Bioactive secondary metabolites , Cyanotoxins , Antimicrobial compounds , Antibacterial compounds, Antifungal compounds, Antiviral compounds,Antialgal compounds, Antiprotozoal compounds , Anticancer compounds

1. INTRODUCTION
Bioactive compounds are organic compounds produced from microalgae. Several secondary
metabolites are synthesized by microalgae which remain accumulated in the cell or released
during cell lysis. Secondary metabolites are not directly invoived in the normal growth,
development, or reproduction of an organism. These compounds are physiologically active
substances with functional properties in the human body. Developing multidrug resistance in
human pathogenic viruses , bacteria and resulting into serious diseases. It makes enthuasism for
the development of and manufacture of various novel bioactive compounds. Microalgae is a rich
source of antimicrobial compounds such as antibacterial compounds (Jaki et al., 2000 ; Izabela
et al., 2014), antifungal compounds ( Kajiyama et al., 1998 ; De flecio et al; 2010 ),
antimicroalgal compounds (Sumathy et al., 2014; Vinod Rishi and A.K.Awasthi, 2015),
antiviral compounds (Bouhlal et al., 2010), and other biological acivities including anticancer (
S. Vijaykumar and M. Menakha, 2015 ), and antiprotozoal compounds ( review by Vinod Rishi
and A.K. Awasthi, 2015).
An interest in production of bioactive compounds from natural sources have recently emerged ,
driven by growing number of scientific studies that demonstrates the beneficial effects of these
compounds on health. Natural products are important in the search for new pharmacologically
active compounds. In general, they play a role in drug discovery for the treatment of human
diseases ( D.J. Newman and G.M. Gragg, 2012). Many clinically viable and commercially
available drugs with antitumor and anti-infective activity originated as natural products.
Microalgae are a natural source of bioactive compounds. Microalgae are known to produce
more than 1100 bioactive compounds and including therapeutically effective compounds that
can be obtained from the biomass or released extracellularly into the medium ( S. Bhagwathy et
al., 2011). Thes microalgae also produce several bioactive compounds which includes peptides ,
polysaccharides , saturated and unsaturated fatty acids , sulfated polysaccharides and several
toxins are produced by cyanobacteria which causes serious health problems in human and
animals . The cyanobacterial toxins such as hepatotoxins (micocystin, nodularin,
cylindrospermopsin ) , neurotoxins ( anatoxin-a, antaoxin-a(S) , saxitoxins ), dermatotoxins etc.
produced by toxigenic genera . Inthis review, an attempt has been made to focus on the natural
compounds from microalgae, which have shown potent biological activity in vivo or in

2. vitro, and have promise to be developed as therapeutic agents and microalgae as a source of
novel antimicrobial compounds and anticancer compounds, antiprotozoal compounds including
cyanobacterial toxins showing wide range of biological activity against viral and bacterial
human pathogns .
Microalgae as source of Bioactive compounds and Biological activities
Bioactive secondary metabolites are organic compounds . These bioactive compounds are
physiologically active substances with functional properties in the human body . Bioactive
metabolites can be categorized into two groups :
1.Antimicrobial compounds and other compounds(Anticancer ,Antiprotozoan)
2. Toxins (Cyanobacterial Toxins )
1.Antimicrobial Compounds: A bioactive substance that kill microorganisms or stop their
growth .
i. Antibacterial compounds
ii. Antifungal compounds
iii. Antimicroalgal compounds
iv. Antiviral compounds
v. Antiprotozoal compounds
vi. Anticancer compounds
i. Antibacterial compounds
A large number of bioactive compounds have been isolated and identified from various species
of microalgae those have remarkable potential against different gram-positive and gram-negative
bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis,

3. Enterococcus aerogenes, Salmonella typhi, Mycobacterium tuberculosis, Mycobacterium laprae,
Vibrio cholera, Bacillus subtilis, Bacillus cereus, Escherichia coli, Klebsiella pneumoniae etc.
Hormothamnions are cyclic undecapeptides, produced from marine cyanobacterium
Hormothamnion enteromorphoides, shows activity against bacteria (Gerwick et al.,1989; 1992)
and undecapeptides schizotrin from Schizothrix sp. ( Pergament and Carmeli, 1994). The epilthic
cyanobacterium Nostoc spongiaeforme var.tenue known for the production of cyclic
hexapeptide -tenuecyclamides which also active against bacteria (Banker and Carmeli,1998).
Muscoride A , an antibacterial peptide is isolated from Nostoc muscorum (Nagatsu et al.,1995) .
Malyngolides are a group of antibacterial compounds produced by marine cyanobacterium
Lyngbya majuscula (Gerwick et al.,1987; Burja et al., 2001). Noscomin , obtained from Nostoc
commune, shows antibacterial activity against Bacillus cereus, Staphylococcus epidermidis,
Escherechia coli (Zaki et al., 1999). Ambiguine-1 isonitrile from Fischerella sp. active against
E.coli , Staphylococcus albus and Bacillus substilis (Raveh and Carmeli, 2007); Hapalindole –T
from Fischerella sp. active against Staphylococcus aureus, Pseudomonasaeruginosa, Salmonella
typhi and E.coli (Asthana et al., 2006). Pratt et al., 1944 isolated first antibacterial compound
from a microalga, Chlorella sp., chlorellin shows inhibitory activity against both Gram+ve and
Gram-ve bacteria. Pressurized liquid ethanol extract of Haematococcus pluvialis contain short
chain fatty acids (butanoic acid and methyl lactate) active against E.coli , Staphylococcus aureus
( Santoyo et al., 2009), compounds synthesized by Scenedesmus costatum, long chain fatty acids
show activity against Vibrio sp.. Some of the important antibacterial compounds produced by
microalgae are listed in table 1.
Table 1: Some important Antibacterial compounds produced by Microalgae
S.no. Species Bioactive
compound
Target
organism
References
1. Fishcerella sp. Ambiguine 1
isonitrile
Bacillus subtilis,
E.coli,
Staphylococcus
aureus
Mo et al., 2009
2. Fischerella sp. Haplindol -T Staphylococcus Asthana et al.,

4. aureus,
Salmonella
typhi,
Pseudomonas
aeruginosa
2006
3. Harmothamnion
entermorphoides
Hormothamnins Bacillus subtilis,
E.coli,
Staphylococcus
aureus
Gerwick et al.,
1992
4. Lyngbya majuscula,
Phormidium sp.
Malyngolide Mycobacterium
smegmatis
Burja et al., 2001
5. Nostoc spongiaeforme Tenuecyclamides Bacillus cereus,
Salmonella typhi
Banker and
Carmeli , 1998
6. Nostoc commune Noscomin Bacillus cereus,
Staphylococcus
epidermidis
,E.coli
Zaki et al., 1999
7. Scytonema sp.UTEX1163 Scytocalarol Bacillus
anthraci
,Staphylococcus
,E.coli
,Mycobacterium
tuberculosis
Mo et al., 2009
8. Schizothrix sp. Schizotrin A Bacillus subtilis Pergament and
Carmeli,1994
9. Haematococcus pluvialis Short chain
fattyacids
Escherichia coli
Staphylococcus
aureus
Santoyo et al.,
2009
10. Skeletonema costatum Long chain fatty
acids
Vibrio spp. Naviner et al.,
1999
11. Chlamydomonas reinhardtii Metahnolic and S. aureus, Ghasemi et al.,

5. and Chlorella vulgaris hexane extracts S.epidermidis,
Bacillus subtilis,
E.coli,
Salmonella typhi
2007
12. Chlorococcum sp. Aqueous extract E.coli, S.aureus,
Salmonella typhi
Bhadury and
Wright , 2004
ii. Antifungal compounds:
Microalgae shows remarkable activity against various fungi and inhibit their growth and
development. Antifungal potential was observed in a large number of cyanobacterial extracts
(Ishibashi et al., 1986). The cryptophycins comprises the largest class of cyanobacterial
depsipeptides (Trimurtulu et al., 1994). Cryptophycin-1, an important member of cryptophycin
class, was first isolated from Nostoc ATCC53787 which exhibited antifungal properties (Hirsch
et al., 1990; Schwartz et al., 1990). Another compound, scytophycin, having antifungal
potential was also reported from various species of cyanobacteria (Patterson and Carmeli, 1992).
Scytophycins are highly cytotoxic metabolites. Ambigols are polychlorinated aromatic
compound, isolated from terrestrial cyanobacterium Fischerella ambigua, having potent activity
against several fungi (Falch et al., 1993) and other compound named parsiguine (Ghasemi et
al., 2004). Cyanobacterium Hapalosiphon fontinalis produce a group of indole
alkaloids,hapalolindoles, act as antifungal agent (Moore et al., 1987a). Ambiguine isonitrilsare
hapalolindole type alkaloids, with antifungal properties, produced by Fischerellaambigua,
Hapalosiphon hibernicus and Westiellopsis sp. (Smitka et al., 1992). Pressurized liquid ethanol
extracts of Haematococcus pluviallis was tested by Santoyo et al; 2009 against Candida albicans
and Aspergillus niger. Methanolic extract of Chlamydomonas reinhardtii and Chlorella vulgaris
shows antifungal activity against Candida kefir, Aspergillus niger, A. fumigates. Some important
antifungal compounds produced by different microalgae are listed in Table 2.

6. Table 2: Some important Antifungal compounds produced by Microalgae
S.no. Species Bioactive
compound
Target organism References
1. Chlamydomonas
reinhardtii ,
Chlorella vulgaris
Methanolic
extracts
Candida kefir,
Aspergillus niger,
Aspergillus fumigatus
Ghasemi et al.,
2007
2. Haematococcus
pluvialis
Butanoic acid
and Methyl
lactate
Candida albicans Santayo et al., 2009
3. Chlorella
pyrenoidosa ,
Scenedesmus
quadricauda
Methanolic and
hexane extracts
Aspergillus niger, A.
flavus, Penicillium
herquei, Fusarium
moniliforme,
Helminthosporiumsp.,
Alternaria brassicae,
Saccharomyces
cerevisae, Candida
albicans
Abedin et al., 2008
4. Goniodoma
pseudogoniaulax
Gonidomin A - Bhadury and
Wright, 2004
5. Calothrix fusca Calophycin - Moon et al., 1992
6. Hormothamnion
enteromorphoides
Hormothamnion
A
- Gerwick et al.,
1992
7. Haplosiphon
fontinalis
Haplindol - Burja et al., 2001
8. Fischerella Fischerellin - Dahms et al., 2006

7. muscicola
9. Nostoc sp. Nostocyclamides - Moore,et.al.,1988
10. Scytonema
ocellatum
Tolytotoxins - Pattersion and
Carmeli,1996
iii. Antialgal compounds:
Various metabolites from microalgae have been isolated and identified as antialgal agent i.e. they
inhibit the growth and development of different algal species. These metabolites are
Galactosyldiacylglycerols from Phormidium tenue (Murakami et al., 1991), Nostocin-A from
Nostoc spongiaeforme (Hirata et al., 1996), Cyanobacterin LU-1 from Nostoc linckia (Gromov
et al., 1991), Cyanobactericin from Scytonema hoffmanii (Abarzua et al., 1999), Fischerellin
from Fischerella muscicola (Dahms et al., 2006) and Aponin form Gomphosphaeria aponia
(Bhadury and Wright, 2004). Some important antialgal compounds produced by different
microalgae are listed in Table 3.
Table 3: Some important Antialgal compounds produced by Microalgae.
S.no. Species Bioactive compound Target
organism
References
1. Peridinium bipes Water-soluble extract Microcystis
aeruginosa
Bhadury and
Wright, 2004
2. Isochrysis galbana C22H38O7 –cell free
filtrates
Dunaliella
salina,
Platymonas
elliptica,
Chlorella
vulgaris,
C.gracilis
Yingying et
al., 2008

8. ,Chaetoceros
muelleri
,Nitzschia
closterium
3. Fischerella muscicola Fischerellin - Dahms et
al.,2006
4. Gomphosphaera aponina Aponin - Bhadury and
Wright, 2004
5. Nostoc linckia Cyanobacterin LU-1 - Gromov et al.,
1996
6. Nostoc spongiaforme Nostocine A - Hirata et al.,
1996
7. Phormidium tenue Galactosyldiacylglycerols - Bhadury and
Wright, 2004
8. Scytonema hofmanni Cyanobactericin - Abarzua et al.,
1999
iv. Antiviral compounds
Several cyanobacterial species have been identified for theproduction of novel compounds which
shows potent activity against a variety of viralpathogens including HIV. It is well known that
cyanobacteria have potential against avast variety of viruses (Damonte et al., 2004; Meyer and
Hamann 2005; Meyer et al., 2009). Many observations made for the approval of antiviral
metabolites andextracellular polymeric substances from various cyanobacteria (Guang Zhou et
al., 2004; Rechter et al., 2006; Santoyo et al., 2006; Rodriguez-Meizso et al., 2008).
Indolocarbazoles shows activity against herpes virus which produced by

9. Nostocsphaericum(Knubel et al., 1990). A polysaccharide, Ca Spirulan, exhibit the
potentactivity against HIV which produced by Spirulina platensis (Hayashi et al., 1991; Santoyo
et al., 2006). Ca- spirulan shows activity against HIV-1, HIV-2, Influenzavirus and other
enveloped viruses. Ca-spirulan inhibits the activity of reversetranscriptase of HIV-1 and also
inhibits the attachment of virus to the host. Caspirulanprevent the fusion of HIV infected and
uninfected CD4 lymphocytes (Feldmann et al., 1999). Another acidic polysaccharide, Nostoflan,
have beenisolated from Nostoc flagelliforme with virucidal potential against Herpes
SimplexVirus (Kenji et al., 2005). Carbolins, form cyanobacterium Dichothrix baueriana,have
activity against HSV-II (Larsen et al., 1994). Cyanovirin-N, from Nostocellipsosporum, is a
proteinaceous compound has potential against HIV (Boyd et al., 1997). Cyanovirin-N 101 amino
acid long and 11 KDa polypeptide and inhibit thebinding of HIV GP 120 protein to the CD4+
receptors (Klasse et al., 2008). In vitrostudies revealed that Cyanovirin-N also inhibits the
growth of HSV-VI and meselsvirus (Dey et al., 2000). Scytovirin is a 95 amino acid long
polypeptide with 9.7KDa molecular weight which was first isolated from Scytonema varium
(Bokesch et al., 2003). It binds to the envelope glycoprotein of HIV such as GP120, GP160,
GP41etc. and inactivates the virus activity (Xiong et al., 2006). Glycolipids from Oscillatoria
limnetica (Reshef et al., 1997), Oscillatoria trichoides (Loya et al.,1998) and sulfolipids from
Lyngbya lagerheimii and Phormidium tenue (Gustafson et al., 1989) have potential against HIV.
Cyclic peptides (Ichthyopeptin A & B) from Microcystis ichthyoblabe shows activity against
Influenza A Virus (Zainuddin et al., 2007). Some important antiviral compounds produced by
different Microalgae are listed in Table 4.
Table 4: Some important Antiviral compounds produced by Microalgae
S.no. Species Bioactive Compound Target
organism
References
1. Lyngbya
majuscula
Cyclic peptides HSV Rajeev and
Xu,2004
2. Lyngbya
lagerheimii
Sulfolipids HIV-1 Rajeev and
Xu,2004
3. Lyngbya
lagerheimii
Sulfolipids HIV Gustafson et
al., 1989

10. 4. Microcystis
ichthyoblabe
Ichthyopeptins A,B Influenza
virus
Zainuddin et
al.,
2007
5. Nostoc
sphaericum
Indolocarbazoles HSV Larson et al.,
1994
6. Nostoc
ellipsosporum
Cyanovirin-N HIV-1 Boyd et al.,
1997
7. Oscillatoria
raoi
Acelated sulfoglycolipids Reshef et al.,
1997
8. Phormidium
tenue
Galactosyldiacylglycerols Rajeev and
Xu, 2004
9. Phormidium
tenue
Cyanovirin HIV-1 Boyd et al.,
1997
10. Spirulina
platensis
Ca- Spirulan HIV-1,2,
HSV,
Influenza
virus
Hayashi et
al.,1991
11. Scytonema
varium
Scytovirin HIV Bokesch et
al.,
2003
12. Gyrodinium
impuddicum
Sulfated
exopolysaccharide
HSV1 Yim et al.,
2004
13. Navicula
directa
Polysaccharide HSV1 & 2,
influenzaVirus
Lee et al.,
2006
Vi. Antiprotozoal compounds
An estimate of World Health Organization (WHO) said that more than one billion people among
the world are suffering from tropical diseases caused by Plasmodium, Trypanosoma and
Leishmania (Simmons et al., 2008). Currently available medicines for the treatment of malaria
and leishmaniasis are unable to cure the disease symptoms due to development of resistance by
these parasites (Lanzer and Rohrbach, 2007; Prioto et al., 2007). Almiramide B and C are liner
lipopeptides, isolated from Lyngbya majuscula, have potential to inhibit the growth of
Leishmania donovani (Sanchez et al., 2010). Calothrixin A and B (Indolophenanthridine
alkaloids) from Calothrix sp. is suppress the growth of chloroquine-resistant Plasmodium
falciparum (Rickards et al., 1999). Ambigol C from Fischerella ambigua inhibits the growth of

11. Trypanosoma rhodesiense and Plasmodium falciparum (Wright et al., 2005). Some important
Antiprotozoal compounds produced by different microalgae are listed in Table 5.
Table 5: Some important Antiprotozoal compounds produced by microalgae
S.no. Species Bioactive
Compound
Target
organism
References
1. Calothrix sp. Calothrixin A,B Chloroquine
resistant P.
falciparum
Rickards et
al., 1999
2. Fischerella
Ambigua
Ambigol C Trypanosoma
rhodesiense
Wright et al.,
2005
3. Lyngbya
Majuscule
Drgomabin,
Carmabin A,
Dragonamide A
W2-chloroquine
resistant
malaria
parasites
McPhail et al.,
2007
4. Lyngbya
Majuscule
Almiramide B,C L. donovani Sanchez et
al., 2010
5. Lyngbya
Majuscule
Dragonamide A,E
and Herbamide B
L. donovani Balunas et al.,
2010
6. Lyngbya
Majuscule
Lagunamie A,B Lagunamie A,B Tripathi et al.,
2010
7. Oscillatoria sp. Venturamide A,B W2-chloroquine
resistant P.
falciparum
Linnington et
al., 2007
8. Oscillatoria
Nigroviridis
Viridamide A Trypanosoma,
Leismania
Simmons et
al., 2008
9. Phormidium sp. Hierridin B Plasmodium
Falciparum
Papendorf et
al., 1998
10. Symploca sp. Symplocamide A W2-chloroquine
resistant P.
falciparum , T.
cruzi,
Leismania
Donovani
Linnington et
al., 2008
11. Schizothrix sp. Gallinamide A P. falciparum Linnington et
al., 2009

12. vi. Anticancer compounds
The capability to reduce the growth of cancer cell lines by natural products may lead to the
discovery of novel, effective anti-cancer drugs. Various cyanobacteria species collected from
various coastal and deep sea regions of the marine environment has proved to be a predominant
source for the production of different chemical classes of natural products with anti-proliferative,
anti-tumor and anti-cancer properties. The first anticancer compound ‘Tolytoxin’ isolated by
Moore (1981) from cyanobacteria. Tantazoles and mirabazoles are modified cytotoxic peptides
of Scytonema mirabile (Pattenden and Thom, 1993). Tantazoles and mirabazoles are tumor
selective cytotoxins but Tantazole-B and Didehydromirabazole A have potent activity against
tumor (Vareriote et al., 1994). Hapalosiphonwelwitschii produce a novel cyclic depsipeptide
‘hapalosin’ have reverse Pglycoprotein-mediated multidrug resistance in tumor cell lines
(Stratmann et al., 1994). Cryptophycin-I is a microtubule depolymerising agent (Smith, et. al.,
1994)which exhibits excellent activity against a wide range of solid tumors implanted inmice
including drug resistance and multidrug resistance (Trimurtulu et al., 1994). Cryptophycin-I was
isolated from Nostoc sp. GSV224 in Moore’s lab (Patterson et al., 1991). Its IC50 is 5PG/Ml for
KB human nasopharyngeal cancer cell lines and3PG/Ml for LoVo human colorectal cancer cell
lines. It has been observed that it is100-1000 times more potent than other antitumor drugs (Shin
and Teicher, 2001;Liang et al., 2005). Curacin-A is a novel antimitotic and antiproliferative
metaboliteproduced by Lyngbya majuscula (Gerwick et al., 1994). Dolastatin-10 is a
potentproliferative agent . It binds to tubulin on the rhizoxinbindingsite and affects the assembly
of microtubules in mitotic phase of cell cycle.Dolastatin-10 first isolated in fewer amounts from
Dolabella auricularia but now, ithas been proved that it is a cyanobacterial compound which
later isolated fromSymploca sp. (Luesch et al., 2001a). Apratoxin-A is a cyclodepsipeptide
whichisolated from Lyngbya sp. showed activity against human tumor cell lines (Luesch et al.,
2001b). Tolyporphin is isolatedfrom Tolypothrix nodosa has potential photosensitizing activity
against tumor cell sand 5000 time more efficient than the photodynamic treatment (Morliere et
al., 1998). Somocystinamide-A is a product of marine species of Lyngbya majusculewhich act as
antitumor agent (Wrasidlo et al., 2008). Some important anticancercompounds produced by
different microalgae are listed in Table 6.

13. Table 6: Some important Anticancer compounds produced by Microalgae
S.no. Source Bioactive compound Target cell lines References
1. L. bouillonii Apratoxins F and G H-460 human lung
cancer cells
Tidgewell
et al.,
2010
2. Phormidium
spp.
Caylobolide B HT29 colorectal
adenocarcinoma and
HeLa cervical
carcinoma cells
Salvador et
al.,
2010
3. L. majuscula Cocosamides A and
B
MCF7 and HT-29
cells
Gunasekera
et al., 2011
4. L. crossbyana Crossbyanol A H-460 human lung
cancer cells
Choi et al., 2010
5. L. majuscula Hantupeptin B and
C
Leukemia (MOLT-4)
and breast cancer
(MCF-7) cell lines
Tripathi et
al., 2010b
6. L. majuscula Isomalyngamide A
and A-1
MCF-7 and MDA-
MB-
231 breast cancer cell
lines
Chang, et. al.,
2011
7. L. majuscula Lagunamides A and B P388 murine
leukemia
Tripathi et
al., 2010b
8. L. bouillonii 27-
Deoxylyngbyabellin
A,
lyngbyabellin B
and lyngbyabellin J
HT29 cancer cells;
HeLa cancer cells
Mathew et al.,
2010
9. Lyngbya sp. Lyngbyacyclamides
A and B
B16 mouse
melanoma
Cells
Maru et al.,
2010
10. L. sordida Malyngamide 2 H-460 human lung
carcinoma cell line
Malloy et al.,
2011
11. L. majuscula Malyngamide 3 MCF7 and HT-29
cells
Gunasekera,
et al., 2011
12. L. majuscula Nhatrangins A and B Colon cancer cell
line
(CoL-2)
Chlipala et
al., 2010
13. L. majuscula Palmyramide A Human lung
carcinoma
Taniguchi et
al., 2010

14. cell line (H-460)
14, Symploca cf.
hydnoides,
Veraguamides A G HT29 cell line;
HeLa
cell line
Salvador et
al., 2011
14.
L. majuscula
Palmyramide A Human lung
carcinoma
cell line (H-460
Taniguchi et.
al., 2010
15. Oscillatoria
margaritifera
Veraguamide A H-460 human lung
Carcinoma
Mevers et
al., 2011
Modes of action
Antimicrobial componds :
Thec mode of action of the compound depends on the nature of interaction between donor and
target organism , the activity of these compounds being directed against either competitors or
predators . Competition which is mainly with other photoautotrophic organisms .These bioactive
compounds can inhibit photosynthesis,kill the competitors or exclude it from the donor vicinity
(settling, paralysis). As a predator defence ,bioactive metabolites would be efficient by poisoning
grazers orby inducing resistant forms in other algae .In biological system, antimicrobial
compounds show various modes of action :
i. Inhibition of Photosynthesis
ii. Cellular Paralysis
iii. Inhibition of Nucleic acid synthesis
iv. Reactive Oxygen Species (ROS) generation
I.Inhibitionof Photosynthesis :
Growth inhibition and eventually, death by inhibition of photosynthesis is a quite widespread
mode of action for cyanobacteria . Cyanobacterial bioactive compounds generally soluble in
organic solvents , insoluble in water and have a low molecular weight . These properties help
them to reach the thylakoid mebranes where photosynthesis occurs (Smith&Doan,1990).
Allelopathic compounds producrd by the cyanobacteria Scytonema hofmanni produces
Cyanobacterin , that inhibits the photosystem -II mediated photosynthetic electron
transfer(Gleason& Baxa,1986; Von elert & Jutner,1997). Fischerellin A , produced by

15. Fischerella muscicola is another compound acting against the PS-II (Gross, Wolk &Jutner,1991)
but Srivatava et al., 1998 ; reported four sites of target in PS-II.
(1) Effect on the rate constant of QA- reoxidation;
(2) Primary photochemistry trapping;
(3) Inactivation of PSII reaction center; and
(4) Segregation of individual units from grouped units.
ii. Cellular paralysis:
The cyanobacterium Anabaena-flos-aquaeproduces anatoxin-a ,can induce paralysis and faster
settling of the cells of the competing motile green alga Chlamydomonas reinhardtii (Kearns &
Hunter,2001). This may create competitor free zone for the cyanobacterium.
iii. Inhibition of nucleic acid synthesis :
Two alkaloids isolated from Fischerella sp. (12-epihaplindole E) and Calothix sp.(Calothrixine
A) exhibitan inhibitory activity directed against the RNA polymerase of bacteria , fungi and
green algae(Doan et al.,2000). This activity is strongly dependent on polymrerase concentation
and leads to growth inhibition because of protein synthesis inhibition. Calothrixine A also
inhibits DNA synthesis.
iv.ROS generation :
The violet pigment nostocine A, produced by Nostoc spongiaeforme, is highly cytotoxic for
several micro-algae(Hirata,et.al.,2003) and accelerate the formation of reactive oxygen species
(ROS) green alga Chlamydomonas reinhardtii . Inside the target cell, nostocine A is reduced
specifically by intracellular reductants such as NAD(P)H. When the level of O2 is sufficiently
higher than that of nostocine A, the reduced product of nostocine A is oxidized by O2 generates
the production of superoxide anion(O2
-
). O2
-
and the ROS subsequently derived from O2
-
may
cause the cytotoxicity of the nostocine A (Hirata et al., 2004).
Mechanism of action of nostocine A (ROS generation)
Nostocine A is produced by cyanobacteriumNostoc spongiaeforme, is highly cytotoxic for
several microalgae (Hirata et al., 2003) . It has been found to accelerate the the formation of

16. reactive species (ROS ) in the green alga Chlamydomonas reinhardtii . Nostocine A is low
molecular weight and insoluble in water and soluble in organic sovents which make it permeate
into the cell of Chlamyodomonas reinhardtii. It reaches to the thylakoid membrane and other
organelles . Inside the target cell nostocine A is reduced specifically by intracellular reductants
such as NAD(P)H . When the level of O2 is sufficiently higher than that of nostocine A , the
reduced product of nostocine A is oxidized by O2 which generates the production of superoxide
radical anion O2
-
. O2
-
and the ROS subsequently derived from O2
-
may cause the cytotoxicity of
the nostocine A (Hirata et al., 2004). ROS induces apoptosis in the cell.
Fig. 1. Nostocine A toxicity in Clamydomonas reinhardtii
TOXINS (Cyanobacterial Toxins)
Cyanobacterial toxins are toxic substances that are produced by cyanobacteria . They are
nonreplicative, noninfectious materials but can be extremely hazardous, even in minute quanties.
Cyanobacterial toxins can be categorised into :
1.Hepatotoxins
2.Neurotoxins
3.Dermatotoxins and cytotoxins

17. 1. Hepatotoxins
These bioactive secondary metabolites are cyclic peptides (penta and heptapeptides) and
guanidine alkaloids. The group of hepatotoxins includes microcystinsm ,nodularinsm
,cylindrospermopsins , have destructive influence on hepatocytes , kidney . The symptoms of
hepatotoxin poisoning includes stomach ,intestine and liver disorders ,intraliver bleeding and
physiological insufficiency of these are gone . These compounds can induce apoptosis of liver
cells and tumor promoters.
S.no. Toxin Number
of
structural
variants
Structure and activity Toxigenic genera
1. Microcystins 85-90 Cyclic
heptapepeptide,hepatotoxic,
protein phosphatise
inhibition, membrane
integrity and conductsnce
distruption ,tumor
promoters
Microcystis ,
Anabaena , Nostoc,
Anabaenopsis
,Planktothrix
,Oscillatoria,
Haplosiphon
2. Nodularins 14 Cyclic pentapeptide
,hepatotoxic ,protein
phosphatise inhibition
,membrane integrity and
conductance
distruption,tumor
promoters , carcinogenic
Nodularia
spumegena ,
Theonella ( sponge
containing
cyanobacterial
symbionts)
3. Cylindrospermopsins 5 Guanidine alkaloids
,necrotic injury to liver,
kidneys spleen, lungs
Cylindrospermopsis,
Aphanizomenon ,
Umezakia ,

18. ,genotoxic , protein
synthesis inhibition
Anabaena ,
Raphidiopsis
Mechanism of Hepatotoxins
After consuming toxic cyanobacteria by animals or humans ,hepatotoxins are released due to
cyanobacterial cells lysis in the digestive tract and permeate to blood in ileum . In the further
stage they transported to hepatocytes , where they inhibit protein phosphatise activity. As the
result of this process, disorders in phosphorylation and dephosphorylation in a cell take place .
Microcysin and nodularin deform liver cell , affecting cytoskeleton and network protein chains
while give cells their shape ( Carmichael, 2001). The components of the cytoskeleton ,which are
most susceptible to toxins are polymers known as intermediate filaments and microfilaments .
Intermediate filaments and microfilaments undergo changes , when the cytoskeleton shrinks
,withdrawal of microvilli takes place , throughwhich hepatocytes interacts withneighouring cells
causing the interruption of of cells contact other hepatocytes and sinusoidal capillaries ( Ding et
al., 2000).
Microcystin
Covalent bond of cysteine 273 & cysteine 266 respectively responsible for phosphatases PP1 and
PP2 dephorylation. Dephosphorylated protein phosphatases, PP1 & PP2A type phosphoserine,
phosphothreonine, & their inhibition leads to hyperphosphrylation of cytoskeletal protein which
results in hepatocyte deformation (Ding et al., 2000; Mc Elhiney et al., 2001) & of liver
cytoskeleton.
Com[pounds acts by inhibiting eukaryotic protein phosphatases and also activates the enzymes
phosphorelase b, which are crucial for regulating cellular processes such as growth, protein
synthesis, glycogen metabolism and muscle contraction(Carmichael; 2001). Microcystin
contributes to the development of tumors by PP1 & PP2A inhibitions which are integrally
connected and regulates cellular cycles-i.e. okadoic acid. The functional(substituent of ADDA) is

19. also necessary to bond toxins with protein phosphatases ; which is done by covalent bond and is
highly specific which results in excessive phosphorylation of cytoskeleton triggering apoptosis.
MC cannot pass through plasma membrane directly , after intake through the plasma membrane
by organic anion transporting polypeptide system (OATP) , Microcystin binds specifically to
serine/ threonine protein phosphatases (PP1 &PP2A), Inhibiting them leading to a cascade of
events responsible for the microcystin toxicity.
Fig. 2.. Schematic representation of molecular mechanism of Microcystin (MC) toxicity
Nodularins
Nodularins is a cyclic penta peptides, hepatotoxic inhibits protein phosphatases and distruption
of cell membrane integrity and conductance, tumor promoting & carcinogenic. Nodularin have
similar hepatotoxic effects as microcystins mediated through the potent inhibition of protein

20. phosphatases (Fowler’s Zoo and Wild Animal Medicine; 2012). ADDA” group of nodularins
blocks phosphatases via interaction within hydrophobic groove and obstructs acess to active site.
Nodularin PP-1 bond is extremely strong. This results in non-covalent inhibition of enzymes
(phosphatases ) activity intended for nodularin.
Fig. 3. Nodularins structure showing active site for phosphatase interaction and hydrophobic groove
Cylindrospermopsins
These are guanidine alkaloids causes injury to liver, kidney, spleen . Pathological changes
associated with cylindrospermopsin poisoning – in four distinct stages
(i)Inhibition of of protein synthesis
(ii)Proliferation of membranes
(iii) Lipid accumulation within cells
(iv)Cell death

21. Cytochrome P450 has been implicated in the toxicity of Cylindrospermopsin, as blocking the
action of P450 reduces the toxicity of Cylindrospermopsin. Activated P450 – derived
metabolites of CYN is the main cause of cytotoxicity ( Froscio et.al.,2003).
Due to structure of cylindrospermopsin , which includes sulphate, guanidine, and uracil groups
, it has been suggested that CYN act on DNA or RNA. Shaw,et.al.,2000 , reported covalent
bonding of cylindrispermopsin or its metabolites to DNA in mice and DNA breakage also have
been observed (Shaw, et.al.,2000). Humpage,et.al.,postulated that CYN, a metabolite acts on
either the spindle or centromeres during cell division. The Uracil group of Cylindrospermopsin
has been identified as a pharmacophor of the toxin.
2. Neurotoxins
These are alkaloids , carbamate alkaloids , guanidine phosphate ester which have strong potential
active as post synaptic , depolarising neuromuscular blockers or Neuro suppressive agents .
S.no. Toxin Number of
variants
Structure and
activity
Toxigenic genera
1. Anatoxin-a (
including
homoanatoxin-a)
7 Alkaloids,
Postsynaptic,
depolarising
neuromuscular
blockers
Anabaena,
Oscillatoria,
Phormidium,
Aphanizomenon,
Raphidiopsis
2. Anatoxin-a(s) 2 Guanidine methyl
phosphate ester ,
inhibits acetylcholine
esterase
Anabaena spp.
3. Saxitoxins 23 Carbamate alkaloids ,
sodium channel
Aphanizomenon,
Anabaena , Lyngbya

22. blockers ,Cylindrospermopsis
,Planktothrix
1.Anatoxin-a :
Anatoxin-a is a antagonist of both neuronal Alppha4Beta4 and Alpha 4 nicotinic acetylcholine
receptor present in the CNS as well the Alpha12BetaGammaSigma muscle type nicotinic
acetylcholine receptors that are present at the Neuromuscular junction (chemical synapse-formed
by contact between a motor neuron and muscle fibre .
Anatoxin-a have affinity for these receptors that is about 20 times greater than that of
acetylcholine. In normal circumstances, acetylcholine binds to nicotinic Acetylcholine Receptors
(nAChRs) in the post synaptic neuronal membrane, causing a conformational change in the
extracellular domain of the receptor which in turnopens the channel pore. This allows Na--
and
Ca++
ions to move into the neuron, causing cell depolarisation and inducing the generation of
active potentials, which allows for muscle contraction. The acetylcholine neurotransmitter then
dissolves from the nicotinic acetylcholine receptor, where it is rapidly cleaved into acetate and
choline by acetylcholine esterase (Purves et al., 2012). Anatoxin-a binding to thesenicotinic
acetyl choline receptors cause the same effects in neurons. However anatoxin-a binding is
irreversible ,and the anatoxin-a nicotinic acetylcholine receptor complex can not be broken down
by acetylcholine esterase . Thus, then nAchR is temporally locked open and after off period of
time become desentisized. In this desensitized state the a nicotinic acetylcholine receptors no
longer let cations passed through, which ultimately leads to blockage of neuromuscular
transmissio
2. Anatoxin-a(S)
In normal condition : Neuron cell axonal membrane release neurotransmitter acetylcholine and
binds to rnicotinic acetycholine receptors and regulates muscle contraction through Na+
/ K++
channels in the membrane of muscle . Acetylcholine is released from receptor and further go for

23. degaradation byacetylcholine esterase form complex and thus prevents bindinding of
acetylcholine and breakdown into actate and choline , results in over stimulation of muscle cell.
In presenc of Anatoxin-a(S): it binds rapidly than acetylcholine to form a stable complex with
acetylcholine esterase and thus prevents breakdown of acetylcholine into acetate and choline
,resulting into overstimulation of muscle.
Fig. 4. Events in toxicity of Anatoxin-a and Anatoxin-a(S) ( source :Valerio E et al., 2010)

24. 3. Saxitoxins
Saxitoxin is a carbamate alkaloid , it is a potent neurotoxin and the best known paralytic selfish
toxin(PST). Ingestion of saxitoxin , by consumption of shellfish contaiminated algal bloom is responsible
for human illness known as paralytic shellfish poisoning (PSP). Saxitoxin is a neurotoxin that act as a
selective sodium channel blocker, one of the most potent known natural toxins ,it acts on the voltage
gated sodium channels of neurons, preventing normal cellular function and leading to paralysis . The
voltage gated sodium channel exists as integral membrane proteins interspersed along the axon of a
neuron and possessing four domainsthat span along the cell membrane opening of the voltage gated
sodim channels occur when there s a change in voltage or ligand binding in the right way and essential fo
propagation of an action potential . Due to lack of action potential ,the nerve cells becomes unable to
transmit signals and the region of the body get cut off from the nervous system.
Fig: 5. Events in toxicity of Saxitoxin (Source : Valerio E et al., 2010)
Dermatotoxins and cytotoxins : It includes Aplysiatoxins and lyngbyatoxins-especially
Debromoaplysiatoxin have two effects on cell growth ; it has tumour promoting activity as well
as antiproliferation activity and can be used as therapy for cancer . The methyl group is found to
be a cause for tumour proliferative activity ,and removal of methoxy group causes the
antiproliferation activity to increase without changing tumour promoting activity.

25. Conclusion
Microalgae constitute a unique group of prokaryotic cyanobacteria and eukaryotic microscopic
algae , populate in abundance,throught the world in diverse habitats. Their potential as a source
of new therapeutic novel compounds , as several bioactive molecules obtained from microalgae
show a broad spectrum of activities , such as antimicrobial activities (antibacterial, antifungal,
antimicroalgal and antiviral ) and other as antiprotozoal & anticancer effects . Another advantage
of microalgae as a microbial source for drug discovery lies in the economy of their cultivation
copmpared other microorganisms, as microalgae require only simple simple inorganic nutrients
for growth. Thus, it seems that the microalgae have the potential for expanded utilization in drug
discovery for multidrug-resistant human pathogens and serious pathogenic diseases . Microalgae
have high degree of microbial diversity , microalgal secondary metabolites may constitute a
prolific source of new entities leading to the development of new pharmaceuticals. Microalgae
havethe potential to expand the variety of natural products obtained from microorganisms.
Microalgal sources of natural products , as well as the huge chemical diversity and biological
activities of their products, has made them attractive sources of novel drugs for use in diverse
therapeutic areas.

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33. Contents Page
1.Inroduction 1
2. Microalgae as source of Bioactive Compounds
- Biological Activities
i. Antibacterial compounds 2-4
ii. Antifungal compounds 4-6
iii. Antialgal compounds 6-8
iv. Antiviral compounds 8-9
v. Antiprotozoal compounds 9-11
vi. Anticancer compounds 11-13
3. Modes of Action-
i. Inhibiton of Photosynthesis 14
ii. Cellular Paralysis 15
iii. Inhibition of Nucleic Acid Syntheiss 15
iv. ROS generation 15
Mechanism of Action of Nostocine A 16
4. Cyanobacterial Toxins
i. Hepatotoxins 17
Mechanism of Hepatotoxins
-Microcystins 18-19
-Nodularins 19-20
- Cylindrospermopsins 20-21
ii. Neurotoxins
-Anatoxin-a 22
- Anatoxin-a(S) 22- 23
- Saxitoxins 24
iii. Dermatotoxins and Cytotoxins 24
5. Conclusion 25
6. References 26-33