated from the Taiwanese cultured soft coral Sinularia flexibilis and observed suppression of LPS-phenotypic maturation, cytokine and NO production and co-stimulatory molecule expression of murine bone marrow-derived dendritic cells, as well as signaling pathways, concluding "that sinulariolide may be utilized in the treatment of autoimmune andinflammatory disorders" [215]. Gao and colleagues determined significant effects of several peptides (199) isolated from Indian Ocean deep (1654 m) sediment-derived actinomycete Williamsia sp. MCCC 1A11233 on both IgE-sensitized RBL-2H3 mast cell histamine and proinflammatory cytokine release, and a murine model of passive cutaneous anaphylaxis, thus observing that "the three compounds have the potential to prevent or treat IgE-sensitized allergic disorders" [216].
Five marine compounds were shown to bind K + channels (206,207), calcium channels (208), nicotinic acetylcholine receptors (nACHR) (209) and serotonin receptor 5-HT 7 (218). Moreels and colleagues electrophysiologically demonstrated that the novel peptide APETx4 (206) isolated from the marine sea anemone Anthopleura elegantissima inhibited the K + channel K v 10.1 by keeping it in a closed state and thus, because the K v 10.1 is overexpressed in a human tumors, APETx4 could become a "scaffold for design and synthesis of more potent and safer anticancer drugs" [223]. Goda and colleagues conducted detailed studies that determined that the marine xanthophyll carotenoid astaxanthin (207) reversed the toxicity of the calcium-dependent Maxi-K (BK) K + channel antagonist food mycotoxin penitrem A (PA) "by restoring normal levels of the targeted neurotransmitters" both in Schwann cells CRL-2765 in vitro and in both the nematode Caenorhabditis elegans and rat in vivo models thus concluding astaxanthin might be useful "for in vivo prevention of PA-induced brain toxicity [224]. Mendez and colleagues investigated the marine guanidine alkaloid crambrescidin 816 (208) produced by the Mediterranean sponge Crambe crambe and known to block voltage dependent L-type Ca 2+ channels, and observed that cytotoxicity was concomitant with an increase of cytosolic Ca 2+ in a primary culture of cortical neurons by a mechanism that "was mediated by both NMDA and AMPA glutamate receptor subtypes" activation [225]. Jiang and colleagues discovered a novel O-conotoxin GeXXVIIA linear peptide (209) from the venom of the South China sea cone snail Conus generalis that potently inhibited the human α9α10 nicotinic acetylcholine receptor (nACh), a nAChR receptor expressed in both the nervous system, as well as in other non-neuronal cells, by a non-competitive and voltage-independent mechanism. The data suggest that this new inhibitor "would facilitate unraveling the functions of this nAChR subtype" [226]. Uchimasu and colleagues reported a novel guanidine alkaloid mellpaladine A (218) isolated from a Palauan Didemnidae tunicate that modulated mice behavioral profiles after an intracerebroventricular injection with particular selectivity for the serotonin receptor 5-HT 7 , thus, supporting the notion that "marine alkaloids are unique . . . source of neuroactive compounds" [239].
Two additional studies extended the pharmacology of conopeptides (210)(211). Bernáldez and colleagues discovered a novel 25-mer peptide member of the γ-conotoxin family PiVIIA (210) in the venom of the Mexican marine snail Conus princepts that increased Ca 2+ currents in dorsal root ganglion neurons without affecting the Na + , K + or acid sensing ionic channel currents, further studies being proposed to "define its potential use as a positive modulator of neuronal activity" [227]. Brust and colleagues identified a previously uncharacterized nine amino acid conorphin-T (211) from a Conus textile venom peptide library with selectivity for κ-opioid receptors (KOR) that led to the development of several novel KOR agonists, which potently inhibited splanchnic colonic nociceptors, thus, becoming promising leads "for the development of irritable bowel syndrome treatments" [228].
One study contributed to nociceptive pharmacology. Logashina and colleagues reported that the novel peptide Ms 9a-1 (219), isolated from the venom of the sea anemone Metridium senile, produced significant analgesic and anti-inflammatory effects in a murine thermal hyperalgesia model by a mechanism that potentiated the response of transient receptor potential ankyrin-repeat 1 receptor (TRPA1) and was followed by loss of TRPA1expressing neurons [240].
The neuroprotective activity of marine compounds (151, 212, 214, 216, 220, 223, 225) was reported in ten studies. Three studies reported on the neuroprotective pharmacology of the marine carotenoid fucoxanthin (151) isolated from several brown algae: Undaria pinnatifida, Ecklonia stolonifera and Sargassum horneri: Jung and colleagues studied β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), which is strongly correlated with Alzheimer's disease, and observed that fucoxanthin inhibited BACE1 activity exhibiting mixed-type inhibition in vitro, while molecular docking simulations showed that two fucoxanthin hydroxyl groups interacted with two BACE1 residues (Gly11 and Ala127), mechanistic studies that suggest fucoxanthin "may be a good template for anti-AD drugs" [232]. Lin and colleagues demonstrated that in mice fucoxanthin reversed scopolamine-induced cognitive impairments by inhibiting brain acetylcholinesterase by a non-competitive mechanism, as well as increasing choline acetyltransferase activity and brain-derived neurotrophic factor (BDNF) expression in hippocampus and cortex. The studies appear to anticipate fucoxanthin's "therapeutic efficacy for the treatment of AD by acting on multiple targets" [233]. Zhang and colleagues discovered that fucoxanthin provided neuroprotection in an experimental murine model of traumatic brain injury (TBI), "a major public health problem" by alleviating TBI-induced secondary brain injury, cerebral edema and lesions, while also demonstrating that it attenuated TBI-induced apoptosis and oxidative stress "at least partly" via regulation of the nuclear factor erythroid 2-related factor (Nrf2)-antioxidant-response element (ARE) and Nrf2-autophagy pathways, thus, making fucoxanthin "an attractive therapeutic agent in the treatment of TBI in the future" [234]. Two studies were reported by the same research group describing the neuroprotective and anti-inflammatory effects of the cembranolide analog 11-dehydrosinulariolide (11-de) (212) isolated from the soft coral Sinularia flexibilis: Feng and colleagues observed that 11-de increased the expression of BDNF in a neuroblastoma cell line in vitro and had a protective effect in both an in vivo zebrafish and rat Parkinson's disease model, results that the investigators hoped would "help treat patients diagnosed with Parkinson's disease" [229]. Chen and colleagues reported that 11-de improved the functional recovery in a rat thoracic spinal cord contusion injury experimental model with an antiapoptotic and anti-inflammatory mechanism that attenuated iNOS and TNF-α, thus, proposing "this compound may be a promising therapeutic agent for spinal cord injury" [230]. Fang and colleagues showed that a new cyclopentenone 5-hydroxycyclopenicillone (214) isolated from a culture of the marine sponge Hymeniacidon perleve-derived fungus Trichoderma sp. HPQJ-34 acted as a moderate free radical scavenger, and had anti-Aβ fibrillization and neuroprotective properties, concluding that this compound "might be of interest to neuropharmacology research and anti-AD drug discovery programs" [235]. Alonso and colleagues evaluated the pyrroloiminoquinone makaluvamine J (216), isolated from a Fijian marine sponge Zyzzya sp. and showed that it "provided full neuroprotection", as it potently reduced mitochondrial damage by reactive oxygen species, as well as improved endogenous glutathione and catalase in mouse and human neuronal models, thus, potentially contributing to "antioxidant therapies in neurodegenerative diseases" [237]. Kim and colleagues found that the phlorotannin phlorofucofuroeckol (220) isolated from the brown seaweed Ecklonia cava, increased cell viability in glutamate-treated rat adrenal phaeochromocytoma PC12 cells by inhibiting apoptotic cell death as well as mitochondrial reactive oxygen species generation, results, which taken together, suggest PFF may be developed as " a neuroprotective agent in ischemic stroke" [241]. Perni and colleagues discovered that the aminosterol squalamine (223) isolated from the dogfish shark Squalus acanthias displaced the "intrinsically disordered" protein α-synuclein, associated with Parkinsons's disease, from lipid vesicles and membranes by competitively binding at the surfaces, as well as suppressed muscle paralysis in a nematode worm Caenorhabditis elegans strain oversexpressing α-synuclein, suggesting squalamine "could be a means for a therapeutic intervention in Parkinsons's disease" [244]. Pan and colleagues extended the pharmacology of xyloketal B (225) isolated from the mangrove fungus Xylaria sp. by investigating effects of xyloketal in an adult mice stroke model, observing that pre-and post-treatment treatment reduced both brain infarct volume and the generation of ROS and pro-inflammatory cytokines by suppression of ROS/TLR4/NF-κB inflammatory signaling pathway, thus providing evidence for "potential application of xyloketal B in stroke therapy" [246].
As shown in Table 2, five marine compounds were shown to modulate other molecular targets, i.e., the acetylcholinesterases (213,217,224), endogenous transient receptor potential canonical type 1 channel (TRPC1) (215), human monoamine oxidase B enzyme (221), and prolonged synaptic transmission (222). Botic Lee and colleagues discovered that the brominated alkaloid discorhabdin G (213) isolated from the Antarctic Latrunculia biformis sponge inhibited electric eel and human acetylcholinesterases by a reversible and competitive mechanism, observations that could potentially lead to new Alzheimer's disease "cholinesterase inhibitors based on the scaffold of discorhabdins" [231]. Adelhameed and colleagues reported the isolation and structure elucidation of a new phytoceramide MEC-1-4 (217) from the Egyptian Red Sea sponge Mycale euplectellioides that moderately inhibited acetylcholinesterase by interacting with the enzyme "via hydrogen bonding, hydrophobic contacts and hydrophilic-hydrophobic interactions", thus suggesting MEC-1-4 might become a "valuable lead compound for AD management" [238]. Moodie and colleagues evaluated the known brominated phenethylamine derivative stryphnusin (224) isolated from the Norwegian sponge Stryphus fortis that moderately inhibited electric eel acetylcholinesterase by a reversible competitive mechanism and with no effect on muscle function or neuromuscular transmission thus contributing to novel and promising approaches for "symptomatic treatment of AD" [245]. Flores and colleagues investigated the marine polyether toxin maitotoxin (215) produced by the dinoflagellate Gambierdiscus toxicus that is responsible for ciguatera fish poisoning, demonstrating that its mechanism of action involves activation of the non-voltage-gated cation TRPC1 in X. laevis oocytes and thus proposing this toxin as a "useful tool for further studies of TRPC1 channels" [236]. Lee and colleagues reported that the polyketide piloquinone (221) isolated from a Californian marine sediment-derived Streptomyces sp. CNQ-027 potently inhibited recombinant human monoamine oxidase B enzyme considered a "target in AD and Parkinson's disease", by a competitive and reversible mechanism which highlighted the importance of the "ester functionality in the ring system for bioactivity", thus possibly becoming "a new potential lead compound for the development of MAO inhibitors" [242]. Caplan and colleagues extended the pharmacology of the marine diterpene glycoside pseudopterosin A (222) isolated from the Bahamanian gorgonian soft coral Pseudopterogorgia elisabethae by demonstrating it prolonged synaptic transmission in an experimental oxidative stress model, as well as extensively distributed in murine brain, findings that suggested a "potential as a novel neuromodulatory agent" [243].

Reviews on Marine Pharmacology and Pharmaceuticals
In 2016-2017 several reviews covered general and/or specific areas of marine preclinical pharmacology: (a) marine pharmacology and marine pharmaceuticals: new marine natural products and relevant biological activities published in 2016 and 2017 [330,331]; chemistry and biology of guanidine natural products [332,333]; biological properties of secondary metabolites from sea hares of Aplysia genus [334]; alkynyl-containing peptides of marine cyanobacteria and molluscs [335]; bioactive cyanobacterial secondary metabolites for health [336]; biological active metabolites from marine-derived myxobacteria [337]; antimicrobial metabolites from the marine bacteria genus Pseudoalteromonas [338]; marine natural products from marine-derived Penicillium fungi [339]; biological activity of secondary metabolites from marine-algal-derived endophytic fungi [340]; pharmacological potential of fucosterol from marine algae [341]; pharmacological activities of Antarctic marine natural products [342]; bioactive acetylated triterpene glycosides from Holothuroidea in the past six decades [343]; terpenoids from octocorals of the genus Pachyclavularia [344]; bioactive marine natural products from sponges of the genus Hyrtios [345]; secondary metabolites from the marine sponge genus Phyllospongia [346]; discovery strategies of bioactive compounds synthetized by nonribosomal peptide synthetases and type-1 polyketide synthase derived from marine microbiomes [347]; developing natural product drugs: supply problems and how they have been overcome [348]; the global marine pharmaceutical pipeline in 2020: U.S. Food and Drug Administration-approved compounds and those in Phase I, II and III of clinical development http://marinepharmacology.midwestern.edu/clinPipeline.htm; (b) antimicrobial marine pharmacology: antimycobacterial metabolites from marine invertebrates [349]; antimicrobials from cnidarians [350]; (c) antiprotozoal and antimalarial marine pharmacology: natural products in drug discovery against neglected tropical diseases [351]; antimycobacterial natural products from marine Pseudopterogorgia elisabethae [352]; (d) immuno-and anti-inflammatory marine pharmacology: marine natural products inhibitors of neutrophil-associated inflammation [353]; (e) cardiovascular and antidiabetic marine pharmacology: bioactive components from fish for dyslipidemia and cardiovascular risk reduction [354]; (f) nervous system marine pharmacology: marine natural products from sponges with neuroprotective activity [355]; a transcriptomic survey of ion channel-based conotoxin in the Chinese cone snail Conus betulinus [356]; dinoflagellate cyclic imine toxins as potent antagonists of nicotinic acetylcholine receptors [357]; inhibition of nociception and pain transmission by analgesic conopeptides ion channel inhibition by targeting G protein-

Reviews on Marine Pharmacology and Pharmaceuticals
In 2016-2017 several reviews covered general and/or specific areas of marine preclinical pharmacology: (a) marine pharmacology and marine pharmaceuticals: new marine natural products and relevant biological activities published in 2016 and 2017 [330,331]; chemistry and biology of guanidine natural products [332,333]; biological properties of secondary metabolites from sea hares of Aplysia genus [334]; alkynyl-containing peptides of marine cyanobacteria and molluscs [335]; bioactive cyanobacterial secondary metabolites for health [336]; biological active metabolites from marine-derived myxobacteria [337]; antimicrobial metabolites from the marine bacteria genus Pseudoalteromonas [338]; marine natural products from marine-derived Penicillium fungi [339]; biological activity of secondary metabolites from marine-algal-derived endophytic fungi [340]; pharmacological potential of fucosterol from marine algae [341]; pharmacological activities of Antarctic marine natural products [342]; bioactive acetylated triterpene glycosides from Holothuroidea in the past six decades [343]; terpenoids from octocorals of the genus Pachyclavularia [344]; bioactive marine natural products from sponges of the genus Hyrtios [345]; secondary metabolites from the marine sponge genus Phyllospongia [346]; discovery strategies of bioactive compounds synthetized by nonribosomal peptide synthetases and type-1 polyketide synthase derived from marine microbiomes [347]; developing natural product drugs: supply problems and how they have been overcome [348]; the global marine pharmaceutical pipeline in 2020: U.S. Food and Drug Administration-approved compounds and those in Phase I, II and III of clinical development http://marinepharmacology.midwestern.edu/clinPipeline.htm; (b) antimicrobial marine pharmacology: antimycobacterial metabolites from marine invertebrates [349]; antimicrobials from cnidarians [350]; (c) antiprotozoal and antimalarial marine pharmacology: natural products in drug discovery against neglected tropical diseases [351]; antimycobacterial natural products from marine Pseudopterogorgia elisabethae [352]; (d) immuno-and anti-inflammatory marine pharmacology: marine natural products inhibitors of neutrophil-associated inflammation [353]; (e) cardiovascular and antidiabetic marine pharmacology: bioactive components from fish for dyslipidemia and cardiovascular risk reduction [354]; (f) nervous system marine pharmacology: marine natural products from sponges with neuroprotective activity [355]; a transcriptomic survey of ion channel-based conotoxin in the Chinese cone snail Conus betulinus [356]; dinoflagellate cyclic imine toxins as potent antagonists of nicotinic acetylcholine receptors [357]; inhibition of nociception and pain transmission by analgesic conopeptides ion channel inhibition by targeting G protein-coupled receptors [358]; (g) miscellaneous molecular targets and uses: ichthyotoxicity evaluation of marine natural products [359]; pharmacological potential of non-ribosomal peptides from marine sponges and tunicates [360]; aeroplysinin-1 as a multi-targeted bioactive sponge-derived natural product [361]; therapeutic potential of the phycotoxin yessotoxin [362], and new modalities for challenging drug targets in pharmaceutical discovery [363].

Conclusions
This marine pharmacology 2016-2017 review is the eleventh contribution to the marine preclinical pharmacology pipeline review series that was initiated by Alejandro M. S. Mayer (AMSM) in 1998 [1][2][3][4][5][6][7][8][9][10], with the aim of providing a systematic overview of selected peer-reviewed preclinical marine pharmacological literature. The global preclinical marine pharmacology research highlighted in this review involved chemists and pharmacologists from 54 countries, a remarkable increase from our last review, namely: Australia, Austria, Bangladesh, Belgium, Brazil, Canada, China, Costa Rica, Croatia, Cuba, Denmark, Egypt, Fiji, France, Germany, Greece, Hungary, Iceland, India, Indonesia, Ireland, Israel, Italy, Japan, Jordan, Kazakhstan, Malaysia, Mexico, Morocco, Myanmar, the Netherlands, Nigeria, New Zealand, Norway, Oman, Panama, Papua New Guinea, Philippines, Poland, Portugal, Russian Federation, Saudi Arabia, Serbia, Slovenia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States and Vietnam. Thus, during 2016-2017 the marine preclinical pharmaceutical pipeline continued to provide novel pharmacology and potential new leads for the marine clinical pharmaceutical pipeline. As shown at the marine preclinical and clinical pharmaceutical pipeline website: https://www.midwestern.edu/departments/marinepharmacology.xml there are currently 13 marine-derived pharmaceuticals approved by the U.S. Food and Drug Administration and 1 by Australia, and more than 23 marine-derived compounds in Phases I, II and III of global clinical pharmaceutical development. Funding: We acknowledge financial support from Midwestern University to AMSM; and NIH-SC1 Award (Grant 1SC1GM086271-01A1) of the University of Puerto Rico to ADR, and a grant from Regione Campania-POR Campania FESR 2014/2020 "Combattere la resistenza tumorale: piattaforma integrata multidisciplinare per un approccio tecnologico innovativo alle oncoterapie-Campania Oncoterapie" (Project N. B61G18000470007) to OTS. The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.