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Marine Pharmacology in 2009–2011: 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 †

Alejandro M. S. Mayer
Abimael D. Rodríguez
Orazio Taglialatela-Scafati
3 and
Nobuhiro Fusetani
Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers Grove, Illinois 60515, USA
Department of Chemistry, University of Puerto Rico, San Juan, Puerto Rico 00931, USA
Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy
Fisheries and Oceans Hakodate, Hakodate 041-8611, Japan
Author to whom correspondence should be addressed.
Dedicated to the memory of Ernesto Fattorusso, a pioneer in marine natural products chemistry.
Mar. Drugs 2013, 11(7), 2510-2573;
Submission received: 12 April 2013 / Revised: 4 June 2013 / Accepted: 14 June 2013 / Published: 16 July 2013


The peer-reviewed marine pharmacology literature from 2009 to 2011 is presented in this review, following the format used in the 1998–2008 reviews of this series. The pharmacology of structurally-characterized compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities were reported for 102 marine natural products. Additionally, 60 marine compounds were observed to affect the immune and nervous system as well as possess antidiabetic and anti-inflammatory effects. Finally, 68 marine metabolites were shown to interact with a variety of receptors and molecular targets, and thus will probably contribute to multiple pharmacological classes upon further mechanism of action studies. Marine pharmacology during 2009–2011 remained a global enterprise, with researchers from 35 countries, and the United States, contributing to the preclinical pharmacology of 262 marine compounds which are part of the preclinical pharmaceutical pipeline. Continued pharmacological research with marine natural products will contribute to enhance the marine pharmaceutical clinical pipeline, which in 2013 consisted of 17 marine natural products, analogs or derivatives targeting a limited number of disease categories.

1. Introduction

The current article presents a systematic review of the preclinical pharmacology of the marine natural products literature in 2009–2011, with a similar format to previous reviews [1,2,3,4,5,6,7], and which resulted from extensive searches of several databases, including Marinlit, PubMed, Current Contents® and Chemical Abstracts®. We have limited this review to the peer-reviewed literature that reported bioactivity or pharmacology of structurally characterized marine chemicals, and have continued to use a modification of Schmitz’s chemical classification [8] to assign marine structures to 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 presented in Table 1, with the corresponding structures shown in Figure 1. Marine compounds that affect the immune and nervous systems, as well as those with antidiabetic and anti-inflammatory effects are shown in Table 2, with their corresponding structures presented in Figure 2. Finally, marine compounds that have been demonstrated to affect a wide variety of cellular and molecular targets are exhibited in Table 3, and their structures presented in Figure 3. Several publications during 2009–2011 described extracts or as yet structurally uncharacterized marine compounds, and although they have been excluded from the current review, they certainly deserve further investigation because they report novel and interesting in vitro or in vivo preclinical pharmacology: antimicrobial and antistaphylococcal biofilm activity of three 5-kDa peptides isolated from coelomocyte effector cells of the sea urchin Paracentrotus lividus that could benefit patients with medical device-associated infections [9]; an antibacterial polyunsaturated fatty acid, eicosapentanoic acid, isolated from extracts of the marine diatom Phaeodactylum tricornutum with activity against a range of Gram-positive and Gram-negative bacteria, including multidrug-resistant Staphyloccus aureus [10]; potent anticoagulant activity of sulfated polysaccharides isolated from the Brazilian brown seaweed Dictyota cervicornis, which was close to that of clinically used low molecular weight heparin [11]; potent anticoagulant activity of a sulfated polysaccharide isolated from the Chinese green seaweed Monostroma latissimum by a mechanism involving thrombin inhibition in the presence of heparin cofactor II [12]; in vitro antileishmanial activity of dichloromethane extracts of a Tunisian sponge Sarcotragus sp., which demonstrated concomitant morphological alterations of Leishmania major promastigotes in vitro [13]; in vivo and in vitro antifilarial activity of the marine sponge Haliclona exigua extracts against adult nematode Brugia malayi, a parasite that may cause lymphatic filariasis [14]; significant nontoxic and anti-herpes simplex virus HSV-1 and HSV-2 activity in sulfated polysaccharide extracts isolated from four species of red and brown marine algae from New Zealand [15]; anti-herpes simplex virus HSV-1 activity in high molecular weight exopolysaccharides purified from the French marine sponge Celtodoryx girardae and its symbiotic bacteria [16]; anti-inflammatory activity of the crude extracts and fractions of the Mediterranean sponge Spongia officinalis in the in vivo rat carrageenan-induced paw edema assay [17]; in vivo anti-inflammatory activity in polyphenolic extracts from the red alga Laurencia undulata resulting in significant inhibition of asthmatic reactions [18]; in vitro anti-inflammatory effect in an ethanolic extract from the brown alga Ishige okamurae via inhibition of NF-κB transcription factor [19]; induction of oxidative death in a human glioma cell line through a caspase-9 apoptotic pathway by extracts from the marine sponge Polymastia janeirensis [20]; apoptotic activity in extracts from the marine diatom Cocconeis scutellum associated with activation of caspases-8 and -3 in human breast cancer lines [21]; human neutrophil anti-elastase activity of purified sulfated polysaccharides from the red alga Delesseria sanguinea [22]; high antioxidant activity in methanolic extracts of the Korean red alga Polysiphonia morrowii that protected against hydroxyl radical-induced DNA damage in vitro [23]; antioxidant activity in phenolic compounds from the marine alga Halimeda monile that protected against chemically induced rat liver injury in vivo [24]; significant antioxidant properties of polysaccharides from a marine fungus Penicillium sp. F23-2 against superoxide and hydroxyl radicals [25]; in vitro antioxidant activities of acetylated, phosphorylated and benzoylated derivatives of the marine red alga Porphyra haitanensis phorphyran [26]; acceleration of skin wound healing by amino acids isolated from the mollusc Rapana venosa suggesting a possible therapeutic use in skin burns [27]; neuroprotective effects in extracts of the South Indian green seaweed Ulva reticulata that inhibited both acetyl-and butyryl-cholinesterases, and was comparable to agents currently approved for Alzheimer’s disease treatment [28].

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

Table 1 presents the 2009–2011 preclinical pharmacological research on the antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities of the marine natural products (1102) shown in Figure 1.
Table 1. Marine pharmacology in 2009–2011: Marine compounds with antibacterial, antifungal, antituberculosis, antiviral and other antiprotozoal activities.
Table 1. Marine pharmacology in 2009–2011: Marine compounds with antibacterial, antifungal, antituberculosis, antiviral and other antiprotozoal activities.
Drug ClassCompound/Organism aChemistryPharmacologic ActivityIC50 bMMOA bCountry cReferences
Antibacterialchrysophaentin A (1)/algaShikimate f Methicillin-resistant S. aureus inhibition1.5 μg/mL +Inhibit GTPase activity of FtsZITA, USA[29]
AntibacterialH. salinus phenethylamine (2)/bacteriumShikimate fQuorum sensing inhibition9 μg/mLInhibit homoserine lactone receptor bindingUSA[30]
Antibacteriallyngbyoic acid (3)/cyanobacteriumFatty acid dQuorum sensing inhibition100 μMInhibit homoserine lactone receptor LasRGBR, USA[31]
Antibacterial(−)-discorhabdin Z (4)/spongeAlkaloid fM. luteus inhibition50 μg/mL +Sortase A inhibitionS. KOR[32]
Antibacterialagelasine D (5)/spongeTerpene eS. epidermis inhibition0.09 μM +UndeterminedGBR, DEU, NDL[33]
Antibacterialaqabamycin E (6)/bacteriumAlkaloid fP. vulgaris inhibition3.15 μg/mL +UndeterminedDEU[34]
Antibacterialbacillistatins 1–2 (7,8)/bacteriumPeptide fS. pneumoniae inhibition0.5–2 μg/mL +UndeterminedUSA[35]
Antibacterialbromophycolides (914)/algaTerpene eMethicillin-resistant S. aureus inhibition1.4 μMUndeterminedFJI, USA[36]
Antibacterialcaboxamycin (15)/bacteriumAlkaloid fB. subtilis inhibition8 μg/mLUndeterminedDEU[37]
Antibacterialcrossbyanol B (16)/cyanobacteriumPolyketide dMethicillin-resistant S. aureus inhibition2.0–3.9 μg/mL +UndeterminedUSA[38]
AntibacterialC. dellechiajei alkaloids (1719)/ascidianAlkaloid fE. coli & M. luteus inhibition1.1–10.5 μg/mL +UndeterminedFRA[39]
Antibacterial7,20-diisocyanoadociane (20)/spongeTerpene eE. coli & V. harvey inhibition1–2.5 μg/mLUndeterminedAUS, NOR, USA[40]
Antibacterialeusynstyelamide F (21)/bryozoaPeptide fS. aureus inhibition6.25 μg/mL +UndeterminedNOR, GBR[41]
Antibacterialknightol (22)/coralTerpene eMarine Gram + bacteria inhibition2–8 μg ++UndeterminedCOL[42]
AntibacterialMC21-B (23)/bacteriumShikimate fMethicillin-resistant S. aureus inhibition1–4 μg/mL +UndeterminedJPN[43]
Antibacterialmotualevic acid F (24)/spongeFatty acid eMethicillin-resistant S. aureus inhibition1.2–3.9 μg/mL +UndeterminedUSA[44]
AntibacterialNacardiopsis thiopeptide (25)/bacteriumPeptide fVancomycin-resistant E. faecium inhibition1 μg/mL +UndeterminedCHE, NOR[45]
Antibacterialneurymenolides A–B (26,27)/algaPolyketide dMethicillin-resistant S. aureus inhibition2.1–7.8 μMUndeterminedFJI, USA[46]
AntibacterialPseudoalteromonas sp. metabolites (28,29)/bacteriumPolyketide dMethicillin-resistant S. aureus inhibition1.9–2.2 μg/mLUndeterminedUSA[47]
Antibacterialpseudopterosin U (30)/coralTerpene eS. aureus inhibition2.9–4.5 μMUndeterminedCAN, COL[48]
AntibacterialP. vesiculosa β-carboline (31)/bryozoaAlkaloid fB. subtilis inhibition2–4 μg/mL ++UndeterminedNZL[49]
Antibacterialsalinisporamycin (32)/bacteriumPolyketide dS. aureus inhibition0.46 μg/mL +UndeterminedJPN[50]
Antibacterialsynoxazolidinone A (33)/ascidianPeptide fC. glutamicum inhibition6.25 μg/mL +UndeterminedGBR, NOR[51]
Antifungalgeodisterol sulfates h (34,35)/spongeSteroid eC. albicans & S. cerevisiae inhibitionNDMDR1 efflux pump inhibitionUSA[52]
Antifungaltheonellamide F (36)/spongePeptide fNDNDActivate 1,3-β-d-glucan synthesisJPN[53]
AntifungalP. vesiculosa β-carboline (31)/bryozoaAlkaloid fB. subtilis inhibition4–5 μg/mL ++UndeterminedNZL[49]
Antifungalcitronamide A (37)/spongePeptide fS. cerevisiae inhibition8 μg/mL +UndeterminedAUS[54]
Antifungalmarmoratoside A & 17-hydroxyimpatienside A (38,39)/sea cucumberSteroid glycoside eC. albicans inhibition0.7–11 μg/mL +UndeterminedCHN[55]
Antifungalsaadamycin(40)/bacteriumPolyketide dC. albicans, Aspergillus & Cryptococcus inhibition1–5.2 μg/mL +UndeterminedEGY[56]
Antifungaltheopapuamides B & C (41,42)/spongePeptide fC. albicans inhibition1–5 μg/disk ++UndeterminedITA,USA[57]
Antimalarialplakortin (43)/spongePolyketide dP. falciparum D10 & W2 strain inhibitionNDToxic carbon-radicalITA[58]
Antimalarialhomogentisic acid (44)/spongeShikimate fP. falciparum FcB1 strain inhibition12 μMPfnek-1 enzyme inhibitionCHE, NCL, FRA, UK[59]
Antimalarialbatzelladine alkaloids (4548)/spongeAlkaloid fP. falciparum FcB1 strain inhibition0.2–0.9 μMUndeterminedCOL, FRA[60]
Antimalarialbromophycolides (914)/algaTerpene eP. falciparum 3D7 strain inhibition0.5–2.9 μMUndeterminedFJI, USA[36]
AntimalarialBromophycolides R, S, U) (4951)/algaTerpene eP. falciparum 3D7 strain inhibition0.9–2.1 μMUndeterminedFJI, USA[61]
Antimalarial(+)-7-bromotrypargine (52)/spongeAlkaloid fP. falciparum Dd2 & 3D7 strain inhibition3.5–5.4 μMUndeterminedAUS[62]
AntimalarialC. hooperi diterpene (53)/spongeTerpene eP. falciparum F85, D6, W2 strain inhibition4.3–4.7 ng/mL0.5 μg/mLUndeterminedAUS, NOR, USA[40,63]
Antimalarialepiplakinidioic acid (54)/spongePolyketide dP. falciparum W2 strain inhibition0.3 μg/mLUndeterminedUSA[64]
Antimalarialgallinamide A (55)/bacteriumPeptide fP. falciparum W2 strain inhibition8.4 μMUndeterminedPAN, USA[65]
Antimalarialgracilioether B (56)/spongePolyketide dP. falciparum ItG strain inhibition0.5 μg/mLUndeterminedJPN, NLD[66]
Antimalarial8-isocyanoamphilecta-11(20), 15-diene (57)/spongeTerpene eP. falciparum K1 strain inhibition0.94 μMUndeterminedTHAI[67]
Antimalariallagunamides A & B (58,59)/bacteriumPeptide fP. falciparum NF54 strain inhibition0.19–0.91 μMUndeterminedCHE, NZL,SGP[68]
Antimalarialmanadoperoxide C (60)/spongePolyketide dP. falciparum W2 strain inhibition2.33 μMUndeterminedITA[69]
Antimalarial3,4-dihydro-manzamine J N-oxide (61)/spongeAlkaloid fP. falciparum K1 strain inhibition0.58 μg/mLUndeterminedAUS, JPN[70]
Antimalarialneopetrosiamine A (62)/spongeAlkaloid fP. falciparum inhibition2.3 μMUndeterminedUSA[71]
Antimalarialpsammaplysin F(63)/spongePeptide fP. falciparum 3D7 strain inhibition0.87 μMUndeterminedAUS[72]
AntiprotozoalC. cervicornis diterpene (64)/algaTerpene eL amazonensis inhibition2–12 μg/mLMitochondrial swelling & damageBRA[73]
Antiprotozoalagelasine analogs (6568)/syntheticTerpene eL. infantum, T. brucei brucei & T. cruzi inhibition0.093–0.43 μg/mLUndeterminedBEL, NOR[74]
Antiprotozoalalmiramides B & C (69,70)/bacteriumPeptide fL. donovani inhibition1.9–2.4 μMUndeterminedPAN, USA[75]
Antiprotozoalconvolutamine I (71)/bryozoanAlkaloid fT. brucei brucei inhibition1.1 μMUndeterminedAUS[76]
Antiprotozoallongamide B & dibromopalau’ amine (72,73)/spongeAlkaloid fL. donovani & T. brucei rhodesiense inhibition0.5–3.8 μg/mLUndeterminedCHE, GBR, ITA[77]
AntiprotozoalL. variegata SQDG’s (7476)/algaGlycolipidE. histolytica & T. vaginalis inhibition3.9–8.0 μg/mLUndeterminedMEX[78]
Antiprotozoal3,4-dihydro-manzamine J N-oxide (61)/spongeAlkaloid fT. brucei brucei inhibition0.27 μg/mLUndeterminedAUS, JPN[70]
Antiprotozoal(+)-muqubilone B (77)/spongeTerpene eT. brucei brucei inhibition2 µg/mLUndeterminedUSA[79]
Antiprotozoalnorselic acids A–E (7882)/spongeSteroid fLeishmania sp. inhibition2–3.6 µMUndeterminedUSA[80]
Antiprotozoalpandaroside G & methyl ester (83,84)/spongeSteroid glycoside eL. donovani & T. brucei rhodesiense inhibition0.04–1.3 µMUndeterminedCUB, CHE, FRA, GBR[81]
AntiprotozoalPlakortis sp. polyketide (85)/spongePolyketide dT. brucei brucei inhibition0.049 µMUndeterminedAUS[82]
Antiprotozoalvalinomycin (86)/bacteriumPeptide fL. major & T. brucei brucei inhibition0.0032–0.11 μMUndeterminedGER,USA[83]
Antituberculosishymenidin (87)/spongeAlkaloid fM. tuberculosis H37Rvinhibition6.1 μg/mL +UndeterminedUSA[84]
Antituberculosistrichoderins A, A1, B (8890)/fungusPeptide fM. tuberculosis H37Rv strain inhibition0.12–2 μg/mL +UndeterminedJPN, ZAF, USA[85]
Antituberculosisneopetrosiamine A (62)/spongeAlkaloid fM. tuberculosis H37Rvinhibition7.5 μg/mL +UndeterminedUSA[71]
Antiviralgyrosanols A & B (91,92)/soft coralTerpene eHuman cytomegalovirus inhibition2.6–3.7 μMUndeterminedTWN[86]
Antivirallobophynin C & ehrenberoxide B (93,94)/coralTerpene eHuman cytomegalovirus inhibition4.7–5.8 μMUndeterminedTWN[87]
Antiviralmanzamine A (95)/spongeAlkaloid fHuman herpes simplex virus-1 inhibition1 μM *Early ICPO gene transcription inhibitedUSA[88]
Antiviralxiamycin (96)/bacteriumAlkaloid f Inhibition of HIV-1 infection7.2 μg/mL *Selective inhibition of CCR5 tropic HIVDEU, CHN[89]
Antiviralbaculiferins (97100)/spongeAlkaloid fInhibition of HIV-1 IIIB replication0.2–7.0 μMBinding to Vif, APOBEC3G & gp41DEU, CHN[90]
Antiviralcelebesides A & C (101,102)/spongePeptide fInhibition of HIV-1 infectivity assay1.9 μg/mLUndeterminedITA, USA[57]
a Organism, Kingdom Animalia: ascidian (Phylum Chordata), bryozoa (Phylum Bryozoa), coral (Phylum Cnidaria), sea cucumber (Phylum Echinodermata), sponge (Phylum Porifera); Kingdom Monera: bacterium (Phylum Cyanobacteria); Kingdom Fungi: fungus; Kingdom Plantae: alga; b IC50: concentration of a compound required for 50% inhibition in vitro, *: estimated IC50; ND: not determined; +MIC: minimum inhibitory concentration; ++MID: minimum inhibitory concentration per disk; b MMOA: molecular mechanism of action; c Country: AUS: Australia; BEL: Belgium; BRA: Brazil; CAN: Canada; CHE: Switzerland; CHN: China; COL: Colombia; CUB: Cuba; DEU: Germany; EGY: Egypt; FJI: Fiji; FRA: France; GBR: United Kingdom; ITA: Italy; JPN: Japan; MEX: Mexico; NCL: New Caledonia; NLD: The Netherlands; NOR: Norway; NZL: New Zealand; PAN: Panama; SGP: Singapore; ZAF: S. Africa; S. KOR: South Korea; THAI: Thailand; TWN: Taiwan; UK: United Kingdom; Chemistry: d Polyketide; e Terpene; f Nitrogen-containing compound; g Polysaccharide, modified as in the text; h Named as sulfites in the original paper.
Figure 1. Marine pharmacology in 2009–2011: Marine compounds with antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities.
Figure 1. Marine pharmacology in 2009–2011: Marine compounds with antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities.
Marinedrugs 11 02510 g001a1Marinedrugs 11 02510 g001a2Marinedrugs 11 02510 g001a3Marinedrugs 11 02510 g001a4Marinedrugs 11 02510 g001a5Marinedrugs 11 02510 g001a6Marinedrugs 11 02510 g001a7Marinedrugs 11 02510 g001a8Marinedrugs 11 02510 g001a9

2.1. Antibacterial Activity

During 2009–2011, 35 studies reported antibacterial marine natural products isolated from a diverse group of marine bacteria, ascidians, bryozoans, sponges, soft corals and algae, a persistent effort on which we have reported previously [7], and which continues to contribute to the global health challenge posed by drug-resistant bacteria.
Only four papers reported molecular mechanism of action studies with marine antimicrobial compounds. Plaza and colleagues investigated bisdiarylbutene macrocycle chrysophaentin A (1) from the chrysophyte alga Chrysophaeum taylori that potently inhibited Gram positive methicillin-resistant Staphylococus aureus (minimum inhibitory concentration [MIC]50 = 1.5 μg/mL) and vancomycin-resistant Enterococcus faecium (MIC50 = 2.9 μg/mL) by binding and inhibiting GTPase activity of the essential bacterial cell division protein FtsZ [29]. Two studies contributed to the ongoing search of quorum sensing antagonists as potentially novel antimicrobial drugs: Teasdale and colleagues extended the pharmacology of two previously described phenethylamide metabolites isolated from a marine Gram positive Halobacillus salinus strain [30]. One of these compounds, 3-methyl-N-(2′-phenylethyl)-butyramide (2) interfered with quorum sensing-regulated activities (e.g., bioluminescence inhibition IC50 = 9 μg/mL) in several Gram negative species. Kwan and colleagues isolated a small cyclopropane-containing fatty acid, lyngbyoic acid (3) from the marine cyanobacterium Lyngbya cf. majuscula [31] that affected both quorum sensing pathways (acylhomoserine lactone receptor LAsR (IC50 = 100 µM) as well as gene expression in Pseudomonas aeruginosa. Jeon and colleagues extended the pharmacology of the pyrroloiminoquinone alkaloids of the discorhabdin class isolated from the Korean marine sponge Sceptrella sp. [32]. A new alkaloid (−)-discorhabdin Z (4), possessing a unique hemiaminal group, inhibited sortase A (IC50 = 6.5 μM), a bacterial transpeptidase that has been shown to covalently attach proteins to the bacterial cell wall and has become an important antimicrobial target.
As shown in Table 1 and Figure 1, several marine chemicals, some of them novel, were reported to exhibit antibacterial activity with MICs < 10 μg/mL or 10 μM against several bacterial strains, although no mechanism of action studies were reported for these compounds: a new alkaloid agelasine D (5) isolated from the marine sponge Agelas nakamurai collected in Bali, Indonesia [33]; the maleimide mixture aqabamycin E (6) discovered in a marine Vibrio sp. growing on the surface of the Red Sea soft coral Sinularia polydactyla [34]; two new cyclodepsipeptides, bacillistatins 1 and 2 (7,8) purified from cultures of the Chilean bacterium Bacillus silvestris obtained from a crab [35]; new diterpene–benzoate macrolides bromophycolides J–Q (914) from the Fijian red alga Callophycus serratus [36]; a novel benzoxazole antibiotic caboxamycin (15) produced by the deep-sea Streptomyces sp. NTK 937 isolated in the Canary Basin [37]; a brominated polyphenyl ether crossbyanol B (16) isolated from the Hawai’ian marine cyanobacterium Leptolyngbya crossbyana [38]; three novel pyridoacridine alkaloids (1719) characterized from the Mediterranean ascidian Cystodytes dellechiajei [39]; the previously-described Fijian Cymbastela hooperi diterpene isonitrile (20) recently re-evaluated [40]; a novel alkaloid eusynstyelamide F (21), isolated from an Arctic bryozoan Tegella cf. spitzbergensis [41]; a novel cembranoid diterpene, knightol (22), found in the Colombian gorgonian octocoral Eunicea knighti [42]; the novel antibiotic MC21-B (23) produced by the marine bacterium Pseudoalteromonas phenolica O-BC-30T [43]; a novel long-chain 2H-azirine 2-carboxylic acid, motualevic acid F (24), described from a Fijian marine sponge Siliquariaspongia sp. [44]; the thiopeptide TP-1161 (25), identified in a Norwegian marine-sediment derived Gram positive Nocardiopsis sp. bacterium [45]; two novel α-pyrone macrolides neurymenolides A and B (26, 27) isolated from the Fijian red alga Neurymenia fraxinifolia [46]; two polybrominated metabolites (28, 29) from a Hawai’ian marine bacterium Pseudoalteromonas sp. found on the surface of a nudibranch [47]; pseudopterosin U (30) discovered in the Caribbean octocoral Pseudopterogorgia elisabethae [48]; 5-bromo-8-methoxy-1-methyl-β-carboline (31), an alkaloid isolated from the New Zealand marine bryozoan Pterocella vesiculosa [49]; a new rifamycin antibiotic, salinisporamycin (32), purified from a culture of the Micronesian marine actinomycete Salinispora arenicora YM23-082 [50]; a novel bioactive alkaloid, synoxazolidinone A (33), discovered in the sub-Arctic Norwegian ascidian Synoicum pulmonaria [51].
Furthermore, during 2009–2011, several marine natural products were noted to have MIC or IC50 ranging from 10 to 50 μg/mL, or 10–50 μM, respectively, and thus because of their lower antibacterial potency were excluded from Table 1 and Figure 1: a novel casbane diterpenoid 10-hydroxydepressin (MIC = 17 μg/mL) from the Hainan soft coral Sinularia depressa [91]; a novel guai-2-en-10α-methyl methanoate from the marine alga Ulva fasciata (MIC = 25–30 μg/mL) [92]; a novel gymnochrome F (MIC = 12.5 μg/mL) from the deep-water crinoid Holopus rangii [93]; several novel fatty acids, ieodomycins (MIC = 32–64 μg/mL), from a marine Bacillus sp. [94]; a novel sulfated sesterterpene alkaloid 19-oxofasciospongine A from a marine sponge Fasciospongia sp. (MIC = 20 μg/disk) [95]; a novel phenalenone derivative (MIC = 24 μM) from the marine-derived fungus Coniothyrium cereale [96]; a novel 4,4′-oxybis[3-phenylpropionic acid] from the marine bacterium Bacillus licheniformis (IC50 = 50 μg/disk) [97]; a novel sargafuran (MIC = 15 μg/mL) from the marine brown alga Sargassum macrocarpum [98]; a novel tetracyclic brominated diterpene (MIC = 32 μg/mL) from the red alga Sphaerococcus coronopifolius [99]; and a new bromotyrosine alkaloid tyrokeradine B (MIC = 25 μg/mL) from a Verongid marine sponge [100].
Finally, during 2009–2011, several publications described novel marine antimicrobial peptides: centrocins 1 and 2, two novel dimeric peptides (MIC = 1.3–2.5 μM) from the Norwegian green sea urchin Strongylocentrotus droebachiensis [101]; halocyntin and papillosin, two new peptides (MIC = 0.75–25 μM) isolated from hemocytes of the Mediterranean ascidian Halocynthia papillosa [102]; and hyastatin, a glycine-rich multi-domain peptide (MIC = 0.4–12.5 μM) from hemocytes of the Norwegian spider crab Hyas araneus [103].

2.2. Antifungal Activity

Ten studies during 2009–2011 reported on the antifungal activity of several novel marine natural products isolated from marine bacteria, sponges and bryozoa, a slight decrease from our last review [7], and previous reviews of this series.
As shown in Table 1, only two reports described antifungal marine chemicals with novel mechanisms of action. DiGirolamo and colleagues identified two new sulfated sterols, geodisterol-3-O-sulfate (34) and 29-demethylgeodisterol-3-O-sulfate (35), in a marine sponge Topsentia sp. [52], which enhanced the activity of the clinically used triazole antifungal agent fluconazole by reversing efflux pump-mediated fluconazole resistance in Candida albicans. Nishimura and colleagues extended the pharmacology of the bicyclic antifungal dodecapeptide theonellamide F (36) previously isolated from a sponge Theonella sp. [53]. Chemical-genomic profiling analysis together with detailed subcellular localization studies determined that the antifungal theonellamides represent a new class of sterol-binding molecules that induce membrane damage and activate Rho1-mediated 1,3-β-d-glucan synthesis.
Furthermore, as shown in Table 1 and Figure 1 several marine natural products showed significant antifungal activity (i.e., MICs that were either less than 10 μg/mL, 10 μM, or 10 μg/disk), although no mechanism of action studies were reported in the published articles: the antibacterial alkaloid 5-bromo-8-methoxy-1-methyl-β-carboline (31) isolated from the New Zealand marine bryozoan Pterocella vesiculosa [49]; a novel linear tetrapeptide citronamide A (37) from the Australian sponge Citronia astra [54]; two holostan-type triterpenoid glycosides, marmoratoside A (38) and 17α-hydroxy impatienside A (39), from the Chinese sea cucumber Bohadschia marmorata [55]; the polyketide saadamycin (40) from an endophytic Streptomyces sp. strain Hedaya 48 isolated from the Egyptian sponge Aplysina fistularis [56], and two novel depsipeptides, theopapuamides B & C (41,42), isolated from the Indonesian marine sponge Siliquariaspongia mirabilis [57]. Future mechanism of action studies with these potent compounds will hopefully characterize their molecular pharmacology.
Finally, several novel structurally-characterized marine molecules demonstrated MICs or IC50s greater than 10 μg/mL or 10 μM, and therefore, because of the reported weaker antifungal activity, have been excluded from Table 1 and Figure 1: the maleimide mixture aqabamycin E (6) (MIC = 50 μg/mL) [34]; the novel antibacterial alkaloid synoxazolidinone A (33) (MIC = 12.5 μg/mL) [51], and the new bromotyrosine tyrokeradine B (MIC = 12.5 μg/mL) [100].
These marine compounds may provide novel pharmacological leads thus contributing to the global search for clinically useful antifungal agents.

2.3. Antiprotozoal and Antituberculosis Activity

As shown in Table 1, during 2009–2011 thirty two studies contributed to novel findings on the antiprotozoal and antituberculosis pharmacology of structurally characterized marine natural products, a considerable increase from previous 1998–2008 reviews [7].
Malaria, which is caused by protozoa from the genus Plasmodium (P. falciparum, P. ovale, P. vivax and P. malariae), affects millions of people worldwide. Contributing to the global search for novel antimalarial drugs, and as presented in Table 1, twenty six novel marine molecules were shown during 2009–2011 to possess antimalarial activity, although mechanism of action studies were reported for only two compounds. Taglialatela-Scafati and colleagues extended the molecular pharmacology of plakortin (43), isolated from the Caribbean marine sponge Plakortis simplex, which potently inhibited CQ-resistant strains of Plasmodium falciparum [58]. Plakortin was observed to give rise to toxic carbon radicals which were ultimately “responsible for subsequent reactions leading to Plasmodium death”. Lebouvier and colleagues reported that the homogentisic acid derivative 44 from a Vanuatu marine sponge Pseudoceratina sp. was moderately active in vitro against FcB1 P. falciparum strain, while concomitantly inhibiting the specific protein kinase pfnek-1 of the parasite (IC50 = 1.8 μM). Thus, compound 44 “could serve as a model for the development of new pfnek-1 inhibitors” [59].
Potent (<2 µM) to moderate (>2–10 µM) antimalarial activity was reported for 24 marine natural products. Laville and colleagues isolated several novel guanidine batzelladine alkaloids (4548) from the Caribbean marine sponge Monanchora arbuscula, which showed potent antimalarial activity against the human malaria parasite Plasmodium falciparum strain FcB1 (IC50 = 0.2–0.9 μM) [60]. Lane and colleagues characterized new diterpene–benzoate macrolides bromophycolides J, M, N, O, P and Q (914) from the Fijian red alga Callophycus serratus with potent antimalarial activity against P. falciparum (IC50 = 0.5–2.9 μM) [36]. Furthermore, Lin and colleagues isolated bromophycolides R, S and U (4951) from the same Fijian red alga Callophycus serratus with potent antimalarial activity (IC50 = 0.9–2.1 μM) against P. falciparum [61]. Davis and colleagues identified a novel β-carboline alkaloid, (+)-7-bromotrypargine (52), from an Australian marine sponge Ancorina sp. with moderate antimalarial activity (IC50 = 3.5–5.4 μM) against both chloroquine resistant (Dd2) and chloroquine-sensistive (3D7) P. falciparum strains [62]. Wright and colleagues reported a diterpene formamide (53) from the tropical marine sponge Cyambastela hooperi that had moderate to potent activity (IC50 = 4.3 ng/mL and 0.5 μg/mL) against P. falciparum strains FCR3F86, W2 and D6 [40,63]. Jiménez-Romero and colleagues contributed a novel five-membered-ring polyketide endoperoxide epiplakinidioic acid (54) from the Puerto Rican sponge Plakortis halichondrioides that was potent (IC50 = 0.3 μg/mL) against the W2 chloroquinone-resistant strain of P. falciparum [64]. Linington and colleagues purified a novel linear peptide, gallinamide A (55), from a cyanobacterium Schizothrix sp. with moderate antimalarial activity (IC50 = 8.4 μM) against chloroquine-resistant P. falciparum, yet with a structure that might become an “attractive foundation for further SAR investigations” [65]. Ueoka and colleagues investigated a new polyketide, gracilioether B (56), from the Japanese marine sponge Agelas gracilis that was potent (IC50 = 0.5 µg/mL) against P. falciparum strain ItG [66]. Wattanapiromsakul and colleagues isolated a new isocyanoditerpene, 8-isocyanoamphilecta-11 (20), 15-diene (57), from a Thai sponge Ciocalapata sp. with potent antimalarial activity (IC50 = 0.98 μM) against P. falciparum chloroquine-resistant strain K1 [67]. Tripathi and colleagues found two new cyclic depsipeptides, lagunamides A (58) and B (59), from the Singaporean marine cyanobacterium Lyngbya majuscula with potent antimalarial activity (IC50 = 0.19–0.91 μM) against the drug-sensitive NF54 P. falciparum strain [68]. Fattorusso and colleagues discovered that a new endoperoxyketal, manadoperoxide C (60), from the Indonesian sponge Plakortis cf. simplex, had moderate in vitro antiplasmodial activity (IC50 = 2.3 μM) against the W2 chloroquinone-resistant strain of P. falciparum as well as provided further insight into “the structure activity relationships of simple 1,2-dioxane antimalarials” [69]. Yamada and colleagues identified a novel alkaloid 3,4-dihydro-manzamine J N-oxide (61) from an Okinawan marine sponge Amphimedon sp. with potent in vitro antiplasmodial activity (IC50 = 0.58 μg/mL) against the K1 strain of P. falciparum [70]. Wei and colleagues extracted a new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (62), from the Puerto Rican marine sponge Neopetrosia proxima with moderate antiplasmodial activity (IC50 = 2.3 μM) against P. falciparum and low concomitant cytotoxicity to Vero cells [71]. Yang and colleagues extended the pharmacology of the known bromotyrosine alkaloid psammaplysin F (63) from an Australian marine sponge Hyattella sp. by reporting potent inhibition (IC50 = 0.87–1.4 μM) of P. falciparum 3D7 and Dd2 strains [72].
Eighteen marine compounds were reported to possess activity against other protozoa thus contributing to the ongoing global search for novel agents for the so-called neglected diseases, namely leishmaniasis (caused by several species of the genus Leishmania), amebiasis, trichomoniasis, African sleeping sickness (caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense) and American sleeping sickness or Chagas disease (caused by Trypanosoma cruzi). Dos Santos and colleagues reported that a 4-acetoxydolastane diterpene (64) isolated from the Brazilian brown alga Canistrocarpus cervicornis [73] dose-dependently inhibited promastigote, axenic amastigote and intracellular amastigote forms of Leishmania amazonensis (IC50 = 2.0, 12.0 and 4.0 μg/mL, respectively) by extensive mitochondrial damage and lipid peroxidation.
As shown in Table 1 and Figure 1, several marine natural products were characterized to exhibit antiprotozoal activity, although the mechanism of action of these compounds remains undetermined. Vik and colleagues completed a comprehensive screening of agelasine terpene analogs from a marine sponge Agelas sp. and reported that four agelasine analogs (6568) potently inhibited Leishmania infantum, T. brucei brucei and T. cruzi (IC50 = 0.093–0.11; 0.11–0.23; 0.11–0.43 μg/mL, respectively) with low concomitant cytotoxicity, suggesting they could become novel leads for design of “potent and selective drugs” [74]. Sanchez and colleagues found two novel linear lipopeptides, almiramides B and C (69,70), from the marine cyanobacterium Lyngbya majuscula that inhibited the protozoan parasite Leishmania donovani (IC50 = 1.9–2.4 μM) with minimal cytotoxicity towards Vero cells (IC50 = 33.1–52.3 μM) [75]. Davis and colleagues investigated a new brominated alkaloid, convolutamine I (71), from the bryozoan Amathia tortusa that was highly active towards the parasite Trypanosoma brucei brucei (IC50 = 1.1 μM), yet presenting low cytotoxicity in human embryonic kidney cells (IC50 = 22.0 μM) [76]. Scala and colleagues completed the first antiprotozoal screening of marine bromopyrrole alkaloids isolated from the marine sponges Axinella verrucosa and Agelas dispar and determined that longamide B (72) and dibromopalau’amine (73) inhibited Trypanosoma brucei rhodesiense (IC50 = 1.53 & 0.46 μg/mL, respectively), and Leishmania donovani (IC50 = 3.85 & 1.09 μg/mL, respectively), with low cytotoxicity [77]. Cantillo-Ciau and colleagues isolated two known and one novel sulfoquinovosyl diacylglycerols (7476) from the Mexican tropical brown alga Lobophora variegata with high antiprotozoal activity against E. histolytica (IC50 = 3.9 μg/mL) and moderate activity towards Trichomonas vaginalis trophozoites (IC50 = 8.0 μg/mL), and with a good selectivity index (SI > 10) [78]. Yamada and colleagues characterized a novel alkaloid 3,4-dihydro-manzamine J N-oxide (61) from an Okinawan marine sponge Amphimedon sp. which displayed moderate in vitro activity against Trypanosoma brucei brucei (IC50 = 0.27 μg/mL) [70]. Rubio and colleagues evaluated several known peroxiterpenes as well as a novel (+)-muqubilone B (77) from the Papua New Guinea marine sponge Diacarnus bismarckensis shown to inhibit Trypanosoma brucei brucei (IC50 = 2 μg/mL), concluding that these marine chemicals could become “therapeutic leads” against T. brucei [79]. Ma and colleagues identified novel highly oxidized steroids norselic acids A–E (7882) isolated from an Antarctic marine sponge Crella sp. which moderately inhibited Leishmania sp. (IC50 = 2.0–3.6 μM) [80]. Regalado and colleagues reinvestigated the Caribbean sponge Pandaros acanthifolium and discovered that among several new steroidal glycosides, both pandaroside G (83) and pandaroside G methyl ester (84) potently inhibited the growth of Trypanosoma brucei rhodesiense (IC50 = 0.8 and 0.038 μM, respectively), and Leishmania donovani (IC50 = 1.3 and 0.051 μM, respectively) but with rather high concomitant cytotoxicity [81]. Feng and colleagues isolated a novel cyclic polyketide peroxide, 11,12-didehydro-13-oxo-plakortide Q (85), from an Australian marine sponge Plakortis sp. with significant activity (IC50 = 0.049 μM) against Trypanosoma brucei brucei [82]. Pimentel-Elardo and colleagues reported the isolation of the known cyclic depsipeptide valinomycin (86) from marine Streptomyces sp. strains associated with several Croatian marine sponges, and observed significant activity against both Trypanosoma brucei brucei (IC50 = 0.0032 μM) and Leishmania major (IC50 < 0.11 μM) [83].
As shown in Table 1, four novel marine natural products contributed to the global search for novel antituberculosis agents, a decrease from our previous reviews [7].
Vicente and colleagues extended the pharmacology of the known compound hymenidin (87) from the Puerto Rican marine sponge Prosuberites laughlini by demonstrating its antimycobacterial activity (MIC = 6.1 μg/mL) against M. tuberculosis H37Rv [84]. Pruksakorn and colleagues isolated three new aminolipopeptides, trichoderins A (88), A1 (89) and B (90) from a marine sponge-derived fungus Trichoderma sp. that potently inhibited (MIC = 0.02–2.0 μg/mL) the M. tuberculosis strain H37Rv under both aerobic and dormancy-inducing conditions [85]. Wei and colleagues isolated tetracyclic bis-piperidine alkaloid neopetrosiamine A (62) from the Puerto Rican marine sponge Neopetrosia proxima which inhibited growth (MIC = 7.5 μg/mL) of the pathogenic strain Mycobacterium tuberculosis H37Rv [71]. Although all of these studies demonstrate that marine alkaloids and peptides may potentially become novel antituberculosis leads, further studies are required to determine the molecular pharmacology of these compounds.

2.4. Antiviral Activity

As shown in Table 1, three reports were published during 2009–2011 on the antiviral pharmacology of novel marine natural products against human cytomegalovirus and herpes simplex virus. Cheng and colleagues purified two new diterpenoids, gyrosanols A and B (91,92), and two novel cembranoids, lobophynin C and ehrenberoxide B (93,94), from the Taiwanese soft corals Sinularia capillosa and Sarcophyton ehrenbergi, respectively, which inhibited the herpes virus-5 or cytomegalovirus (HCMV) (IC50 = 2.6–5.8 μM), an interesting preclinical contribution because HCMV infections may be life-threatening in immunocompromised patients [86,87]. Palem and colleagues extended the pharmacology of the known β-carboline alkaloid manzamine A (95), isolated from an Indo-Pacific sponge Acanthostrongylophora sp., by demonstrating the compound inhibited HSV-1 infection (apparent IC50 = 1 μM) in rabbit corneal cells by affecting viral immediate-early gene transcription [88].
Three articles reported preclinical pharmacology of marine compounds active against the human immunodeficiency virus type-1 (HIV-1), the causative agent of the acquired immunodeficiency disease syndrome (AIDS), a decrease from our previous review [7]. Ding and colleagues investigated the novel pentacyclic indolosesquiterpene xiamycin (96) isolated from the Streptomyces sp. GT2002/1503 bacterium and demonstrated selective inhibition against macrophage and T cell β-chemokine receptor CCR5 (5) tropic HIV-infection (estimated IC50 = 7.2 μg/mL), with no effect against α-chemokine receptor CXCR4 (X4) tropic HIV [89]. Fan and colleagues isolated several DOPA-derived pyrrole alkaloids, baculiferins I, J, L and M (97100), from the Chinese marine sponge Iotrochota baculifera, which were found to be potent inhibitors of HIV-1 IIIB (IC50 = 0.2–7.0 μM) by binding to the HIV target proteins Vif, APOBEC3G, and gp41 in an as yet undetermined mechanism [90]. Plaza and colleagues isolated several new cyclic depsipeptides from the Indonesian marine sponge Siliquariaspongia mirabilis including celebesides A and C (101102), which inhibited HIV-1 in an infectivity assay (IC50 = 1.9 ± 0.4 μg/mL), thus correlating the anti-HIV activity of these compounds with the presence of phosphoserine [57].

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

Table 2 presents the preclinical pharmacology of marine chemicals (103162) which demonstrated antidiabetic and anti-inflammatory activity, as well as affected the immune and nervous system, and whose structures are shown in Figure 2.
Table 2. Marine pharmacology in 2009–2011: Marine compounds with antidiabetic and anti-inflammatory activity; and affecting the immune and nervous system.
Table 2. Marine pharmacology in 2009–2011: Marine compounds with antidiabetic and anti-inflammatory activity; and affecting the immune and nervous system.
Drug ClassCompound/organism a+ChemistryPharmacological activityIC50 bMMOA cCountry dReferences
AntidiabeticDPHC (103)/algaPolyketide ePostprandial hyperglycemia inhibition100 mg/kg *α-glucosidase and α-amylase inhibitionS. KOR[104]
Antidiabeticdysidine (104)/spongeTerpene fInsulin signaling and glucose uptake6.7 μMhPTP1b inhibitionCHN[105,106]
Anti-inflammatoryarenamides A & B (105,106)/bacteriumPeptide gModulation of LPS-activated murine macrophages in vitro3–10 μM *Nitric oxide and PGE2 inhibitionUSA[107]
Anti-inflammatorycallysterol (107)/spongeSteroid fMurine hind paw oedema inhibitionNDTXB2 inhibitionEGY, NLD, USA[108]
Anti-inflammatorycapnellene (108)/soft coralTerpene fIn vivo inhibition of microglia activation10 mg/kg *iNOS and COX-2 inhibitionTWN[109]
Anti-inflammatoryelisabethin H (109)/soft coralTerpene fModulation of LPS-activated microglia in vitro7.0 μMTXB2 inhibitionUSA[110]
Anti-inflammatoryfloridosides (110,111)/algaGlycolipidFree-radical oxidative stress inhibition22–43 μM *Myeloperoxidase & MMP inhibitionS.KOR & CHN[111]
Anti-inflammatorymalyngamide 2 (112)/bacteriumPKS/NRPSLPS-activated macrophage in vitro inhibition8.0 μMNO inhibitionPNG, USA[112]
Anti-inflammatorymalyngamide F (113)/bacteriumPKS/NRPSMacrophages NO release & iNOS expression inhibition7.1 μMMyD88-dependent pathway inhibitionUSA[113]
Anti-inflammatoryPFF-A (114)/algaPolyketide eLPS-activated macrophage in vitro inhibition4.7 μMiNOS and COX-2 inhibitionS. KOR[114]
Anti-inflammatoryS. plicata dermatan sulfate (115)/ascidianPolysaccharide hColonic inflammation inhibition8 mg/kg *TNF-α, TGF-β, VEGF inhibitionBRA[115]
Anti-inflammatorysymbiopolyol (116)/dinoflagellatePolyketide eLymphocyte adhesion inhibition6.6 μMVCAM-1 expression inhibitionJPN[116]
Anti-inflammatorytedanol (117)/spongeTerpene fMurine hind paw oedema inhibition1 mg/kg *iNOS, COX-1 and COX-2 inhibitionITA[117]
Anti-inflammatorycarijoside A (118)/coralSteroid glycoside fNeutrophil superoxide and elastase inhibition1.8–6.8 μg/mLUndeterminedTWN[118]
Anti-inflammatorychabrosterol (119)/soft coralSteroid fMacrophage COX-2 & iNOS expression inhibition10 μM *UndeterminedTWN[119]
Anti-inflammatorycoscinolactams (120122)/spongeTerpene fMacrophage PGE2 & nitric oxide inhibition10 μM *UndeterminedITA, ESP, FRA[120]
Anti-inflammatorydurumhemiketalolide C (123)/soft coralTerpene fMacrophage COX-2 & iNOS expression inhibition10 μM *UndeterminedTWN[121]
Anti-inflammatorydurumolide F (124)/soft coralTerpene fMacrophage COX-2 & iNOS expression inhibition10 μM *UndeterminedTWN[122]
Anti-inflammatorygyrosanolides B & C (125,126)/soft coralTerpene fMacrophage iNOS expression inhibition10 μM *UndeterminedTWN[123]
Anti-inflammatoryklysimplexin sulfoxide (127) soft coralTerpene fMacrophage COX-2 & iNOS expression inhibition10 μM *UndeterminedTWN[124]
Anti-inflammatoryL. crassum diterpenes (128,129)/soft coralTerpene fMacrophage NO release & iNOS expression inhibition3.8–4.0 μMUndeterminedJPN[125]
Anti-inflammatoryperthamides C & D (130,131)/spongePeptidegMurine hind paw oedema inhibition0.3 mg/kg *UndeterminedFRA, ITA[126]
Anti-inflammatoryrossinones A & B(132,133)/ascidianTerpene fNeutrophil superoxide inhibition0.8–2.5 μMUndeterminedMYS, NZL[127]
Anti-inflammatorynebrosteroid I (134)/soft coralSteroid fMacrophage iNOS expression inhibition10 μM *UndeterminedTWN[128]
Anti-inflammatorysarcoehrenosides A & B (135,136)/soft coralGlycolipidMacrophage iNOS expression inhibition10 μM *UndeterminedTWN[129]
Anti-inflammatorysarcocrassocolides A & B(137,138)/soft coralTerpene fMacrophage iNOS expression inhibition10 μM *UndeterminedTWN[130]
Anti-inflammatorysimplexin E (139)/soft coralTerpene fMacrophage COX-2 & iNOS expression inhibition10 μM *UndeterminedTWN[131]
Anti-inflammatoryterpioside B (140)/spongeGlycolipidMacrophage iNOS expression inhibition<10 μM *UndeterminedITA[132]
Immune systemgrassystatins A–C (141143)/bacteriumPeptide gT cell antigen presentation inhibition10 μM *Cathepsin E, IL-17 and IFN-γ inhibitionUSA[133]
Immune systemcallyspongidiol (144) & 14,15-dihydrosiphonodiol (145)/spongePolyketide eDendritic cell activation10 μM *IL-10 and Ag-presenting activityDEU, JPN[134]
Immune systemPFF-A (114)/algaPolyketide eBasophil IgE receptor inhibition25 μM *Ca2+ influx and degranulation inhibitionS. KOR[135]
Immune systemsplenocin B (146)/bacteriumPKS/NRPSInterleukin 5 and 13 Inhibition1.6–1.8 nMUndeterminedUSA[136]
Immune systemHCLPS-1 (147)/clamPolysaccharide hIn vivo & in vitro T and B cell activation20 mg/kg *UndeterminedCHN[137]
Immune systemyessotoxin (148)/algaPolyketide(polyether) eMacrophage phagocytosis inhibition1 nM *TNF-α, MIP-1α & MIP-2 inhibitionITA[138]
Nervous systemcalyculin A (149)/spongePKS/NRPS eHippocampal neuron neurite retraction100 mM *Dependent on actomyosin activationJPN[139]
Nervous systemC. olemda purine (150)/spongeAlkaloid gConvulsion induction4 nm/mouse *GABAergic transmission inhibitionJPN, USA[140]
Nervous systemhoiamide B (151)/bacteriumPeptide gNeocortical neuron Ca2+ oscillation inhibition79.8 nMStimulation of sodium influxITA, PNG, USA[141]
Nervous systempalmyrolide A (152)/bacteriumPolyketide eNeocortical neuron Ca2+ oscillation inhibition3.7 µMSodium influx inhibitionMEX, USA[142]
Nervous systemxyloketal B (153)/fungusPolyketide eIschemia-induced PC12 cell injury inhibition100 µM *Free radical scavengingCHN[143]
Nervous systemalotamide (154)/bacteriumPKS/NRPS gNeocortical neuron Ca2+ oscillation stimulation4.18 μMUndeterminedMEX, USA[144]
Nervous system(−)-dibromophakellin (155)/spongeAlkaloid gΑ2B adrenoreceptor agonist4.2 µMUndeterminedAUS[145]
Nervous systemdysideamine (156)/spongeTerpene eHippocampal reactive oxygen species inhibition10 µM *UndeterminedIDN, JPN[146]
Nervous systemircinialactams (157,158)/spongeTerpene fα1 & α3 glycine receptor potentiation0.5 µM *UndeterminedAUS[147]
Nervous systemeusynstyelamides B & C (159,160)/ascidianPeptide g Neuronal nitric oxide synthase inhibition4.3–5.8 µMUndeterminedAUS[148]
Nervous systemnanolobatolide (161)/soft coralTerpene f6-hydroxy-dopamine neurotoxicity inhibition0.1 µM *UndeterminedTWN[149]
Nervous systempulicatin A (162)/bacteriumAlkaloid gHuman serotonin 5-HT2B binding505 nM **UndeterminedPHL, USA[150]
a Organism: Kingdom Animalia: ascidian (Phylum Chordata), coral (Phylum Cnidaria), clam (Phylum Mollusca), fireworm (Phylum Polychaeta), sponge (Phylum Porifera); Kingdom Chromalveolata: dinoflagellates (Phylum Dinoflagellata); Kingdom Fungi: fungus; Kingdom Plantae: alga; Kingdom Monera: bacterium; b IC50: concentration of a compound required for 50% inhibition, *: apparent IC50; **: Ki; ND: not determined; c MMOA: molecular mechanism of action, NO: nitric oxide; d Country: AUS: Australia; BRA: Brazil; CHN: China; DEU: Germany; EGY: Egypt; ESP: Spain; FRA: France; IDN: Indonesia; ITA: Italy; JPN: Japan; MEX: Mexico; MYS: Malaysia; NLD: The Netherlands; NZL: New Zealand; PNG: Papua New Guinea; PHL: Phillipines; S.KOR: South Korea; TWN: Taiwan; e Chemistry: Polyketide; f Terpene; g Nitrogen-containing compound; h polysaccharide, modified as in the text.
Figure 2. Marine pharmacology in 2009–2011:Marine compounds with antidiabetic and anti-inflammatory activity; and affecting the immune and nervous system.
Figure 2. Marine pharmacology in 2009–2011:Marine compounds with antidiabetic and anti-inflammatory activity; and affecting the immune and nervous system.
Marinedrugs 11 02510 g002a1Marinedrugs 11 02510 g002a2Marinedrugs 11 02510 g002a3Marinedrugs 11 02510 g002a4Marinedrugs 11 02510 g002a5

3.1. Antidiabetic Activity

Heo and colleagues extended the pharmacology of diphlorethohydroxycarmalol [DPHC] (103), previously isolated from the marine brown alga Ishige okamurae, by showing that DPHC alleviated postprandial hyperglycemia in diabetic mice by potent inhibition of both α-glucosidase and α-amylase enzymes (IC50 = 0.16 and 0.53 nM, respectively) suggesting a possible use of DPHC “as a nutraceutical or functional food for diabetes” [104]. Li and colleagues evaluated the known sesquiterpene dysidine (104) from the Hainan marine sponge Dysidea villosa, and revealed that it activated the insulin pathway by inhibition of human protein phosphatase 1B (IC50 = 6.70 µM), a well characterized drug target for type-II diabetes and obesity treatment, as well as glucose uptake and glucose transporter 4 translocation in vitro [105,106].

3.2. Anti-Inflammatory Activity

There was a remarkable increase in marine anti-inflammatory pharmacology research during 2009–2011. The molecular mechanism of action of several marine natural products, which were shown in preclinical pharmacological studies to target neutrophils and macrophages both in vitro and in vivo, was reported in several publications. Asolkar and colleagues described two new cyclohexadepsipeptides arenamides A and B (105,106), isolated from the Fijian bacterium Salinispora arenicola, that inhibited LPS-induced murine macrophage RAW 264.7 cells PGE2 and NO production in vitro, by affecting NFκB signaling activity (IC50 = 3.7 and 1.7 μM, respectively), thus highlighting their “anti-inflammatory characteristics” [107]. Three publications yielded potentially novel compounds targeting proinflammatory mediators released by activated brain microglia, a macrophage involved in neuroinflammation and neurodegeneration [151]: Youssef and colleagues described a new steroid callysterol (107) from the Red Sea sponge Callyspongia siphonella, which potently inhibited rat hind paw edema with an activity close to cortisone, and also reduced TXB2 release from LPS-activated rat brain microglia (apparent IC50 > 10 μM) [108]. Jean and colleagues observed that the sesquiterpene capnellene (108) isolated from the Indonesian soft coral Capnella imbricate, attenuated expression of inducible cyclooxygenase-2 both in activated microglia in vitro and in vivo, suggesting it might contribute to “the search for new therapeutic agents for treatment of neuroinflammatory diseases” [109]. Shi and colleagues isolated a new terpene, elisabethin H (109) from the Caribbean gorgonian octocoral Pseudopterogorgia elisabethae, which significantly inhibited superoxide anion (O2) generation from E. coli LPS activated rat neonatal microglia in vitro (IC50 = 7 μM) [110]. Li and colleagues reported that the floridosides (110,111), isolated from the South Korean marine red alga Laurencia undulata, possessed significant antioxidant capacity and inhibited the proinflammatory matrix metalloproteinases MMP-2 and MMP-9, thus suggesting they might be candidates for further development as natural marine antioxidants [111]. Three publications investigated inhibition of pro-inflammatory mediators released by activated macrophage cell lines: Malloy and colleagues reported that the lipopeptide malyngamide 2 (112) from the Papua New Guinea marine cyanobacterium Lyngbya sordida inhibited nitric oxide production in LPS-primed RAW 264.7 macrophage cells (IC50 = 8.0 μM) [112]. In a detailed mechanistic study Villa and colleagues investigated the lipopeptide malyngamide F (113) from the marine cyanobacterium Lyngbya majuscula showing that it inhibited nitric oxide production in LPS-primed RAW 264.7 macrophage cells (IC50 = 7.1 μM) by selectively inhibiting the MyD88-dependent pathway of TLR4 and 9, thus potentially becoming a “useful tool” in cellular biology [113]. Kim and colleagues extended previous studies with the phlorotannin phlorofucofuroeckol A (PFF-A) (114), isolated from the Korean brown alga Ecklonia stolonifera, by demonstrating its antioxidant activity was of similar potency to vitamin C, and that it inhibited nitric oxide and PGE2 production (apparent IC50 = 5–10 μM) by downregulation of iNOS and COX-2 protein expression in LPS-primed RAW 264.7 macrophage cells [114]. Using an in vivo rat colitis model, Belmiro and colleagues provided a detailed molecular characterization of the anti-inflammatory properties of a dermatan sulfate (115), analog of mammalian heparin, purified from the Brazilian ascidian Styela plicata, which at 8 mg/kg per day significantly decreased lymphocyte and macrophage recruitment as well as TNF-α, TGF-β, and VEGF production in the inflamed rat colon [115]. Hanif and colleagues reported that the highly hydroxylated long-chain sulfate symbiopolyol (116), isolated from a symbiotic dinoflagellate of the jellyfish Mastigias papua significantly inhibited (K50 = 6.6 μM) the expression of the inducible adhesion vascular cell adhesion molecule-1 which binds to leukocytes present in early stages of inflammation, and thus might become a “potential anti-inflammatory agent” [116]. Costantino and colleagues reported that tedanol (117), a new brominated and sulfated pimarane diterpene isolated from the Caribbean sponge Tedania ignis, significantly reduced both the acute and subchronic phases of carrageenan-induced inflammation at 1 mg/kg with concomitant inhibition of both COX-2, iNOS expression and cellular infiltration [117].
As shown in Table 2 and in contrast to the marine anti-inflammatory compounds previously discussed, while an anti-inflammatory activity and IC50 were reported, the molecular mechanism of action remained undetermined for the following marine compounds: carijoside A (118) [118]; chabrosterol (119) [119]; coscinolactams (120122) [120]; durumhemiketalolide C (123) [121]; durumolide F (124) [122]; gyrosanolides B and C (125,126) [123]; klysimplexin sulfoxide C (127) [124]; L. crassum diterpenes (128,129) [125]; perthamides C and D (130,131) [126]; rossinones A and B (132,133) [127]; nebrosteroid I (134) [128]; sarcoehrenosides A and B (135,136) [129]; sarcocrassocolides A & B (137,138) [130]; simplexin E (139) [131]; and terpioside B (140) [132].

3.3. Marine Compounds with Activity on the Immune System

In 2009–2011, immune system pharmacology of marine compounds showed a considerable decrease from our previous review.
Kwan and colleagues isolated the linear peptides grassystatins A–C (141143) from a marine cyanobacterium identified as Lyngbya cf. confervoides, demonstrating that the compounds selectively inhibited aspartic protease cathepsin E (IC50 = 0.3–0.8 nM) versus cathepsin D, as well as antigen-stimulated T cell proliferation, with a concomitant reduction of IL-17 and interferon γ [133]. Takei and colleagues reported that the known compounds callyspongidiol (144) and 14,15-dihydrosiphonodiol (145), isolated from a marine sponge Callyspongia sp., activated both functional and phenotypic maturation of human monocyte-derived dendritic cells, as well as higher interleukin-10 production by T cells, thus revealing potential use in autoimmune diseases and cancer [134]. Shim and colleagues observed that the phloroglucinol derivative phlorofucofuroeckol A (PFF-A) (114), purified from the Korean marine seaweed Ecklonia stolonifera, reduced the expression of the human basophil FcεR1 receptor (apparent IC50 = 25 µM), as well as intracellular [Ca2+]i and histamine release, findings which may be relevant for regulation of IgE-mediated allergic reactions [135]. Strangman and colleagues discovered novel splenocin B (146) isolated from the marine bacterium Streptomyces species strain CNQ431 that displayed potent inhibition of murine splenocyte-derived TH2 cytokines interleukin 5 and 13 (IC50 = 1.6–1.8 nM), thus contributing to the development of a “splenocin-derived drug” for allergic inflammation [136]. Dai and colleagues isolated a water soluble polysaccharide HCLPS-1 (147) from the Chinese pearl-producing mollusc Hyriopsis cumingii Lea, which stimulated murine spleen lymphocyte proliferation in vitro and in vivo in a concentration-dependent manner (apparent IC50 less than 20 mg/kg), suggesting HCLPS-1 might become a “potential natural immunomodulator” upon further pharmacological study [137]. Orsi and colleagues contributed to the immunopharmacology of the sulfated dinoflagellate polyether yessotoxin (148), by demonstrating that it decreased macrophage phagocytic activity against the fungus Candida albicans (apparent IC50 = 1 nM), affected the cytoskeleton by inducing F-actin re-organization, and enhanced release of the cytokine TNF-α and chemokines MIP-1α and MIP-2 [138].

3.4. Marine Compounds Affecting the Nervous System

As shown in Table 2, the nervous system pharmacology of marine natural products in 2009–2011 involved some areas of neuropharmacology, namely neuronal neurite retraction, neurotransmission inhibition, neuronal Ca2+ oscillations and free radical inhibition.
Marine natural products have previously been reported to affect neuritogenesis [7], a process required by neurons to respond to the extracellular environment to form synaptic connections. Inutsuka and colleagues contributed novel molecular studies on the effect of calyculin A (149) on neurons, demonstrating that rapid rat hippocampal neuron neurite retraction (apparent IC50 = 100 mM) induced by the toxin was dependent on actin filament polymerization or myosin II motor, yet independent of the microtubule polymerization status, and perhaps resulted from dephosphorylation of myosin light chain kinase [139]. Sakurada and colleagues reported that the novel Palauan sponge Cribrochalina olemda purine (150), which elicited convulsions upon intracerebroventricular injections in mice (4 nM/mouse), inhibited GABAergic transmission in hippocampal neurons [140]. Noteworthy was the author’s observation that this marine purine was “closely related in structure to endogenous neurosignaling molecules and commonly used CNS stimulants”.
As shown in Table 2, two marine compounds (151,152) identified as part of a drug discovery screening program, were shown to inhibit neuronal Ca2+ oscillations, a network phenomenon that appears to depend on voltage-gated sodium channel activation. Choi and colleagues reported that a cyclic depsipeptide hoiamide B (151), isolated from a Papua New Guinean cyanobacteria assemblage of Symploca sp. and Oscillatoria cf. sp., stimulated sodium influx (IC50 = 3.9 µM) in murine neuronal cells in vitro by putative activation of site 2 on the sodium channel, while suppressing spontaneous Ca2+ (IC50 = 79.8 nM) with greater potency, thus revealing that hoiamide B may have more than one molecular target [141]. Pereira and colleagues contributed a novel marine macrolide palmyrolide A (152) isolated from Northern Pacific Palmyra Atoll cyanobacteria assemblages of Leptolyngbya cf. and Oscillatoria sp. that inhibited both sodium influx (IC50 = 5.2 µM) in mouse neuroblastoma cells and spontaneous Ca2+ oscillations (IC50 = 3.7 µM) in primary cultures of murine cerebrocortical neurons, “making it an intriguing candidate for further pharmacological exploration” [142]. Zhao and colleagues reported that the known compound xyloketal B (153), isolated from the marine mangrove fungus Xylaria sp., inhibited ischemia-induced PC12 cell injury (IC50 = 100 µM) by a neuroprotective mechanism involving free radical scavenging and reduction of mitochondrial membrane potential and superoxide generation, suggesting further development for effective stroke therapy [143].
Finally, and as presented in Table 2, during 2009–2011, several other marine compounds were reported to affect the nervous system by demonstrating pharmacological activity on Ca2+ oscillations, several receptors, and neuronal nitric oxide synthase, yet the mechanism of action of these compounds remained undetermined: alotamide A (154) [144], (−)-dibromophakellin (155) [145], dysideamine (156) [146], ircinialactams (157,158) [147], eusynstyelamides B and C (159,160) [148], nanolobatolide (161) [149], and pulicatin A (162) [150].

4. Marine Compounds with Miscellaneous Mechanisms of Action

Table 3 presents the 2009–2011 preclinical pharmacology of 68 marine compounds (163226) with miscellaneous mechanisms of action, with their respective structures shown in Figure 3. Because additional in vitro and in vivo pharmacological data for these compounds remained unpublished, assignment of these marine compounds to a particular drug class was not possible.
As shown in Table 3, the peer-reviewed literature reported a pharmacological activity, an IC50, and a molecular mechanism of action for 21 marine natural products: bisebromoamide (163) [152]; botryllamides I and J (164,165) [153]; dysidine (104) [106]; Ecklonia cava phlorotannins (166,167) [154]; fucophlorethols (168,169) [155]; gonad-stimulating substance (GSS) (170) [156]; halichlorine (171) [157]; hoiamide A (172) [158]; hypochromins A and B (173,174) [159]; mycothiazole (175) [160]; Mycale sp. pyrroles (176,177) [161]; neocomplanines A and B (178,179) [162]; pateamine A (180) [163]; polytheonamide B (181) [164]; and zampanolide (182) [165].
In contrast, although a pharmacological activity was described, and an IC50 for inhibition of an enzyme or receptor determined, detailed molecular mechanism of action studies were unavailable at the time of publication for the following 47 marine compounds included in Table 3: alotaketals A and B (183,184) [166]; aquastatin A (185) [167]; australin E (186) [168]; lyngbyastatins 9 & 10 (187,188) [169]; brunsvicamides A, B and C (189191) [170]; carteriosulfonic acids A, B and C (192194) [171]; Carteriospongia foliascens sesterterpenoids (195,196) [172]; clavatadines D and E (197,198) [173]; fibrosterol sulfates A and B (199,200) [174]; gracilin L (201) [175]; grassystatins A, B and C (141143) [133]; 2-hydroxycircumdatin C (202) [176]; jaspaquinol (203) [177]; largamides A, B and C (204206) [178]; largamide D oxazolidine (207) [179]; Laurencia similis brominated metabolites (208,209) [180]; molassamide (210) [181]; myrothenone A (211) [182]; 42-hydroxy-palytoxin (212) [183]; plectosphaeroic acids A, B and C (213215) [184]; puupehenone (216) [177]; Sinularia numerosa oxylipin (217) [185]; sipholenone E (218) [186]; spartinoxide (219) [187]; 23-nor-spiculoic acid B (220) [188]; tanikolide dimer (221) [189]; tamulamides A and B (222,223) [190]; terretonins E and F (224,225) [191]; and tetrangulol methyl ether (226) [192].
Table 3. Marine pharmacology in 2009–2011: Marine compounds with miscellaneous mechanisms of action.
Table 3. Marine pharmacology in 2009–2011: Marine compounds with miscellaneous mechanisms of action.
Compound/Organism aChemistryPharmacological ActivityIC50 bMMOA cCountry dReferences
bisebromoamide (163)/cyanobacteriumPeptide gIn vitro tumor growth inhibition0.040 μMERK inhibitionJPN[152]
botryllamide I & J (164,165)/ascidianShikimate gMultidrug resistance inhibition27–41 μMABCG2 transporter inhibitionUSA[153]
dysidine (104)/spongeTerpene fInsulin pathway activation10 μMProtein tyrosine phosphatase 1B inhibitionCHN[106]
E. cava phlorotannins (166,167)/algaPolyketide e In vitro antioxidants DPPH, hydroxyl, peroxyl, & superoxide scavengingCHN, S. KOR[154]
fucophlorethols (168,169)/algaPolyketide e DPPH radical scavenging10–14 μMCytochrome P450 CYP1A inhibitionDEU, ISR[155]
GSS (170)/starfishPeptide gOocyte maturation and ovulation2 nMcAMP productionJPN[156]
halichlorine (171)/spongeAlkaloid (polyketide) gInhibition of vascular contractility3 μM *L-type Ca2+ channel inhibitionJPN[157]
hoiamide A (172)/bacteriumPeptide gVoltage-gated sodium channel activator2.3 μMSodium channel site 2 activatorUSA[158]
hypochromin A & B (173,174)/fungusPolyketide e Angiogenesis inhibition13 & 50 μMTyrosine kinase inhibitionJPN[159]
mycothiazole (175)/spongePKS/NRPSAngiogenesis inhibition10 nM *Mitochondrial complex 1 inhibitionUSA[160]
Mycale sp. metabolites (176,177)/spongePolyketide eHypoxia-inducible factor-1 inhibition7.8–8.6 μMMitochondrial electron transport chain inhibitionUSA[161]
neocomplanines A & B (178,179)/firewormPolyketide eMurine footpad inflammationNDPKC activationJPN[162]
pateamine A (180)/spongePKS/NRPSNonsense-mediated mRNA inhibition100 nM *Binding to eukaryotic initiation factor 4AIIIDEU, USA[163]
polytheonamide B (181)/spongePeptide gCytotoxic mammalian channel formation14–29 nMSelectivity towards Cs + cationJPN[164]
zampanolide (182)/spongePolyketide eG2/M cell cycle arrest8 nM *Microtubule bundle formation by tubulin polymerizationNZL[165]
alotaketals A & B (183,184)/spongeTerpene fcAMP cell signaling activation18 & 240 nMUndeterminedCAN, NLD, PAP[166]
aquastatin (185)/fungusPolyketide e Protein phosphatase 1B inhibition0.19 μMUndeterminedS. KOR[167]
australin E (186)/soft coralTerpene fInositol 5-phosphatase SHIP1 activation>100 μMUndeterminedCAN[168]
lyngbyastatins 9 & 10 (187,188)/bacteriumPeptide gElastase and chymotrypsin inhibition0.2–9.3 μMUndeterminedUSA[169] *
brunsvicamides A–C (189191)/bacteriumPeptide gElastase inhibition2.0–4.4 μMUndeterminedDEU[170]
carteriosulfonic acids A, B & C (192194)/spongePolyketide e GSK-3β inhibition6.8–12.5 µMUndeterminedSGP, USA[171]
Carteriospongia foliascens sesterterpenoids (195,196)/spongeTerpene fHuman Ras-converting enzyme inhibition4.2 μg/mL *UndeterminedCAN, IDN,NLD, USA[172]
clavatadines D & E (197,198)/spongeShikimate gFactor XIa inhibition222 μM *UndeterminedAUS[173]
fibrosterol sulfates A & B (199,200)/spongeTerpene fProtein Kinase Cζ inhibition5.6 & 16.4 µMUndeterminedPHL, USA[174]
gracilin L (201)/spongeTerpene fEGF-R tyrosine kinase inhibition<100 μM *UndeterminedGBR, LUX[175]
grassystatins A–C (141143)/bacteriumPeptide gcathepsin E inhibition0.3–43 nMUndeterminedUSA[133]
2-hydroxycircumdatin C (202)/fungusAlkaloid gDPPH radical scavenging activity9.9 µMUndeterminedCHN[176]
jaspaquinol (203)/spongeTerpene f5-lipoxygenase inhibition0.45 µMUndeterminedUSA[177]
largamides A–C (204206)/bacteriumPeptide gElastase inhibition0.53–1.41 µMUndeterminedUSA[178]
largamide D oxazolidine (207)/bacteriumPeptide gElastase and chymotrypsin inhibition0.9–1.5 μMUndeterminedUSA[179]
Laurencia similis brominated metabolites (208,209)/algaPolyketide e Protein phosphatase 1B inhibition2.7–3 μMUndeterminedCAN, CHN[180]
molassamide (210)/bacteriumPeptide gElastase and chymotrypsin inhibition0.03 & 0.23 μMUndeterminedUSA[181]
myrothenone A (211)/fungusPolyketide e Tyrosinase inhibition6.6 μMUndeterminedS. KOR[182]
42-hydroxy-palytoxin (212)/soft coralPKS/NRPSNa+/K+ pump inhibition28 ± 7 nMUndeterminedITA, USA[183]
plectosphaeroic acids A–C (213215)/fungusAlkaloid gIndoleamine 2, 3 dioxygenase inhibtion2 μM *UndeterminedCAN[184]
puupehenone (216)/spongeTerpene f5-lipoxygenase inhibition0.68 μMUndeterminedUSA[177]
Sinularia numerosa oxylipin (217)/soft coralFatty acid e Angiogenesis inhibition20–40 μMUndeterminedJPN[185]
sipholenone E (218)/spongeTerpene fP-glycoprotein multidrug resistance reversal5.7–62 nMUndeterminedEGY, CHN, USA[186]
spartinoxide (219)/fungusTerpene fHuman elastase inhibition6.5 μMUndeterminedDEU[187]
23-nor-spiculoic acid B (220)/spongePolyketide e NFκB inhibition0.47 μMUndeterminedVEN, USA[188]
tanikolide dimer (221)/bacteriumPolyketide e Human sirtuin type 2 inhibition0.176–2.4 μMUndeterminedDEU, S. KOR, USA[189]
tamulamide A & B (222,223)/dinoflagellatePolyketide(polyether) e Brevetoxin-3 binding inhibition0.2–2.5 μMUndeterminedUSA[190]
terretonins E & F (224,225)/fungusTerpene fNADH oxidase inhibition2.9–3.9 μMUndeterminedESP, ITA[191]
tetrangulol methyl ether (226)/bacteriumPolyketide e Quinone reductase-2 inhibition0.16 μMUndeterminedUSA[192]
a Organism, Kingdom Animalia: ascidian (Phylum Chordata), fireworm (Phylum Annelida), soft corals (Phylum Cnidaria), starfish ( Phylum Echinodermata), sponge (Phylum Porifera); Kingdom Chromalveolata: dinoflagellates; Kingdom Fungi: fungus; Kingdom Plantae: alga; Kingdom Monera: bacterium; b IC50: concentration of a compound required for 50% inhibition in vitro; *: estimated IC50; c MMOA: molecular mechanism of action; d Country: AUS: Australia; CAN: Canada; CHN: China; DEU: Germany; EGY: Egypt; ESP: Spain; GBR: United Kingdom; IDN: Indonesia; ISR: Israel; ITA: Italy; JPN: Japan; LUX: Luxembourg; NZL: New Zealand; NLD: The Netherlands; PHL: Phillipines; PAP: Papua New Guinea; SGP: Singapore; S. KOR: South Korea; ESP: Spain; VEN: Venezuela; e Chemistry: Polyketide; f Terpene; g Nitrogen-containing compound; *: Bouillamides A and B are identical with lyngbyastatins 9 and 10. See [193].
Figure 3. Marine pharmacology in 2009–2011: Marine compounds with miscellaneous mechanisms of action.
Figure 3. Marine pharmacology in 2009–2011: Marine compounds with miscellaneous mechanisms of action.
Marinedrugs 11 02510 g003a1Marinedrugs 11 02510 g003a2Marinedrugs 11 02510 g003a3Marinedrugs 11 02510 g003a4Marinedrugs 11 02510 g003a5Marinedrugs 11 02510 g003a6Marinedrugs 11 02510 g003a7

5. Reviews on Marine Pharmacology

Several reviews covering both general and specific areas of marine preclinical pharmacology were published during 2009–2011: (a) marine pharmacology and marine pharmaceuticals: a renaissance in marine pharmacology: from preclinical curiosity to clinical reality [194]; biologically active marine natural products [195]; drug development from marine natural products [196]; biotechnological potential of marine natural products [197]; pharmaceuticals from marine natural products: surge or ebb? [198]; marine pharmacology in Australia: the Roche Research Institute [199]; the global marine pharmaceutical pipeline in 2010: U.S. Food and Drug Administration-approved compounds and those in Phase I, II and III of clinical development [200]; marine drugs from sponge-microbe associations [201]; cyanobacteria as an emerging source for drug discovery [202]; marine invertebrates as a future therapeutic treasure [203]; biodiversity conservation and marine natural products drug discovery [204]; marine invertebrates as a source of guanidines with chemical and pharmacological significance [205]; innovations in the field of marine natural products and a new wave of drugs [206]; (b) antimicrobial marine pharmacology: antibacterial marine natural products [207]; marine microbes and pharmaceutical development [208]; marine microbe-derived antibacterial agents [209]; antimicrobial peptides from marine invertebrates [210]; novel anti-infective compounds from marine bacteria [211]; conventional and unconventional antimicrobials from fish, marine invertebrates and microalgae [212]; (c) antiviral marine pharmacology: antiviral lead compounds from marine sponges [213]; potential anti-HIV agents from marine resources [214]; marine compounds and their antiviral activities [215]; marine organisms as a therapeutic source against herpes simplex virus infection [216]; (d) antiparasitic, antituberculosis, antimalarial and antifungal marine pharmacology: antiparasitic marine invertebrate-derived small molecules [217]; marine antileishmanial natural products [218]; antituberculosis leads from marine microbial metabolites [219]; antimalarial drug discovery from marine sources between January 2003 and December 2008 [220]; antimalarial marine natural products from 2006 to 2008 [221]; antimalarial marine compounds [222]; (e) immuno- and anti-inflammatory marine pharmacology: marine natural product leads for treatment of inflammation [223]; marine natural products targeting phospholipase A2 [224]; marine diterpene glycosides as anti-inflammatory agents [225]; anti-inflammatory compounds from marine algae [226]; (f) cardiovascular marine pharmacology: marine-derived angiotensin-I-converting enzyme inhibitors [227]; (g) nervous system marine pharmacology: conotoxins as natural products drug leads [228]; marine indole alkaloids as new drug leads for depression and anxiety [229]; marine natural products and ion channel pharmacology [230]; neuroprotective effects of marine algae [231]; conopeptides as novel options for pain management [232]; structure-activity studies with α-conotoxins as selective antagonists of nicotinic acetylcholine receptors [233]; (h) miscellaneous molecular targets: calyculins and related marine natural products as serine threonine protein phosphatase inhibitors [234]; NF-κB inhibition by marine natural products [235]; protein kinase inhibitors from marine sponges [236].

6. Conclusions

The global marine preclinical and clinical pharmaceutical pipelines remain remarkably active one year after U.S. Food and Drug Administration approval of brentuximab vedotin (Adcetris®), a conjugate between a monoclonal antibody that targets the cell-membrane protein CD30, an antigen which is highly expressed in lymphoid tumors, and several units of the potent antimitotic agent monomethyl auristatin E, a synthetic analog of the marine compound dolastatin 10 [237].
This review aims to continue contributing to the marine preclinical pipeline review series that was initiated in 1998 [1,2,3,4,5,6,7] and reveals the breadth of preclinical pharmacological research during 2009–2011, resulting from the global research effort of chemists and pharmacologists from Australia, Belgium, Brazil, Canada, China, Colombia, Cuba, Egypt, Fiji, France, Germany, Indonesia, Israel, Italy, Japan, Luxemburg, Malaysia, Mexico, the Netherlands, New Caledonia, New Zealand, Norway, Panama, Papua New Guinea, Philippines, South Africa, South Korea, Singapore, Spain, Switzerland, Taiwan, Thailand, United Kingdom, Venezuela, Vietnam, and the United States. Thus, we feel confident to predict that the marine preclinical pharmaceutical pipeline will most probably continue to provide novel pharmacological lead compounds that will enrich the marine clinical pharmaceutical pipeline [200], which currently consists of 6 U.S. Food and Drug Administration-approved pharmaceuticals and 11 compounds in Phase I, II and III of clinical development and which may be viewed at [238].


This review was made possible with financial support from Midwestern University to AMSM; and NIH-SC1 Award (Grant 1SC1GM086271-01A1) of the University of Puerto Rico to ADR, and EU project Bluegenics (Grant 311848) 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. Article retrieval by library staff members, and students from the Chicago College of Pharmacy, Midwestern University, is gratefully acknowledged. The authors are especially thankful to Mary Hall for the careful review of the manuscript.


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MDPI and ACS Style

Mayer, A.M.S.; Rodríguez, A.D.; Taglialatela-Scafati, O.; Fusetani, N. Marine Pharmacology in 2009–2011: 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. Mar. Drugs 2013, 11, 2510-2573.

AMA Style

Mayer AMS, Rodríguez AD, Taglialatela-Scafati O, Fusetani N. Marine Pharmacology in 2009–2011: 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. Marine Drugs. 2013; 11(7):2510-2573.

Chicago/Turabian Style

Mayer, Alejandro M. S., Abimael D. Rodríguez, Orazio Taglialatela-Scafati, and Nobuhiro Fusetani. 2013. "Marine Pharmacology in 2009–2011: 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" Marine Drugs 11, no. 7: 2510-2573.

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