Review Article Indole Alkaloids from Marine Sources as ...downloads.hindawi.com/journals/bmri/2014/375423.pdfReview Article Indole Alkaloids from Marine Sources as Potential Leads

Review ArticleIndole Alkaloids from Marine Sources as PotentialLeads against Infectious Diseases

Paulo H B Franccedila1 Daniel P Barbosa2 Daniel L da Silva1

Ecircurica A N Ribeiro2 Antocircnio E G Santana1 Baacuterbara V O Santos3

Joseacute M Barbosa-Filho3 Jullyana S S Quintans4 Rosana S S Barreto4

Lucindo J Quintans-Juacutenior4 and Joatildeo X de Arauacutejo-Juacutenior12

1 Institute of Chemistry and Biotechnology Federal University of Alagoas University City BR 101 KM 14 NorteTabuleiro dos Martins 57072-970 Maceio AL Brazil

2 School of Nursing and Pharmacy Federal University of Alagoas Av Lourival de Mello Motta SN Tabuleiro dos Martins57072-970 Maceio AL Brazil

3 Laboratory of Pharmaceutical Technology Federal University of Paraiba 58051-900 Joao Pessoa PB Brazil4Department of Physiology Federal University of Sergipe 49000-100 Sao Cristovao SE Brazil

Correspondence should be addressed to Joao X de Araujo-Junior jotaaraujo2004gmailcom

Received 23 February 2014 Revised 25 April 2014 Accepted 25 April 2014 Published 5 June 2014

Academic Editor Xudong Huang

Copyright copy 2014 Paulo H B Franca et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Indole alkaloids comprise a large and complex class of natural products found in a variety of marine sources Infectious diseasesremain a major threat to public health and in the absence of long-term protective vaccines the control of these infectious diseasesis based on a small number of chemotherapeutic agents Furthermore the emerging resistance against these drugsmakes it urgentlynecessary to discover and develop new safe and effective anti-infective agents In this regard the aim of this review is to highlightindole alkaloids from marine sources which have been shown to demonstrate activity against infectious diseases

1 Introduction

Seas and oceans occupy more than 75 of the Earthrsquossurface and contain nearly all groups of organisms includingrepresentatives of 34 out of 36 phyla described Thus marineecosystems can be considered as having the greatest phyleticbiodiversity with virtually unlimited biotechnological poten-tial [1] The marine environment is massively complexconsisting of extreme variations in pressure salinity temper-ature and biological habitats that have led to the productionof several novel structures with unique biological propertieswhich may not be found in terrestrial natural products [2]In the past 30ndash40 years marine plants and animals have beenthe focus of a worldwide effort to define the natural productsof themarine environment A small number ofmarine plantsanimals andmicroorganisms have already yieldedmore than12000 novel chemicals with hundreds of new compoundsstill being discovered every year These discovery efforts

have yielded several bioactive metabolites that have beensuccessfully developed by the pharmaceutical industry [3]A variety of marine sources including sponges tunicates redalgae acorn worms and symbiotic bacteria have been shownto generate indole alkaloids which represent the largestnumber and most complicated of the marine alkaloids [4ndash7]The alkaloids obtained frommarine organisms frequentlypossess novel frameworks which cannot be found in terres-trially related organisms Marine metabolites often possesscomplexities such as halogen substituents [8] In additionbearing in mind that several species of organisms are asso-ciated with cyanobacteria and bacteria it is considered thatseveral natural products originating in microorganisms canbe isolated from marine animals [9] Indole alkaloids havebeen shown to exhibit awide array of biological activities suchas opioid receptor agonistic [10] antibacterial [11 12] antifun-gal [13 14] anti-inflammatory [15] antileishmanial [16 17]antiplasmodial [18 19] anti-HIV [20] cytotoxic [21] glucose

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 375423 12 pageshttpdxdoiorg1011552014375423

2 BioMed Research International

uptake stimulatory [22] larvicidal [23] trypanocidal [24]and vasodilator [25 26] and inhibition of cholinesterase [27]indoleamine-2 3-dioxygenase [28] calmodulin [29] andCB1 cannabinoid receptor [30] Infectious diseases causedby bacteria fungi viruses and parasites are still a majorthreat to public health despite the tremendous progress inhuman medicine The high prevalence of these diseases andthe emergence of widespread drug resistance developed bythese parasites to current treatments leading to reductionof their efficacy and consequent increase in the cost ofconventional treatments highlight the need for novel andeffective therapeutic alternativeswith fewer or no side-effectsTheir impact is particularly large in developing countries dueto the relative unavailability of medicines [31 32]

Therefore in continuation of our research on bioactivemolecules fromnatural origin [33ndash53] and plant extracts [54ndash63] we offer this compilation of the indole alkaloids frommarine sources

In this review literature was covered in order to highlightalkaloidal compoundswith an indolemoietywhich have beenshown to demonstrate activity against infectious diseases

2 Indole Alkaloids from Marine Sources

Manadomanzamines A and B (Figure 1) 120573-carbolines witha novel rearrangement of the manzamine framework wereisolated from an Indonesian sponge Acanthostrongylophorasp These compounds showed significant activities againstMycobacterium tuberculosis with MIC values of 19 and15 120583gmL respectively Manadomanzamines A and B werealso active against human immunodeficiency virus (HIV-1) with EC

50values of 70 and 165 120583gmL Furthermore

manadomanzamine A was active against the fungus Candidaalbicanswith an IC

50of 20120583gmL whilstmanadomanzamine

B exhibited activity against the fungus Cryptococcus neofor-mans with IC

50value of 35 120583gmL [64]

Manzamine A a 120573-carboline alkaloid present in severalmarine sponge species has been shown to inhibit the growthof the rodent malaria parasite Plasmodium berghei in vivoMore than 90 of the asexual erythrocytic stages of P bergheiwere inhibited after a single intraperitoneal injection of man-zamine A into infected mice Moreover it was demonstratedthat immunostimulatory effects caused by the compoundplay an important role in preventing mouse death due tofulminating recurrent parasitemia in animals treated with100mmol per kg of manzamine A [65]

Several manzamine-type alkaloids were also isolatedfrom an Indonesian sponge of the genus Acanthostrongy-lophora The 120573-carbolines (+)-8-hydroxymanzamine A and6-hydroxymanzamine E (Figure 1) showed strong activ-ity against M tuberculosis H37Rv with MIC values of09 and 04 120583gmL respectively Manzamine A and (+)-8-hydroxymanzamine were strongly active when tested againstPlasmodium falciparum chloroquine-sensitive D6 clone andchloroquine-resistant W2 clone showing respectively IC

50

values of 45 and 60 ngmL toward the former and equally80 ngmL toward the latter Moreover manzamine A man-zamine Y and 6-hydroxymanzamine E (Figure 1) have shown

significant activity against Leishmania donovani with IC50

values of 09 16 and 25 120583gmL respectively [66]Investigation of bioactivity of manzamine alkaloids iso-

lated from an Okinawan sponge Amphimedon sp revealedactive compounds against Trypanosoma brucei brucei and Pfalciparum Zamamidine C (Figure 1) 34-dihydromanzam-ine JN-oxide andmanzamine A showed inhibitory activitiesin vitro against T b brucei with IC

50values of 027 444 and

004 120583gmL respectively and P falciparum with IC50

values058 702 and 097 120583gmL respectively [67]

Seven 120573-carboline-based metabolites designated as eud-istomins Y

1ndashY7(Figure 2) were isolated from a tunicate of

the genus Eudistoma collected in South Korea These newmetabolites differ from previously isolated marine metabo-lites due to the presence of a benzoyl group attached to the120573-carboline nucleus at C-1 Eudistomin Y

6exhibited mod-

erate antibacterial activity against Gram-positive bacteriaStaphylococcus epidermidis ATCC12228 and B subtilis ATCC6633 with MIC values of 125 and 25 120583gmL respectively butshowed no inhibitory activity toward the other two strainsof Gram-positive bacteria S aureus ATCC 6538 and Mlutes ATCC 9341 and the Gram-negative bacteria includingE coli ATCC 11775 Salmonella typhimurium ATCC 14028and Klebsiella pneumoniae ATCC 4352 Eudistomins Y

1and

Y4also displayed the same selectivity as eudistomin Y

6but

demonstrated weak antibacterial activity against the twostrains of bacteria S epidermidis ATCC12228 and B subtilisATCC 6633 with MICs of 50 and 200120583gmL respectively[68]

Investigation of the CH2Cl2extract from the bryozoan

Pterocella vesiculosa collected in New Zealand has led tothe isolation of 5-bromo-8-methoxy-1-methyl-120573-carboline(Figure 2) This alkaloid was evaluated for antibacterial andantifungal activities and showed inhibitory action toward theGram-positive bacterium B subtilis and the fungi C albicansand Trichophyton mentagrophyteswithMID ranges of 2ndash4 4-5 and 4-5 120583gmL respectively [69]

An indole spermidine alkaloid didemnidine B (Figure 3)was described in the New Zealand ascidian Didemnum spEvaluation of the compound against Trypanosoma bruceirhodesiense Trypanosoma cruzi L donovani and Plasmod-ium falciparum K1 chloroquine-resistant strain indicateddidemnidine B to bemildly active toward themalaria parasitewith IC

50value of 15 120583M [70]

In addition chemical investigations of the tropicalmarinesponge Hyrtios sp have resulted in the isolation of severalalkaloids which were evaluated as C albicans isocitratelyase inhibitors Out of the compounds tested the bis-indole alkaloid hyrtiosin B (Figure 4) showed themost potentinhibitory activity with an IC

50value of 507120583M Other

compounds comprised simple indole alkaloids namely 1-carboxy-6-hydroxy-34-dihydro-120573-carboline 5-hydroxy-1H-indole-3-carboxylic acid methyl ester serotonin hyrtiosinA and 5-hydroxyindole-3-carbaldehyde (Figure 3) revealedonly moderate to weak activity against C albicans isocitratelyase with MIC values ranging between 398 and 1529 120583MBy comparing their chemical structures it was found thatthe enzyme inhibitory activities of these 5-hydroxyindole-type alkaloids are markedly affected by a substitution of

BioMed Research International 3

34-Dihydromanzamine J N-oxide

Manzamine A

Manzamine Y

R1 = H

R1 = H

R2 = H

R2 = H

R2 = HR1 = OH

R1 = OH

R2 = OH

6-Hydroxymanzamine E

Manadomanzamine BManadomanzamine A

R1

R2H

O

OH

N

N

N

N

R1

R2H

OH

N

N

N

N

H

OH

N

N

NN

H

H

HH

H

OH

N

N

N

N

N

N

H

H

H

H HHO

O

OH

NN

N

N

H

H

H

H HHO OH

NN

N

N

Zamamidine C

(+)-8-Hydroxymanzamine A

Figure 1 Structures of 120573-carbolines with manzamine-type frameworks


Eudistomin Y1 R1 = H R2 = H R3 = H R4 = H

Eudistomin Y2 R1 = Br R2 = H R3 = H R4 = H

Eudistomin Y3 R1 = H R2 = H R3 = Br R4 = H

Eudistomin Y4 R1 = Br

R1 = Br

R2 = H R3 = Br R4 = H

Eudistomin Y5 R1 = H R2 = H R3 = Br R4 = Br

Eudistomin Y6

R2 = Br

R3 = Br

R3 = Br

R4 = Br

R4 = BrEudistomin Y7 R1 = H

R2 = H

H

H

O

O

N

NR1

R2

R3 R4

1-Carboxy-6-hydroxy-34-dihydro-b-carboline

H

H

O

N

N

COOH

5-Bromo-8-methoxy-1-methyl-b-carboline

HN

N

O

Br

Figure 2 Structures of 120573-carbolines with eudistomin-derived scaffold and simple 120573-carbolines

Matemone Tryptophol

Isoplysin

6-Bromoaplysinopsin

R1 = HR1 = BrR1 = Br

R2 = CH3

R2 = CH3

R2 = HR3 = CH3

R3 = HR3 = H

R4 = HR4 = HR4 = CH3

Didemnidine B 3-Hydroxyacetylindole

N-Acetyl-120573-oxotryptamine

5-Hydroxy-1H-indole-3-carboxylicacid methyl ester

HO HOOCH3

NH

NH

NH

NH

NH

NH

NH

NH N

HNH

O

O

O

O

OO

O

OH

OH

OH

Br

5-Hydroxyindole-3-carbaldehyde

CHO

HN

NH2

R1

HR2N

NR3

NR4

O

9984006-Bromo-2998400-de-N-methylaplysinopsin

Figure 3 Structures of simple indole alkaloids


Dendridine A Hyrtiosin B

Bromodeoxytopsentin Nortopsentin A

H

H

H

HH

H

HH

O

O

O

HO

HO

OO

N

H

H

N

HN

HN

HN

N

N N

N

N

H

H

NHN

NHN

HN

NN

HN

Br

Br

Br

Br

Br

Br

BrHO

cis-34-Dihydrohamacanthin B

Figure 4 Structures of bis-indole alkaloids

functional group at the C-3 position A substitution by ahydrophilic group at the C-3 position results in an increaseof the isocitrate lyase inhibitory activity [71]

Tryptophol (Figure 3) a simple indole alkaloid fromsponge Ircinia spinulosa was screened for antitrypanosomalactivity The compound was active against T b rhodesiensewith an IC

50value of 589 120583gmL but it was 8-fold less active

against T cruzi with IC50value of 4937 120583gmL than against

T b rhodesiense Toward L donovani tryptophol displayedan IC

50value of 960120583gmL compared with 020120583gmL

of the standard drug miltefosine For P falciparum it wasshown that tryptophol presented an IC

50value of 508 120583gmL

compared with 0056120583gmL of chloroquine [72]A bioactive bromine-containing oxindole alkaloid mate-

mone (Figure 3) was isolated from the Indian Ocean spongeIotrochota purpurea Matemone showed marginal antimicro-bial activity against the bacterium Staphylococcus aureus at50 100 and 200 120583gdisk affording inhibitory zones of 7 9 and11mm respectively [73]

Dendridine A (Figure 4) a C2-symmetrical 441015840-bis(7-hydroxy) indole alkaloid was reported in extracts of an Oki-nawan sponge Dictyodendrilla sp Dendridine A exhibitedinhibitory activities against Gram-positive bacteria Bacillussubtilis and Micrococcus luteus with MIC values of 83 and42 120583gmL respectively and the fungus C neoformans withMIC of 83 120583gmL [74]

In order to discover active compounds with inhibitoryactivity againstmethicillin-resistant S aureuspyruvate kinase(MRSA-PK) screening of an extract library of marine

invertebrates resulted in the identification of bis-indole alka-loids from the Topsentia pachastrelloides The most activecompounds cis-34-dihydrohamacanthin B and bromod-eoxytopsentin (Figure 4) were identified as highly potentMRSA-PK inhibitors with IC

50values of 16ndash60 nM and

with at least 166-fold selectivity over human PK isoformsThese novel anti-PK natural compounds exhibited significantantibacterial activities against MRSA with MIC values of125 and 625 120583gmL respectively and selectivity indices(CC50MIC) gt 4 [75]

The bis-indole alkaloid nortopsentin A (Figure 4) presentin enriched fractions of marine sponges from genus Spon-gosorites exhibited potent inhibition of Plasmodium fal-ciparum growth Assays were performed in chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains andIC50

values obtained were 460 nM against the former and560 nM against the latter [76]

The bisindole alkaloid (R)-61015840-debromohamacanthin B(Figure 4) was isolated from the MeOH extract of a marinesponge Spongosorites sp and showedweak antibacterial activ-ity against clinically isolated methicillin-resistant strainswith MIC values of 63120583gmL for S pyogenes 308A and125 120583gmL for S pyogenes 77A S aureus SG 511 S aureus285 S aureus 503 [77]

Bis-indole alkaloids isolated from the Jamaican spongeSmenospongia aurea were tested against the D6 clone ofP falciparum for their in vitro antimalarial activity The com-pound 6-bromoaplysinopsin (Figure 4) exhibited activity atendpoints of 0087 and 034 120583gmL with a selectivity index of


Cl

H

H

H

CN

N

Cl

HCN

OH

HN

Cl

HCN

OH

HN

H

H

H

CN

N

OH

H CNO

HN

Ambiguine A isonitrile Ambiguine H isonitrile Ambiguine I isonitrile

Ambiguine K isonitrile Ambiguine M isonitrile

Figure 5 Structures of ambiguine isonitriles

Fascaplysin Homofascaplysin A

HN

O

N+

HN

O

N+

OH

Figure 6 Structures of fascaplysin and homofascaplysin A

55 and 14 respectively Other compounds such as isoplysinA and 6-bromo-21015840-de-N-methylaplysinopsin (Figure 3)showed moderate activity at 097 11 and 094 120583gmL witha selectivity index of gt49 gt43 and gt51 respectivelyMoreover 6-bromo-21015840-de-N-methylaplysinopsin inhibitedthe antimalarial target plasmepsin II enzyme with IC

50

53 120583M in fluorescence resonance energy transfer (FRET) and66 120583M in fluorescence polarization (FP) assays [78]

Bioassay-guided fractionation of the 7 3 MeOHwaterextract of a cultured cyanobacterium strain identified asFischerella sp yielded nine isonitrile-containing alkaloidsAmbiguine H isonitrile and ambiguine I (Figure 5) isonitrileexhibited strong activity against the bacteria Staphylococcusalbus (MIC values of 0625 and 0078 120583gmL) and B subtilis(MIC values of 125 and 0312 120583gmL) Ambiguine I isonitrilewas strongly active against the fungi Saccharomyces cerevisiae(MIC value of 0312 120583gmL) and C albicans ATCC 90028(MIC value of 039 120583gmL) [79]

A new investigation on ambiguines highlighted thatambiguine A isonitrile showed MIC of 10120583M against Banthracis while ambiguine K and M isonitriles (Figure 5)were more potent towards M tuberculosis with MIC valuesof 66 120583M and 75 120583M respectively [80]

From the CH2Cl2extract of the sponge Hyrtios cf

erecta collected in Fiji 120573-carbolines homofascaplysin Aand fascaplysin (Figure 6) were isolated Evaluation of thebiological activity of the compounds toward P falciparumrevealed that homofascaplysin and fascaplysin are bothpotently active in vitro against the parasite HomofascaplysinA also inhibited the growth of Escherichia coli (50120583g9mm)and Bacillus megaterium (50120583g11mm) Fascaplysin inhib-ited the growth of E coli (50120583g6mm) and B megaterium(50 120583g10mm) Further biological activity for fascaplysinwas found against Trypanosoma b rhodesiense displayingmoderate activity with IC

50value of 017 120583gmL compared

with melarsoprol which showed IC50

value of 2 ngmL


Marinacarboline A R = OCH3Marinacarboline B R = H

N

HN

O

O

R

NH

O

Marinacarboline D

N

O

NH

HN

HN

H

H

H

N

N

O

HN

OGlu

Methylpendolmycin-14 120572-glucoside-O-

Figure 7 Structures of marinacarbolines and pendolmycin derivative

H

H

H

O

O

O

N

N N

N

Figure 8 Structure of indolocarbazole alkaloid staurosporine

The evaluation of antiviral activity of fascaplysin revealedan increased cytopathogenic effect at noncytotoxic con-centrations of 0038 120583gmL toward fetal Rhesus monkeykidney cells (FRhK-4-cells) infected with the HAV-variantHAVcytHB11 Persistently infected FRhK-4-cells (HAV7)showed cytopathogenicity at 0038 120583gmL of fascaplysinwhile untreated FRhK-4-cells remained unchanged Homo-fascaplysin A and fascaplysin were shown to be potentin vitro inhibitors of chloroquine-susceptible (NF54) andchloroquine-resistant P falciparum strains Positive controlsubstances were chloroquine and artemisinin The potencyagainst the K1 strain of homofascaplysin A was stronger thanthat of chloroquine Compared with artemisinin (K1 strain)and with both positive control substances (NF54 strain)homofascaplysin was approximately 10-fold less active [81]

Alkaloids obtained from the fermentation broth ofMari-nactinospora thermotolerans SCSIO 0652 were tested for theirantiplasmodial activities against P falciparum line 3D7 adrug-sensitive strain and Dd2 a multi-drug-resistant strainThe results of the antiplasmodial assays revealed that mari-nacarboline A (Figure 7) and methylpendolmycin-14-O-120572-glucoside (Figure 6) inhibited P falciparum line Dd2 withIC50values of 192 and 503 120583M respectively and marinacar-

bolines C and D inhibited P falciparum lines 3D7 and Dd2with IC

50values between 309 and 539 120583M [82]

The cultivation of Streptomyces sp strains associatedwith theMediterranean spongesAplysina aerophobaAxinellapolypoides Tedania sp and Tethya sp collected in Croa-tia has yielded the indolocarbazole alkaloid staurosporine

H

O

OO

N

N

N

HN

Figure 9 Structure of pyrazinoquinazoline-derived alkaloid oxo-glyantrypine

H

H

H

O

O

O

N

NN

Figure 10 Structure of prenylated indole alkaloids (minus)-stephacidinA

(Figure 8) The compound was screened for anti-infectiveactivities and showed significant antiparasitic activity againstLeishmaniamajorwith IC

50530 120583MandT b bruceiwith IC

50

0022120583M [83] Staurosporine was first isolated in 1977 fromStreptomyces staurisporeus and later also from other actino-mycetes as well as cyanobacteria In the meantime severalstaurosporine analogues were isolated from actinomycetesand also from marine invertebrate including among otherssponges mollusks and tunicates Interestingly in severalcases staurosporine and related derivativeswere isolated fromStreptomyces spThe occurrence of such compoundmay sug-gest the presence of associated microorganisms responsiblefor the biosynthesis of staurosporine [84]

A novel indole alkaloid containing pyrazinoquinazoline-derivative framework (14S)-oxoglyantrypine (Figure 9)


Nakijinamine A R = BrNakijinamine B R = H

Nakijinamine C

HOOH

N

N

N

HN H

R

+

+

OH

N

HN

HN

NH

N+

+

Br

Figure 11 Structures of heteroaromatic aaptamine-type indole alkaloids

Hyrtimomine F Hyrtimomine G Hyrtimomine I

Hyrtimomine A Hyrtimomine B

HO

NHHO

N

HN

O

ON

HNHO

NH

O

HO

HO

HONHHN

OH

OH

O OOH

NH

NH

O

O

O

+

OHN

NN

O

O

Figure 12 Structures of hyrtimomine-type alkaloids

isolated from the culture of the mangrove-derived fungusCladosporium sp PJX-41 exhibited activity against influenzavirus H1N1 with IC

50value of 85 120583M [85]

From marine Aspergillus sp a prenylated indole alkaloidwas isolated and its antibacterial activity was assayed (minus)-Stephacidin A (Figure 10) showed MIC value of 215 120583Magainst S epidermidis [86]

Nakijinamines A B and C (Figure 11) have been shownto present antibacterial and antifungal activity These com-pounds present a heteroaromatic aaptamine-type frameworkand a halogenated indole moiety Nakijinamine A was activeagainst C albicans (IC

50025120583gmL) C neoformans (IC

50

05 120583gmL) Trichophyton mentagrophytes IC50(025 120583gmL)

S aureus (MIC 16 120583gmL) B subtilis (MIC 16 120583gmL) andMicrococus luteus (MIC 2 120583gmL) Nakijinamines B and Cwere only active againstC albicanswith IC

50value of 8120583gmL

each [87]Alkaloids with hyrtimomine-type framework (Figure 12)

were isolated from Hyrtios spp Hyrtimomines F G and I

exhibited inhibitory effects against Aspergillus niger (IC50

80 120583gmL each) while hyrtimomine I showed inhibitoryeffect againstC neoformans (IC

5040 120583gmL) Hyrtimomines

A and B also showed antifungal activities against C albicans(IC50

10 120583gmL each) and C neoformans (IC50

20 and40 120583gmL resp) Hyrtimomine A exhibited an inhibitoryactivity against A niger (IC

5040 120583gmL) [88]

Meridianins A-G (Figure 13) comprise indole alkaloidssubstituted at the C-3 position by a 2-aminopyridine ringand had been previously isolated from the tunicate Aplidiummeridianum Investigations on the antimalarial and antileish-manial activity of meridianin C and G were carried out andshowed that these two compounds inhibited P falciparumD6 and W2 clones with IC

50values in the range of 44 to

144 120583M Meridianin C was also active against L donovanipromastigotes showing an IC

50value of 64 120583M [89]

Simple indole-derived alkaloids were isolated fromthe marine bacterium Bacillus pumilus Compounds3-hydroxyacetylindole and 119873-acetyl-120573-oxotryptamine


Meridianin C Meridianin G

N

N

N

H2N

H

N

N

Br

H2N

NH

Figure 13 Structures of meridianins C and G

R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3

Figure 14 Structures of hyrtioerectines DndashF

(Figure 3) promoted inhibition on the growth of amastigotesfrom T cruzi with IC

50values of 206 and 194 120583M

respectively [90]Hyrtioerectines DndashF (Figure 14) were isolated from Hyr-

tios species and had their antimicrobial activities screenedThese 120573-carboline-derived compounds showed inhibitionzones of 17 9 and 14mm against C albicans compared to35mm illustrated by clotrimazole at the same concentrationIn addition they caused inhibition zones of 20 10 and 16mmagainst S aureus respectively compared to 30mm illustratedby ampicillin as well as inhibition zones of 7ndash9mm againstPseudomonas aeruginosa compared to 30mm illustrated byimipenem [91]

As noted in the study above the main source of marineindole alkaloids are sponges whilst pharmacological assaysfocus on activity toward parasites from the genus Plasmod-ium and Trypanosoma Although few indole alkaloids frommarine sources have been tested for anti-infective activitythere are some promising compounds which demonstratehigh level of activity against several infectious diseases agentsincluding bacteria fungi and protozoaThese active alkaloidsshow simple as well as complex frameworks and unliketerrestrial organisms they frequently contain halogenatedmoieties Therefore this review highlighted some marineindole alkaloids which may be considered as potentialstarting points for the development of novel agents for thetreatment of infectious diseases

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

Financial supportwas provided byCNPq (ConselhoNacionalde Desenvolvimento Cientıfico e Tecnologico) PRONEX-FAPESQ-PB (Programa de Apoio a Nucleos de Excelencia-Fundacao de Apoio a Pesquisa do Estado da Paraıba) andINCT AmbTropic (httpwwwinctambtropicorg)

References

[1] L V Costa-lotufo D V Wilke P C Jimenez and R D A Epi-fanio ldquoMarine organisms as a source of new pharmaceuticalshistory and perspectivesrdquoQuımica Nova vol 32 no 3 pp 703ndash716 2009

[2] J V Rao P K Usman and J B Kumar ldquoLarvicidal andinsecticidal properties of some marine sponges collected inPalk Bay and Gulf of Mannar watersrdquo African Journal ofBiotechnology vol 7 no 2 pp 109ndash113 2008

[3] M Donia and M T Hamann ldquoMarine natural products andtheir potential applications as anti-infective agentsrdquoThe LancetInfectious Diseases vol 3 no 6 pp 338ndash348 2003

[4] E T de Souza D P de Lira A C de Queiroz et al ldquoTheantinociceptive and anti-inflammatory activities of caulerpina bisindole alkaloid isolated from seaweeds of the genusCaulerpardquoMarine Drugs vol 7 no 4 pp 689ndash704 2009

[5] K CGuven A Percot andE Sezik ldquoAlkaloids inmarine algaerdquoMarine Drugs vol 8 no 2 pp 269ndash284 2010

[6] S Sagar M Kaur and K P Minneman ldquoAntiviral lead com-pounds from marine spongesrdquoMarine Drugs vol 8 no 10 pp2619ndash2638 2010

[7] A Longeon B R Copp E Quevrain et al ldquoBioactive indolederivatives from the South Pacific marine sponges Rhopaloei-des odorabile and Hyrtios sprdquo Marine Drugs vol 9 no 5 pp879ndash888 2011

[8] W Gul and M T Hamann ldquoIndole alkaloid marine naturalproducts an established source of cancer drug leads withconsiderable promise for the control of parasitic neurologicaland other diseasesrdquo Life Sciences vol 78 no 5 pp 442ndash4532005

[9] A M P Almeida R G S Berlinck and E Hajdu ldquoAlcaloidesalquilpiridınicos de esponjas marinhasrdquoQuımica Nova vol 20pp 170ndash185 1997

[10] M Kitajima K Misawa N Kogure et al ldquoA new indolealkaloid 7-hydroxyspeciociliatine from the fruits of MalaysianMitragyna speciosa and its opioid agonistic activityrdquo Journal ofNatural Medicines vol 60 no 1 pp 28ndash35 2006

[11] J C A Tanaka C C da Silva A J B de Oliveira C VNakamura and B P Dias Filho ldquoAntibacterial activity of indolealkaloids fromAspidosperma ramiflorumrdquo Brazilian Journal OfMedical and Biological Research vol 39 pp 387ndash391 2006

[12] R B Williams J Hu K M Olson et al ldquoAntibiotic indolesesquiterpene alkaloid from Greenwayodendron suaveolenswith a new natural product frameworkrdquo Journal of NaturalProducts vol 73 no 5 pp 1008ndash1011 2010

[13] F Soriano-Agaton D Lagoutte E Poupon et al ldquoExtractionhemisynthesis and synthesis of canthin-6-one analogues Eval-uation of their antifungal activitiesrdquo Journal of Natural Productsvol 68 no 11 pp 1581ndash1587 2005

[14] J Zhang J Gao T Xua et al ldquoAntifungal activity of alkaloidsfrom the seeds of Chimonanthus praecoxrdquo Chemistry andBiodiversity vol 6 no 6 pp 838ndash845 2009


[15] Y Chen P Kuo H Chan et al ldquo120573-carboline alkaloids fromStellaria dichotoma var lanceolata and their anti-inflammatoryactivityrdquo Journal of Natural Products vol 73 no 12 pp 1993ndash1998 2010

[16] E V CostaM L B Pinheiro CM Xavier et al ldquoA pyrimidine-120573-carboline and other alkaloids from Annona foetida withantileishmanial activityrdquo Journal of Natural Products vol 69 no2 pp 292ndash294 2006

[17] J C Delorenzi M Attias C R Gattass et al ldquoAntileishmanialactivity of an indole alkaloid from Peschiera australisrdquo Antimi-crobial Agents and Chemotherapy vol 45 no 5 pp 1349ndash13542001

[18] G Philippe P de Mol M Zeches-Hanrot et al ldquoIndolomonot-erpenic alkaloids from Strychnos icaja rootsrdquo Phytochemistryvol 62 no 4 pp 623ndash629 2003

[19] R Verpoorte M Frederich C Delaude et al ldquoMoandaensinea dimeric indole alkaloid from Strychnos moandaensis (Loga-niaceae)rdquo Phytochemistry Letters vol 3 no 2 pp 100ndash103 2010

[20] H Zhou H He X Luo et al ldquoThree new indole alkaloids fromthe leaves of Alstonia scholarisrdquoHelvetica Chimica Acta vol 88no 9 pp 2508ndash2512 2005

[21] T Feng Y Li X Cai et al ldquoMonoterpenoid indole alkaloidsfromAlstonia yunnanensisrdquo Journal of Natural Products vol 72no 10 pp 1836ndash1841 2009

[22] H Shittu A Gray B Furman and L Young ldquoGlucoseuptake stimulatory effect of akuammicine fromPicralima nitida(Apocynaceae)rdquo Phytochemistry Letters vol 3 no 1 pp 53ndash552010

[23] M Miyazawa J Fujioka and Y Ishikawa ldquoInsecticidalcompounds from Evodia rutaecarpa against Drosophilamelanogasterrdquo Journal of the Science of Food and Agriculturevol 82 no 13 pp 1574ndash1578 2002

[24] I Ngantchou B Nyasse C Denier C Blonski V Hannaertand B Schneider ldquoAntitrypanosomal alkaloids from Polyalthiasuaveolens (Annonaceae) their effects on three selected gly-colytic enzymes of Trypanosoma bruceirdquoBioorganic andMedic-inal Chemistry Letters vol 20 no 12 pp 3495ndash3498 2010

[25] Y Hirasawa M Hara A E Nugroho et al ldquoBisnicalaterinesB and C atropisomeric bisindole alkaloids from hunteriazeylanica showing vasorelaxant activityrdquo Journal of OrganicChemistry vol 75 no 12 pp 4218ndash4223 2010

[26] K Koyama Y Hirasawa K Zaima T C Hoe K Chan and HMorita ldquoAlstilobanines A-E new indole alkaloids fromAlstoniaangustilobardquoBioorganic andMedicinal Chemistry vol 16 no 13pp 6483ndash6488 2008

[27] A P G MacAbeo W S Vidar X Chen et al ldquoMycobacteriumtuberculosis and cholinesterase inhibitors from Voacanga glo-bosardquo European Journal of Medicinal Chemistry vol 46 no 7pp 3118ndash3123 2011

[28] H C Brastianos E Vottero B O Patrick et al ldquoExiguamine Aan indoleamine-23-dioxygenase (IDO) inhibitor isolated fromthemarine spongeNeopetrosia exiguardquo Journal of the AmericanChemical Society vol 128 no 50 pp 16046ndash16047 2006

[29] S Martınez-Luis R Rodrıguez L Acevedo M C Gonzalez ALira-Rocha andRMata ldquoMalbrancheamide a new calmodulininhibitor from the fungus Malbranchea aurantiacardquo Tetrahe-dron vol 62 no 8 pp 1817ndash1822 2006

[30] M Kitajima M Iwai R Kikura-Hanajiri et al ldquoDiscovery ofindole alkaloids with cannabinoid CB1 receptor antagonisticactivityrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no7 pp 1962ndash1964 2011

[31] P Cos A J Vlietinck D V Berghe and LMaes ldquoAnti-infectivepotential of natural products How to develop a stronger in vitrolsquoproof-of-conceptrsquordquo Journal of Ethnopharmacology vol 106 no3 pp 290ndash302 2006

[32] E Galeano A Martınez O P Thomas S Robledo andD Munoz ldquoAntiparasitic bromotyrosine derivatives from thecaribbean marine sponge aiolochroia crassardquo Quımica Novavol 35 no 6 pp 1189ndash1193 2012

[33] F M M Amaral M N S Ribeiro J M Barbosa-Filho A SReis F R F Nascimento and R O Macedo ldquoPlants and chem-ical constituents with giardicidal activityrdquo Revista Brasileira deFarmacognosia vol 16 pp 696ndash720 2006

[34] N C Andrade E V L Cunha M S da Silva M F Angraand J M Barbosa-Filho ldquoTerpenoids of the Annonaceaedistribution and compilation of 13C NMR datardquo in RecentResearch Developments in Phytochemistry A Gayathri Ed pp1ndash85 Research Signpost Kerala India 2003

[35] J Barbosa-Filho E Vasconcelos Leitao da-Cunha and A IGray ldquoAlkaloids of the menispermaceaerdquo in Alkaloids Chem-istry and Biology pp 1ndash190 Academic Press 2000

[36] J M Barbosa Filho I M F Sette E V L da Cunha D NGuedes and M S Silva ldquoProtoberberine alkaloidsrdquo in TheAlkaloids G A Cordell Ed p 75 Elsevier Amsterdam TheNetherlands 2005

[37] J M Barbosa-Filho T H C Vasconcelos A A Alencar L MBatista R A G Oliveira and D N Guedes ldquoPlants and theiractive constituents from South Central and North Americawith hypoglycemic activityrdquo Revista Brasileira de Farmacog-nosia vol 15 pp 392ndash413 2005

[38] J M Barbosa-Filho M R Piuvezam M D Moura et al ldquoAnti-inflammatory activity of alkaloids a twenty-century reviewrdquoRevista Brasileira de Farmacognosia vol 16 pp 109ndash139 2006

[39] J M Barbosa Filho K C Paula Medeiros M F F M Dinizet al ldquoNatural products inhibitors of the enzyme acetyl-cholinesteraserdquo Revista Brasileira de Farmacognosia vol 16 pp258ndash285 2006

[40] J M Barbosa-Filho V K M Martins L A Rabelo et alldquoNatural products inhibitors of the angiotensin convertingenzyme (ACE) a review between 1980ndash2000rdquo Revista Brasileirade Farmacognosia vol 16 pp 421ndash446 2006

[41] J M Barbosa-Filho F A do Nascimento Junior A C deAndrade Tomaz et al ldquoNatural products with antileproticactivityrdquo Brazilian Journal of Pharmacognosy vol 17 no 1 pp141ndash148 2007

[42] JM Barbosa-Filho A A Alencar X P Nunes et al ldquoSources ofalpha- beta- gamma- delta- and epsilon-carotenes a twentiethcentury reviewrdquo Brazilian Journal of Pharmacognosy vol 18 no1 pp 135ndash154 2008

[43] LM Conserva C A B Pereira and JM Barbosa-Filho ldquoAlka-loids of the Hernandiaceae occurrence and a compilation oftheir biological activitiesrdquo in Alkaloids Chemistry and BiologyG A Cordell Ed pp 175ndash243 Academic Press 2005

[44] H de Sousa Falcao J A Leite J M Barbosa-Filho et alldquoGastric and duodenal antiulcer activity of alkaloids a reviewrdquoMolecules vol 13 no 12 pp 3198ndash3223 2008

[45] M C R Goncalves L S A Moura L A Rabelo J MBarbosa-Filho H M M Cruz and J Cruz ldquoProdutos naturaisinibidores da enzimaHMGCoA redutaserdquo Revista Brasileira deFarmacognosia vol 81 pp 63ndash71 2000

[46] N S Lira R C Montes J F Tavares et al ldquoBrominatedcompounds from marine sponges of the genus aplysina and a


compilation of their 13CNMR spectral datardquoMarine Drugs vol9 no 11 pp 2316ndash2368 2011

[47] L C S L Morais J M Barbosa-Filho and R N AlmeidaldquoPlants and bioactive compounds for the treatment of Parkin-sonrsquos diseaserdquo Arquivos Brasileiros de Fitomedicina Cientıficavol 1 pp 127ndash132 2003

[48] K S de LiraMota G ENDiasM E F Pinto et al ldquoFlavonoidswith gastroprotective activityrdquoMolecules vol 14 no 3 pp 979ndash1012 2009

[49] S L Oliveira M S da Silva J F Tavares et al ldquoTropane alka-loids from erythroxylum genus distribution and compilation of13C-NMR spectral datardquo Chemistry and Biodiversity vol 7 no2 pp 302ndash326 2010

[50] S Palmeira Junior L Conserva and J Barbosa-Filho ldquoClero-dane diterpenes from Croton species distribution and thecompilation of their 13C NMR spectral datardquo Natural ProductCommunications vol 1 pp 319ndash344

[51] L G Rocha J R G S Almeida R O Macedo and J MBarbosa-Filho ldquoA review of natural products with antileishma-nial activityrdquo Phytomedicine vol 12 no 6-7 pp 514ndash535 2005

[52] A L Souto J F Tavares M S da Silva M F F M de Diniz P Fde Athayde-Filho and J M Barbosa Filho ldquoAnti-inflammatoryactivity of alkaloids an update from 2000 to 2010rdquo Moleculesvol 16 no 10 pp 8515ndash8534 2011

[53] J G Sena Filho J Duringer G L A Maia et al ldquoEcdysteroidsfrom Vitex species distribution and compilation of their 13C-NMR spectral datardquo Chemistry and Biodiversity vol 5 no 5pp 707ndash713 2008

[54] J X de Araujo-Junior C Antheaume R C P Trindade MSchmitt J Bourguignon and A E G SantrsquoAna ldquoIsolationand characterisation of the monoterpenoid indole alkaloids ofAspidosperma pyrifoliumrdquo Phytochemistry Reviews vol 6 no1 pp 183ndash188 2007

[55] J X de Araujo-Junior E V L da-Cunha M C D O Chavesand A I Gray ldquoPiperdardine a piperidine alkaloid from Pipertuberculatumrdquo Phytochemistry vol 44 no 3 pp 559ndash561 1997

[56] J X de Araujo-Junior M S G de Oliveira P G V Aquino MS Alexandre-Moreira and A E G SantrsquoAna ldquoA phytochemicaland ethnopharmacological review of the genus Erythrinardquo inPhytochemicals A Global Perspective of Their Role in Nutritionand Health V Rao Ed InTech 2012

[57] H S Falcao I O Lima V L dos Santos et al ldquoReview ofthe plants with anti-inflammatory activity studied in Brazilrdquo inRevista Brasileira de Farmacognosia vol 15 pp 381ndash391 2005

[58] G L de Azevedo Maia V D S Santos Falcao-Silva P G VAquino et al ldquoFlavonoids from Praxelis clematidea RM Kingand Robinson modulate bacterial drug resistancerdquo Moleculesvol 16 no 6 pp 4828ndash4835 2011

[59] I R Mariath H D S Falcao J M Barbosa-Filho et al ldquoPlantsof the American continent with antimalarial activityrdquo BrazilianJournal of Pharmacognosy vol 19 pp 158ndash192 2009

[60] S L de Oliveira J F Tavares M V S C Branco et al ldquoTropanealkaloids from erythroxylum caatingae plowmanrdquo Chemistryand Biodiversity vol 8 no 1 pp 155ndash165 2011

[61] G L Pessini P G V Aquino V B Bernardo et al ldquoEvaluationof antimicrobial activity of three Aspidosperma speciesrdquo Phar-macologyonline vol 1 no 1 pp 112ndash119 2012

[62] J R Filho H de Sousa Falcao L M Batista J M B Filho andM R Piuvezam ldquoEffects of plant extracts on HIV-1 proteaserdquoCurrent HIV Research vol 8 no 7 pp 531ndash544 2010

[63] L J Q Junior J R G S Almeida J T Lima et al ldquoPlantswith anticonvulsant properties a reviewrdquo Revista Brasileira deFarmacognosia vol 18 pp 798ndash819 2008

[64] J Peng J Hu A B Kazi et al ldquoManadomanzamines A andB a Novel Alkaloid Ring system with potent activity againstMycobacteria and HIV-1rdquo Journal of the American ChemicalSociety vol 125 no 44 pp 13382ndash13386 2003

[65] K K H Ang M J Holmes T Higa M T Hamann andU A K Kara ldquoIn vivo antimalarial activity of the beta-carboline alkaloid manzamine Ardquo Antimicrobial Agents andChemotherapy vol 44 no 6 pp 1645ndash1649 2000

[66] K V Rao M S Donia J Peng et al ldquoManzamine B and E andircinal A related alkaloids from an Indonesian Acanthostrongy-lophora sponge and their activity against infectious tropicalparasitic andAlzheimerrsquos diseasesrdquo Journal of Natural Productsvol 69 no 7 pp 1034ndash1040 2006

[67] M Yamada Y Takahashi T Kubota et al ldquoZamamidineC 34-dihydro-6-hydroxy-1011-epoxymanzamine A and 34-dihydromanzamine J N-oxide new manzamine alkaloids fromsponge Amphimedon sprdquo Tetrahedron vol 65 no 11 pp 2313ndash2317 2009

[68] W Wang S Nam B Lee and H Kang ldquo120573-carboline alkaloidsfrom a Korean tunicate Eudistoma sprdquo Journal of NaturalProducts vol 71 no 2 pp 163ndash166 2008

[69] R Finlayson A N Pearce M J Page et al ldquoDidemnidinesA and B indole spermidine alkaloids from the New Zealandascidian didemnum sprdquo Journal of Natural Products vol 74 no4 pp 888ndash892 2011

[70] M Till and M R Prinsep ldquo5-bromo-8-methoxy-1-methyl-120573-carboline an Alkaloid from the New ZealandMarine BryozoanPterocella Wesiculosardquo Journal of Natural Products vol 72 no4 pp 796ndash798 2009

[71] H Lee K Yoon Y Han et al ldquo5-hydroxyindole-type alkaloidsas Candida albicans isocitrate lyase inhibitors from the tropicalspongeHyrtios sprdquo Bioorganic and Medicinal Chemistry Lettersvol 19 no 4 pp 1051ndash1053 2009

[72] I Orhan B Sener M Kaiser R Brun and D TasdemirldquoInhibitory activity of marine sponge-derived natural productsagainst parasitic protozoardquo Marine Drugs vol 8 no 1 pp 47ndash58 2010

[73] I Carletti B Banaigs and P Amade ldquoMatemone a new bioac-tive bromine-containing oxindole alkaloid from the indianocean sponge Iotrochota purpureardquo Journal of Natural Productsvol 63 no 7 pp 981ndash983 2000

[74] M Tsuda Y Takahashi J Fromont Y Mikami and JKobayashi ldquoDendridine A a Bis-indole alkaloid from a marinesponge Dictyodendrilla speciesrdquo Journal of Natural Productsvol 68 no 8 pp 1277ndash1278 2005

[75] R Zoraghi L Worrall R H See et al ldquoMethicillin-resistantStaphylococcus aureus (MRSA) pyruvate kinase as a target forbis-indole alkaloids with antibacterial activitiesrdquoThe Journal ofBiological Chemistry vol 286 no 52 pp 44716ndash44725 2011

[76] S Alvarado B F Roberts A E Wright and D ChakrabartildquoThe bis(Indolyl)imidazole alkaloid nortopsentin a exhibitsantiplasmodial activityrdquo Antimicrobial Agents and Chemother-apy vol 57 no 5 pp 2362ndash2364 2013

[77] Q BaoQ Sun X Yao et al ldquoBisindole alkaloids of the topsentinand hamacanthin classes from a marine sponge Spongosoritessprdquo Journal of Natural Products vol 70 no 1 pp 2ndash8 2007

[78] J Hu J A Schetz M Kelly et al ldquoNew antiinfective and human5-HT2 receptor binding natural and semisynthetic compounds


from the Jamaican sponge Smenospongia aureardquo Journal ofNatural Products vol 65 no 4 pp 476ndash480 2002

[79] A Raveh and S Carmeli ldquoAntimicrobial ambiguines from thecyanobacterium Fischerella sp collected in Israelrdquo Journal ofNatural Products vol 70 no 2 pp 196ndash201 2007

[80] S Mo A Krunic G Chlipala and J Orjala ldquoAntimicro-bial ambiguine isonitriles from the cyanobacterium Fischerellaambiguardquo Journal of Natural Products vol 72 no 5 pp 894ndash899 2009

[81] G Kirsch G M Kong A D Wright and R Kaminsky ldquoA newbioactive sesterterpene and antiplasmodial alkaloids from themarine sponge Hyrtios cf erectardquo Journal of Natural Productsvol 63 no 6 pp 825ndash829 2000

[82] H Huang Y Yao Z He et al ldquoAntimalarial 120573-carboline andindolactam alkaloids fromMarinactinospora thermotolerans adeep sea isolaterdquo Journal of Natural Products vol 74 no 10 pp2122ndash2127 2011

[83] S M Pimentel-Elardo S Kozytska T S Bugni C M IrelandH Moll and U Hentschel ldquoAnti-parasitic compounds fromStreptomyces sp strains isolated fromMediterranean spongesrdquoMarine Drugs vol 8 no 2 pp 373ndash380 2010

[84] M A Andreo P C Jimenez J B C N Siebra et al ldquoSystematicUPLC-ESI-MSMS study on the occurrence of staurosporineand derivatives in associated marine microorganisms fromEudistoma vannameirdquo Journal of the Brazilian Chemical Societyvol 23 no 2 pp 335ndash343 2012

[85] J Peng T Lin W Wang et al ldquoAntiviral alkaloids producedby the mangrove-derived fungus Cladosporium sp PJX-41rdquoJournal of Natural Products vol 76 no 6 pp 1133ndash1140 2013

[86] M Chen C Shao X Fu et al ldquoBioactive indole alkaloids andphenyl ether derivatives from a marine-derived Aspergillus spfungusrdquo Journal of Natural Products vol 76 no 4 pp 547ndash5532013

[87] Y Takahashi N Tanaka T Kubota et al ldquoHeteroaromatic alka-loids nakijinamines from a sponge Suberites sprdquo Tetrahedronvol 68 no 41 pp 8545ndash8550 2012

[88] N Tanaka R Momose A Tsubasa-Nakaguchi T Gonoi JFromont and J Kobayashi ldquoHyrtimomines indole alkaloidsfrom Okinawan sponges Hyrtios spprdquo Tetrahedron vol 70 p832 2014

[89] S B Bharate R R Yadav S I Khan et al ldquoMeridianin G andits analogs as antimalarial agentsrdquo MedChemComm vol 4 no6 pp 1042ndash1048 2013

[90] S Martınez-Luis J F Gomez C Spadafora H M GuzmanandMGutierrez ldquoAntitrypanosomal alkaloids from themarinebacterium Bacillus pumilusrdquoMolecules vol 17 no 9 pp 11146ndash11155 2012

[91] D T A Youssef L A Shaala and H Z Asfour ldquoBioactivecompounds from the Red Sea marine sponge Hyrtios speciesrdquoMarine Drugs vol 11 no 4 pp 1061ndash1070 2013

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


uptake stimulatory [22] larvicidal [23] trypanocidal [24]and vasodilator [25 26] and inhibition of cholinesterase [27]indoleamine-2 3-dioxygenase [28] calmodulin [29] andCB1 cannabinoid receptor [30] Infectious diseases causedby bacteria fungi viruses and parasites are still a majorthreat to public health despite the tremendous progress inhuman medicine The high prevalence of these diseases andthe emergence of widespread drug resistance developed bythese parasites to current treatments leading to reductionof their efficacy and consequent increase in the cost ofconventional treatments highlight the need for novel andeffective therapeutic alternativeswith fewer or no side-effectsTheir impact is particularly large in developing countries dueto the relative unavailability of medicines [31 32]

Therefore in continuation of our research on bioactivemolecules fromnatural origin [33ndash53] and plant extracts [54ndash63] we offer this compilation of the indole alkaloids frommarine sources

In this review literature was covered in order to highlightalkaloidal compoundswith an indolemoietywhich have beenshown to demonstrate activity against infectious diseases

2 Indole Alkaloids from Marine Sources

Manadomanzamines A and B (Figure 1) 120573-carbolines witha novel rearrangement of the manzamine framework wereisolated from an Indonesian sponge Acanthostrongylophorasp These compounds showed significant activities againstMycobacterium tuberculosis with MIC values of 19 and15 120583gmL respectively Manadomanzamines A and B werealso active against human immunodeficiency virus (HIV-1) with EC

50values of 70 and 165 120583gmL Furthermore

manadomanzamine A was active against the fungus Candidaalbicanswith an IC

50of 20120583gmL whilstmanadomanzamine

B exhibited activity against the fungus Cryptococcus neofor-mans with IC

50value of 35 120583gmL [64]

Manzamine A a 120573-carboline alkaloid present in severalmarine sponge species has been shown to inhibit the growthof the rodent malaria parasite Plasmodium berghei in vivoMore than 90 of the asexual erythrocytic stages of P bergheiwere inhibited after a single intraperitoneal injection of man-zamine A into infected mice Moreover it was demonstratedthat immunostimulatory effects caused by the compoundplay an important role in preventing mouse death due tofulminating recurrent parasitemia in animals treated with100mmol per kg of manzamine A [65]

Several manzamine-type alkaloids were also isolatedfrom an Indonesian sponge of the genus Acanthostrongy-lophora The 120573-carbolines (+)-8-hydroxymanzamine A and6-hydroxymanzamine E (Figure 1) showed strong activ-ity against M tuberculosis H37Rv with MIC values of09 and 04 120583gmL respectively Manzamine A and (+)-8-hydroxymanzamine were strongly active when tested againstPlasmodium falciparum chloroquine-sensitive D6 clone andchloroquine-resistant W2 clone showing respectively IC

50

values of 45 and 60 ngmL toward the former and equally80 ngmL toward the latter Moreover manzamine A man-zamine Y and 6-hydroxymanzamine E (Figure 1) have shown

significant activity against Leishmania donovani with IC50

values of 09 16 and 25 120583gmL respectively [66]Investigation of bioactivity of manzamine alkaloids iso-

lated from an Okinawan sponge Amphimedon sp revealedactive compounds against Trypanosoma brucei brucei and Pfalciparum Zamamidine C (Figure 1) 34-dihydromanzam-ine JN-oxide andmanzamine A showed inhibitory activitiesin vitro against T b brucei with IC

50values of 027 444 and

004 120583gmL respectively and P falciparum with IC50

values058 702 and 097 120583gmL respectively [67]

Seven 120573-carboline-based metabolites designated as eud-istomins Y

1ndashY7(Figure 2) were isolated from a tunicate of

the genus Eudistoma collected in South Korea These newmetabolites differ from previously isolated marine metabo-lites due to the presence of a benzoyl group attached to the120573-carboline nucleus at C-1 Eudistomin Y

6exhibited mod-

erate antibacterial activity against Gram-positive bacteriaStaphylococcus epidermidis ATCC12228 and B subtilis ATCC6633 with MIC values of 125 and 25 120583gmL respectively butshowed no inhibitory activity toward the other two strainsof Gram-positive bacteria S aureus ATCC 6538 and Mlutes ATCC 9341 and the Gram-negative bacteria includingE coli ATCC 11775 Salmonella typhimurium ATCC 14028and Klebsiella pneumoniae ATCC 4352 Eudistomins Y

1and

Y4also displayed the same selectivity as eudistomin Y

6but

demonstrated weak antibacterial activity against the twostrains of bacteria S epidermidis ATCC12228 and B subtilisATCC 6633 with MICs of 50 and 200120583gmL respectively[68]

Investigation of the CH2Cl2extract from the bryozoan

Pterocella vesiculosa collected in New Zealand has led tothe isolation of 5-bromo-8-methoxy-1-methyl-120573-carboline(Figure 2) This alkaloid was evaluated for antibacterial andantifungal activities and showed inhibitory action toward theGram-positive bacterium B subtilis and the fungi C albicansand Trichophyton mentagrophyteswithMID ranges of 2ndash4 4-5 and 4-5 120583gmL respectively [69]

An indole spermidine alkaloid didemnidine B (Figure 3)was described in the New Zealand ascidian Didemnum spEvaluation of the compound against Trypanosoma bruceirhodesiense Trypanosoma cruzi L donovani and Plasmod-ium falciparum K1 chloroquine-resistant strain indicateddidemnidine B to bemildly active toward themalaria parasitewith IC

50value of 15 120583M [70]

In addition chemical investigations of the tropicalmarinesponge Hyrtios sp have resulted in the isolation of severalalkaloids which were evaluated as C albicans isocitratelyase inhibitors Out of the compounds tested the bis-indole alkaloid hyrtiosin B (Figure 4) showed themost potentinhibitory activity with an IC

50value of 507120583M Other

compounds comprised simple indole alkaloids namely 1-carboxy-6-hydroxy-34-dihydro-120573-carboline 5-hydroxy-1H-indole-3-carboxylic acid methyl ester serotonin hyrtiosinA and 5-hydroxyindole-3-carbaldehyde (Figure 3) revealedonly moderate to weak activity against C albicans isocitratelyase with MIC values ranging between 398 and 1529 120583MBy comparing their chemical structures it was found thatthe enzyme inhibitory activities of these 5-hydroxyindole-type alkaloids are markedly affected by a substitution of



Manzamine A

Manzamine Y

R1 = H

R1 = H

R2 = H

R2 = H

R2 = HR1 = OH

R1 = OH

R2 = OH



R1

R2H

O

OH

N

N

N

N

R1

R2H

OH

N

N

N

N

H

OH

N

N

NN

H

H

HH

H

OH

N

N

N

N

N

N

H

H

H

H HHO

O

OH

NN

N

N

H

H

H

H HHO OH

NN

N

N

Zamamidine C








R1 = Br

R2 = H R3 = Br R4 = H


Eudistomin Y6

R2 = Br

R3 = Br

R3 = Br

R4 = Br


R2 = H

H

H

O

O

N

NR1

R2

R3 R4


H

H

O

N

N

COOH


HN

N

O

Br


Matemone Tryptophol

Isoplysin

6-Bromoaplysinopsin


R2 = CH3

R2 = CH3

R2 = HR3 = CH3

R3 = HR3 = H

R4 = HR4 = HR4 = CH3




HO HOOCH3

NH

NH

NH

NH

NH

NH

NH

NH N

HNH

O

O

O

O

OO

O

OH

OH

OH

Br


CHO

HN

NH2

R1

HR2N

NR3

NR4

O






H

H

H

HH

H

HH

O

O

O

HO

HO

OO

N

H

H

N

HN

HN

HN

N

N N

N

N

H

H

NHN

NHN

HN

NN

HN

Br

Br

Br

Br

Br

Br

BrHO























Cl

H

H

H

CN

N

Cl

HCN

OH

HN

Cl

HCN

OH

HN

H

H

H

CN

N

OH

H CNO

HN





HN

O

N+

HN

O

N+

OH



50








value of 2 ngmL



N

HN

O

O

R

NH

O

Marinacarboline D

N

O

NH

HN

HN

H

H

H

N

N

O

HN

OGlu



H

H

H

O

O

O

N

N N

N







H

O

OO

N

N

N

HN


H

H

H

O

O

O

N

NN




50





Nakijinamine C

HOOH

N

N

N

HN H

R

+

+

OH

N

HN

HN

NH

N+

+

Br




HO

NHHO

N

HN

O

ON

HNHO

NH

O

HO

HO

HONHHN

OH

OH

O OOH

NH

NH

O

O

O

+

OHN

NN

O

O



50value of 85 120583M [85]




50












5040 120583gmL) [88]




50value of 64 120583M [89]




N

N

N

H2N

H

N

N

Br

H2N

NH


R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3



50values of 206 and 194 120583M






Acknowledgments


References








































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



Manzamine A

Manzamine Y

R1 = H

R1 = H

R2 = H

R2 = H

R2 = HR1 = OH

R1 = OH

R2 = OH



R1

R2H

O

OH

N

N

N

N

R1

R2H

OH

N

N

N

N

H

OH

N

N

NN

H

H

HH

H

OH

N

N

N

N

N

N

H

H

H

H HHO

O

OH

NN

N

N

H

H

H

H HHO OH

NN

N

N

Zamamidine C








R1 = Br

R2 = H R3 = Br R4 = H


Eudistomin Y6

R2 = Br

R3 = Br

R3 = Br

R4 = Br


R2 = H

H

H

O

O

N

NR1

R2

R3 R4


H

H

O

N

N

COOH


HN

N

O

Br


Matemone Tryptophol

Isoplysin

6-Bromoaplysinopsin


R2 = CH3

R2 = CH3

R2 = HR3 = CH3

R3 = HR3 = H

R4 = HR4 = HR4 = CH3




HO HOOCH3

NH

NH

NH

NH

NH

NH

NH

NH N

HNH

O

O

O

O

OO

O

OH

OH

OH

Br


CHO

HN

NH2

R1

HR2N

NR3

NR4

O






H

H

H

HH

H

HH

O

O

O

HO

HO

OO

N

H

H

N

HN

HN

HN

N

N N

N

N

H

H

NHN

NHN

HN

NN

HN

Br

Br

Br

Br

Br

Br

BrHO























Cl

H

H

H

CN

N

Cl

HCN

OH

HN

Cl

HCN

OH

HN

H

H

H

CN

N

OH

H CNO

HN





HN

O

N+

HN

O

N+

OH



50








value of 2 ngmL



N

HN

O

O

R

NH

O

Marinacarboline D

N

O

NH

HN

HN

H

H

H

N

N

O

HN

OGlu



H

H

H

O

O

O

N

N N

N







H

O

OO

N

N

N

HN


H

H

H

O

O

O

N

NN




50





Nakijinamine C

HOOH

N

N

N

HN H

R

+

+

OH

N

HN

HN

NH

N+

+

Br




HO

NHHO

N

HN

O

ON

HNHO

NH

O

HO

HO

HONHHN

OH

OH

O OOH

NH

NH

O

O

O

+

OHN

NN

O

O



50value of 85 120583M [85]




50












5040 120583gmL) [88]




50value of 64 120583M [89]




N

N

N

H2N

H

N

N

Br

H2N

NH


R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3



50values of 206 and 194 120583M






Acknowledgments


References








































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






R1 = Br

R2 = H R3 = Br R4 = H


Eudistomin Y6

R2 = Br

R3 = Br

R3 = Br

R4 = Br


R2 = H

H

H

O

O

N

NR1

R2

R3 R4


H

H

O

N

N

COOH


HN

N

O

Br


Matemone Tryptophol

Isoplysin

6-Bromoaplysinopsin


R2 = CH3

R2 = CH3

R2 = HR3 = CH3

R3 = HR3 = H

R4 = HR4 = HR4 = CH3




HO HOOCH3

NH

NH

NH

NH

NH

NH

NH

NH N

HNH

O

O

O

O

OO

O

OH

OH

OH

Br


CHO

HN

NH2

R1

HR2N

NR3

NR4

O






H

H

H

HH

H

HH

O

O

O

HO

HO

OO

N

H

H

N

HN

HN

HN

N

N N

N

N

H

H

NHN

NHN

HN

NN

HN

Br

Br

Br

Br

Br

Br

BrHO























Cl

H

H

H

CN

N

Cl

HCN

OH

HN

Cl

HCN

OH

HN

H

H

H

CN

N

OH

H CNO

HN





HN

O

N+

HN

O

N+

OH



50








value of 2 ngmL



N

HN

O

O

R

NH

O

Marinacarboline D

N

O

NH

HN

HN

H

H

H

N

N

O

HN

OGlu



H

H

H

O

O

O

N

N N

N







H

O

OO

N

N

N

HN


H

H

H

O

O

O

N

NN




50





Nakijinamine C

HOOH

N

N

N

HN H

R

+

+

OH

N

HN

HN

NH

N+

+

Br




HO

NHHO

N

HN

O

ON

HNHO

NH

O

HO

HO

HONHHN

OH

OH

O OOH

NH

NH

O

O

O

+

OHN

NN

O

O



50value of 85 120583M [85]




50












5040 120583gmL) [88]




50value of 64 120583M [89]




N

N

N

H2N

H

N

N

Br

H2N

NH


R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3



50values of 206 and 194 120583M






Acknowledgments


References








































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




H

H

H

HH

H

HH

O

O

O

HO

HO

OO

N

H

H

N

HN

HN

HN

N

N N

N

N

H

H

NHN

NHN

HN

NN

HN

Br

Br

Br

Br

Br

Br

BrHO























Cl

H

H

H

CN

N

Cl

HCN

OH

HN

Cl

HCN

OH

HN

H

H

H

CN

N

OH

H CNO

HN





HN

O

N+

HN

O

N+

OH



50








value of 2 ngmL



N

HN

O

O

R

NH

O

Marinacarboline D

N

O

NH

HN

HN

H

H

H

N

N

O

HN

OGlu



H

H

H

O

O

O

N

N N

N







H

O

OO

N

N

N

HN


H

H

H

O

O

O

N

NN




50





Nakijinamine C

HOOH

N

N

N

HN H

R

+

+

OH

N

HN

HN

NH

N+

+

Br




HO

NHHO

N

HN

O

ON

HNHO

NH

O

HO

HO

HONHHN

OH

OH

O OOH

NH

NH

O

O

O

+

OHN

NN

O

O



50value of 85 120583M [85]




50












5040 120583gmL) [88]




50value of 64 120583M [89]




N

N

N

H2N

H

N

N

Br

H2N

NH


R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3



50values of 206 and 194 120583M






Acknowledgments


References








































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Cl

H

H

H

CN

N

Cl

HCN

OH

HN

Cl

HCN

OH

HN

H

H

H

CN

N

OH

H CNO

HN





HN

O

N+

HN

O

N+

OH



50








value of 2 ngmL



N

HN

O

O

R

NH

O

Marinacarboline D

N

O

NH

HN

HN

H

H

H

N

N

O

HN

OGlu



H

H

H

O

O

O

N

N N

N







H

O

OO

N

N

N

HN


H

H

H

O

O

O

N

NN




50





Nakijinamine C

HOOH

N

N

N

HN H

R

+

+

OH

N

HN

HN

NH

N+

+

Br




HO

NHHO

N

HN

O

ON

HNHO

NH

O

HO

HO

HONHHN

OH

OH

O OOH

NH

NH

O

O

O

+

OHN

NN

O

O



50value of 85 120583M [85]




50












5040 120583gmL) [88]




50value of 64 120583M [89]




N

N

N

H2N

H

N

N

Br

H2N

NH


R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3



50values of 206 and 194 120583M






Acknowledgments


References








































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



N

HN

O

O

R

NH

O

Marinacarboline D

N

O

NH

HN

HN

H

H

H

N

N

O

HN

OGlu



H

H

H

O

O

O

N

N N

N







H

O

OO

N

N

N

HN


H

H

H

O

O

O

N

NN




50





Nakijinamine C

HOOH

N

N

N

HN H

R

+

+

OH

N

HN

HN

NH

N+

+

Br




HO

NHHO

N

HN

O

ON

HNHO

NH

O

HO

HO

HONHHN

OH

OH

O OOH

NH

NH

O

O

O

+

OHN

NN

O

O



50value of 85 120583M [85]




50












5040 120583gmL) [88]




50value of 64 120583M [89]




N

N

N

H2N

H

N

N

Br

H2N

NH


R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3



50values of 206 and 194 120583M






Acknowledgments


References








































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



Nakijinamine C

HOOH

N

N

N

HN H

R

+

+

OH

N

HN

HN

NH

N+

+

Br




HO

NHHO

N

HN

O

ON

HNHO

NH

O

HO

HO

HONHHN

OH

OH

O OOH

NH

NH

O

O

O

+

OHN

NN

O

O



50value of 85 120583M [85]




50












5040 120583gmL) [88]




50value of 64 120583M [89]




N

N

N

H2N

H

N

N

Br

H2N

NH


R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3



50values of 206 and 194 120583M






Acknowledgments


References








































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



N

N

N

H2N

H

N

N

Br

H2N

NH


R2OR1

HN

HN

N

OH

Hyrtioerectine D

Hyrtioerectine E

Hyrtioerectine F

R1 = COOH

R1 = COOH

R1 = CONH2

R2 = H

R2 = H

R2 = CH3



50values of 206 and 194 120583M






Acknowledgments


References








































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


























































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology























Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Documents

Review Article Indole Alkaloids from Marine Sources as ...downloads.hindawi.com/journals/bmri/2014/375423.pdfReview Article Indole Alkaloids from Marine Sources as Potential Leads