Page 1
Metabolites from freshwater aquatic microalgae and fungias potential natural pesticides
Beatriz Hernandez-Carlos •
M. Marcela Gamboa-Angulo
Received: 2 April 2010 / Accepted: 27 July 2010
� Springer Science+Business Media B.V. 2010
Abstract Microorganisms are recognized world-
wide as the major source of secondary metabolites
with mega diverse structures and promissory biolog-
ical activities. However, as yet many of them remain
little or under-explored like the microbiota from
freshwater aquatic ecosystems. In the present review,
we undertook a recompilation of metabolites reported
with pesticidal properties from microalgae (cyano-
bacteria and green algae) and fungi, specifically from
freshwater aquatic habitats.
Keywords Bioactive metabolites � Cyanobacteria �Freshwater ecosystems � Fungi � Microalgae
Introduction
The term microorganism defines protists as unicellu-
lar organisms, colonial eukaryotes, and even fungi
(Zavarzin 2008). All microorganisms have the ability
to biosynthesize secondary metabolites, which gen-
erally correspond to chemical structures of low
molecular weight (\3,000 daltons) and are produced
in very small quantities. These metabolites are also
known as microbial natural products (MNP), whose
variety and quantity in the organisms could be
regulated by external factors such as biotic and
abiotics (Turner and Aldridge 1983; Frisvad et al.
1998; Strohl 2000). In nature, it is estimated that
there are approximately 250,000 different plant
species, more than 30 million insect species, 1.5 mil-
lion species of fungi, between 200,000 and 800,000
species of microalgae and a similar number of
prokaryotes (Hawksworth 1993; Drews 2000). How-
ever, until now less than 1% of microbial diversity
has been explored in terms of metabolic production,
even though these are considered the most diverse
group of organisms after insects (Rossman 1994;
Harvey 2000). To date, there are reported 22,500
biologically active compounds that have been
obtained so far from microbes, 45% are produced
by actinomycetes, 38% by fungi and 17% by
unicellular bacteria (Berdy 2005). Therefore, it is
possible to confirm that this knowledge is minimal
compared to the known biological diversity (Harvey
2000). This coupled with the estimation of microbial
diversity and the intense interactions between them
make MNP, a vast unexplored source of chemicals
structures. In addition, research with uncultivated
microorganisms following metagenomics strategies is
helping to expand knowledge about their huge
B. Hernandez-Carlos
Instituto de Recursos, Universidad del Mar,
Puerto Angel, Oaxaca 70902, Mexico
M. M. Gamboa-Angulo (&)
Centro de Investigacion Cientıfica de Yucatan, A.C.,
Unidad de Biotecnologıa, Calle 43 No. 130,
Col. Chuburna, Merida, Yucatan 97200, Mexico
e-mail: [email protected]
123
Phytochem Rev
DOI 10.1007/s11101-010-9192-y
Page 2
genetic and metabolic reservoir. So, it is feasible to
assume that there are a variety of secondary metab-
olites of microbial origin that remain to be discovered
(Verpoorte 1998; Bhadury et al. 2006; Demain and
Sanchez 2009).
The diversification in the search for microbial
strains and their products with biotechnological
potential has led to evaluate microorganisms that
inhabit different locations off the ground directing the
search towards habitats with different characteristics
or extreme conditions. Some of these, places with
high salinity, pH and temperature extremes as well as
those that are inhabiting marine sponges, mangrove
roots, the exoskeleton of arthropods, small fish,
bivalves, marine water sediments or just those that
are developed with different characteristics to those
of environments explored (Del Giorgio and Cole
1998; Gonzalez Del Val et al. 2001; Basilio et al.
2003; Knight et al. 2003). From this point of view,
the freshwater inhabiting microorganisms have
adapted to conditions close to distilled water where
minerals and other nutrients, such as nitrogen and
phosphorus are deficient. Moreover, in the aquatic
environment of rapidly moving nutrients and inter-
actions to gain space and food plays a vital role in
these ecosystems, stimulating the production of
allelopathic substances (Macıas et al. 2008; Zavarzin
2008).
Among the most studied microorganisms in
freshwaters are the micro green algae and cyanobac-
teria, which are recognized by their toxins. These
toxins include a diversity of nitrogen-rich alkaloids
and peptides, feared by man, but also have a huge
potential for the development of pharmaceutical and
agricultural applications (Berry et al. 2008). In
contrast, the freshwater micromycetes fungi have
not received enough attention to generate the basic
knowledge about their secondary metabolites and
their possible applications. In general, the MNP have
many applications beneficial to man, which have
transcended beyond their antibiotic properties,
including the use as pesticides (Chin et al. 2006;
Pelaez 2006). According to the U.S. EPA’s pesticides
are substances used to prevent, repel, destroy or
mitigate any pest, any body considered as pests that
are not wanted or causes damage to crops or humans
or other animals, these can be insects, animals,
unwanted plants (weeds), microorganisms (bacteria,
fungi, viruses) and prions. Then, hopefully some of
the products of microbial metabolism produced for
competition or defense might be used as a strategy to
control pests.
In the present review are documented species of
microalgae and micromycetes fungi living in fresh-
water aquatic enviroments, which have been sub-
jected to chemical and biological studies and reported
over the past 25 years. Specifically, we collected
those studies directed toward the control of pests and
diseases of major importance in plant pathology such
as algaecides, antimicrobials, larvicides and
nematicides.
Freshwater microalgae
There currently exists a great variety and number of
compounds that come from microalgae, in only two
strains of Aphanizomenon flos-aquae 20 volatile
compounds containing nitrogen have been detailed
(Dembitsky et al. 2000). Up until 2004 an investiga-
tion group in Japan had isolated approximately 30
peptides of freshwater cyanobacteria including the
genus Anabaena, Microcystis, Nodularia, Nostoc and
Oscillatoria (Harada 2004). Among the great diver-
sity of compounds isolated from green microalgae
and cyanobacteria there are those with useful biolog-
ical activities for developing plaguicides. The metab-
olites with algaecidal, antimicrobial, antiprotozoal,
antifeedant, insecticidal and larvicidal activities (1–
112) discovered to date are presented in Table 1,
Fig. 1 and in the next paragraph are mentioned some
of the most interesting contributions.
Metabolites with algaecidal activity
The algaecidal activity of the cyanobacteria has been
principally observed in diverse genera such as
Anabaena, Microcystis (Lam and Silvester 1979),
Calothrix, Fischellera, Nostoc (Smith and Doan
1999), Nodularia (Volk 2005, 2006) and Phormidium
(Jaiswal et al. 2005). In the Oscillatoria genus, the
inhibiting effect of a non-polar natured extract was
observed over the growth of the cyanobacterium
Anacystis nidulans, and of Brassica compestris and
Coriandrum sativum plants (inhibitor of photo system
II); interestingly this extract wasn’t toxic in mice at
intraperitoneal dosis of 16 lg/ml (Chauhan et al.
1992). Examples of algaecidal compounds with
Phytochem Rev
123
Page 3
Ta
ble
1M
etab
oli
tes
fro
mfr
esh
wat
erm
icro
alg
aew
ith
pes
tici
dal
pro
per
ties
Sp
ecie
sM
etab
oli
teT
yp
eo
fco
mp
ou
nd
Act
ivit
yF
rom
Ref
eren
ce
An
ab
aen
ala
xaL
axap
hy
cin
sA
(36
),B
(37)
Lip
op
epti
de
An
tifu
ng
al
Cy
toto
xic
US
AF
ran
km
oll
eet
al.
(19
92
)
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ab
aen
asp
iro
ides
Sp
iro
ides
in(1
)L
ipo
pep
tid
eA
lgae
cid
alJa
pan
Kay
aet
al.
(20
02
)
Ca
loth
rix
sp.
Cal
oth
rix
ins
A(1
6)
and
B(1
7)
Ind
ol
ph
enan
thri
din
eA
nti
pro
tozo
al
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toto
xic
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stra
lia
Ric
kar
ds
etal
.(1
99
9)
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loth
rix
sp.
PC
C7
50
7E
rem
op
hil
on
e(3
4)
Ses
qu
iter
pen
eIn
sect
icid
e
An
ticr
ust
acea
n
Sw
itze
rlan
dH
ock
elm
ann
etal
.(2
00
9)
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ind
rosp
erm
um
lich
enif
orm
e2
(R),
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)-b
is-(
Hy
dro
xy
met
hy
l)-3
(R),
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)-d
ihy
dro
xy
py
rro
lid
ine
(DM
DP
,3
5)
Py
rro
lid
ine
Inse
ctic
ide
An
ticr
ust
acea
n
US
AJu
ttn
eran
dW
esse
l(2
00
3)
Cyl
ind
rosp
erm
um
mu
scic
ola
Scy
top
hy
cin
B(9
5),
6-H
yd
rox
ysc
yto
ph
yci
nB
(10
1)
Scy
top
hy
cin
E(9
8)
6-H
yd
rox
y-7
-O-m
eth
yls
cyto
ph
yci
nE
(10
2)
Alk
alo
idC
yto
tox
ic
An
tifu
ng
al
Haw
aii
Jun
get
al.
(19
91
)
Dic
ho
thri
xb
au
eria
na
Bau
erin
eA
(10
6)
Bau
erin
eB
(10
7)
b-C
arb
oli
ne
An
tiv
iral
Cy
toto
xic
ity
Haw
aii
Lar
sen
etal
.(1
99
4)
Eu
gle
na
san
gu
inea
Eu
gle
no
ph
yci
n(1
4)
Alk
alo
idA
lgae
cid
al
Cy
toto
xic
US
AZ
imb
aet
al.
(20
10)
Fis
cher
ella
am
big
ua
Am
big
ol
A(4
5),
B(4
6)
Po
lych
lori
nat
edar
om
atic
An
tim
icro
bia
l
Mo
llu
scic
idal
An
tiv
iral
Sw
itze
rlan
dF
alch
etal
.(1
99
3)
Am
big
ol
C(1
8)
Po
lych
lori
nat
edar
om
atic
An
tip
roto
zoal
Sw
itze
rlan
dW
rig
ht
etal
.(2
00
5)
Am
big
uin
eA
–F
iso
nit
rile
s(4
7–
52)
Ind
ol
alk
alo
idA
nti
fun
gal
Haw
aii
Sm
itk
aet
al.
(19
92
)
Am
big
uin
eK
–O
(55–
59)
iso
nit
rile
sIn
do
lal
kal
oid
An
tib
acte
rial
US
AM
oet
al.
(20
09
a)
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sig
uin
e(4
4)
Po
lym
erA
nti
mic
rob
ial
Iran
Gh
asem
iet
al.
(20
04)
Fis
cher
ella
mu
scic
ola
Fis
chel
leri
nA
(7)
Alk
alo
idA
llel
och
emic
alU
SA
Gro
sset
al.
(19
91
)
An
tim
icro
bia
l
Her
bic
idal
Hag
man
nan
dJu
ttn
er(1
99
6)
Fis
cher
elli
nB
(8)
Alk
alo
idA
lgae
cid
alP
apk
eet
al.
(19
97
)
Fis
cher
ella
sp.
Fis
cher
elli
nA
(7)
12
-ep
i-H
apal
ind
ole
F(1
0)
Alk
alo
id
Ind
ol
alk
alo
id
Alg
aeci
dal
Bra
zil
Etc
heg
aray
etal
.(2
00
4)
Am
big
uin
eH
(53),
I(5
4)
iso
nit
rile
Ind
ol
alk
alo
idA
nti
mic
rob
ial
Isra
elR
aveh
and
Car
mel
i(2
00
7)
c-L
ino
len
icac
id(4
1)
Fat
tyac
idA
nti
bac
teri
alIn
dia
Ast
han
aet
al.
(20
06)
Phytochem Rev
123
Page 4
Ta
ble
1co
nti
nu
ed
Sp
ecie
sM
etab
oli
teT
yp
eo
fco
mp
ou
nd
Act
ivit
yF
rom
Ref
eren
ce
Fis
cher
ella
sp.
AT
CC
43
23
9
12
-ep
i-H
apal
ind
ole
C(3
0),
E(3
1),
J(3
2),
hap
alin
do
leL
(33
)is
on
itri
les
Alk
alo
idIn
sect
icid
eU
SA
Bec
her
etal
.(2
00
7)
Ha
ema
toco
ccu
sp
luvi
ale
sP
rop
ano
icac
id(4
2)
Bu
tan
oic
acid
(43)
Fat
tyac
idA
nti
mic
rob
ial
Sp
ain
Ro
drı
gu
ez-M
eizo
soet
al.
(20
10
)
Ha
pa
losi
ph
on
fon
tin
ali
sF
on
ton
amid
e(7
4)
An
hy
dro
hap
alo
xin
do
leA
(75
)
Ind
ol
alk
alo
idC
yto
tox
ic
An
tifu
ng
al
Haw
aii
Mo
ore
etal
.(1
98
7a)
Hap
alin
do
les
C–
H(7
6–
81),
L(3
3),
J–K
(82
–8
3),
M–
Q(8
4–
88),
T–
V(8
9–
91)
Ind
ol
alk
alo
idA
nti
bac
teri
al
An
tifu
ng
al
Haw
aii
Mo
ore
etal
.(1
98
7b
)
Ha
pa
losi
ph
on
wel
wit
sch
iiW
elw
itin
do
lin
on
eA
iso
nit
rile
(92)
N-M
eth
ylw
elw
itin
do
lin
on
eC
iso
cian
ate
(93
)
Ind
ole
alk
alo
idA
nti
fun
gal
An
ti-H
IV
Au
stra
lia
Str
atm
ann
etal
.(1
99
4)
Lyn
gb
yasp
.P
ahay
ok
oli
de
A(5
)C
ycl
icp
epti
de
Alg
aeci
dal
Cy
toto
xic
An
tim
icro
bia
l
US
AB
erry
etal
.(2
00
4)
Mic
roco
leu
sla
cust
ris
20
-No
r-3a-
acet
ox
y-a
bie
ta-5
,7,9
,11
,13
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taen
e(1
03)
20
-No
r-3a-
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ox
y-1
2-h
yd
rox
y-a
bie
ta-5
,7,9
,
11
,13
-pen
taen
e(1
04)
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rab
ieta
ne
Dit
erp
eno
id
An
tib
acte
rial
Mex
ico
Per
ez-G
uti
erre
zet
al.
(20
08
)
Mic
rocy
stis
aer
ug
ino
saK
asu
mig
amid
e(2
)P
epti
de
Alg
aeci
dal
Jap
anIs
hid
aan
dM
ura
kam
i
(20
00
)
Aer
ucy
clam
ides
A(1
9)
and
B(2
0)
Hex
acy
clo
pep
tid
eA
nti
cru
stac
ean
Fra
nce
Po
rtm
ann
etal
.(2
00
8a)
Aer
ucy
clam
ides
C–
D(2
1–
22)
Hex
acy
clo
pep
tid
esA
nti
pro
tozo
al
Cy
toto
xic
Fra
nce
Po
rtm
ann
etal
.(2
00
8b
)
No
du
lari
ah
arv
eya
na
No
rhar
man
e(1
2)
Ind
ol
alk
alo
idA
lgae
cid
alG
erm
any
Vo
lk(2
00
5)
No
rhar
mal
ane
(13
)In
do
lal
kal
oid
Alg
aeci
dal
Ger
man
yV
olk
(20
06
)
No
sto
cC
CC
53
74
-[(5
-Car
bo
xy
-2-h
yd
rox
y)-
ben
zyl]
-1,1
0-
dih
yd
rox
y-3
,4,7
,11
,11
-
pen
tam
eth
ylo
ctah
yd
rocy
clo
pen
ta\
a[n
aph
thal
ene
(60)
Nap
hth
alen
eA
nti
bac
teri
alA
nta
rtic
Ast
han
aet
al.
(20
09
)
No
sto
cco
mm
un
eN
ost
ofu
ng
icid
ine
(70
)L
ipo
pep
tid
eA
nti
fun
gal
Jap
anK
ajiy
ama
etal
.(1
99
8)
No
sco
min
(61)
Dit
erp
ene
An
tib
acte
rial
Sw
itze
rlan
dJa
ki
etal
.(1
99
9)
8-[
(5-C
arb
ox
y-2
,9-e
po
xy
)ben
zyl]
-2,5
-dih
yd
rox
y-1
,1,4
a,7
,
8-p
enta
met
hy
l-1
,2,3
,4,4
a,6
,7,8
,9,1
0,1
0a-
do
dec
ahy
dro
ph
enan
thre
ne
(67
)
1,8
-Dih
yd
rox
y-4
-met
hy
lan
thra
qu
ino
ne
(68)
4-H
yd
rox
y-7
-met
hy
lin
dan
-1-o
ne
(69)
Ph
enan
thre
ne
An
thra
qu
ino
ne
An
tim
icro
bia
lS
wit
zerl
and
Jak
iet
al.
(20
00
a)
Co
mn
ost
ins
A-
E(6
2–
66)
Nap
hth
alen
eA
nti
bac
teri
alS
wit
zerl
and
Jak
iet
al.
(20
00
b)
Phytochem Rev
123
Page 5
Ta
ble
1co
nti
nu
ed
Sp
ecie
sM
etab
oli
teT
yp
eo
fco
mp
ou
nd
Act
ivit
yF
rom
Ref
eren
ce
No
sto
cfl
ag
elli
form
eN
ost
ofl
an(1
12)
Po
lysa
cch
arid
eA
nti
vir
alJa
pan
Kan
ekiy
oet
al.
(20
05
)
No
sto
cin
sula
re4
,40 -
Dih
yd
rox
yb
iph
eny
l(1
1)
Bip
hen
yl
Alg
aeci
dal
Ger
man
yV
olk
(20
05
)
No
sto
c7
8-1
2A
No
sto
carb
oli
ne
(9)
Alk
alo
idB
uty
rylc
ho
lin
este
rase
-
inh
ibit
or
Alg
aeci
dal
US
AB
ech
eret
al.
(20
05
),
Blo
met
al.
(20
06)
No
sto
carb
oli
ne
dim
ers
(23
–2
9)
Alk
alo
idA
nti
pro
tozo
alB
arb
aras
etal
.(2
00
8)
No
sto
csp
.3
1N
ost
ocy
clam
ide
(3)
Pep
tid
eA
nti
cyan
ob
acte
ria
Alg
aeci
dal
US
AT
od
oro
va
etal
.(1
99
5)
No
sto
cycl
amid
eM
(4)
Pep
tid
eA
llel
op
ath
icU
SA
Jutt
ner
etal
.(2
00
1)
Car
bam
ido
cycl
op
han
esA
–C
(71
–7
3)
Par
acy
clo
ph
ane
Ch
lori
nat
ed
An
tib
acte
rial
Cy
toto
xic
Vie
tnam
Bu
iet
al.
(20
07
)
No
sto
csp
on
gia
efo
rme
No
sto
cin
eA
(6)
Tri
azin
on
eA
lgae
cid
alJa
pan
Hir
ata
etal
.(1
99
6)
Ph
yto
tox
ic
Alg
aeci
dal
An
tife
edan
t
Th
aila
nd
Hir
ata
etal
.(2
00
3)
Osc
illa
tori
ara
oi
Su
lfo
gly
coli
pid
(10
8,
10
9)
Su
lfo
gly
coli
pid
An
tiH
IVIs
rael
Res
hef
etal
.(1
99
7)
Osc
illa
tori
are
dek
eia-
Dim
orp
hec
oli
cac
id(3
8)
Co
rio
lic
acid
(39)
Fat
tyac
ids
An
tib
acte
rial
Ger
man
yM
un
dt
etal
.(2
00
3)
Osc
illa
tori
atr
ich
oid
esS
ulf
og
lyco
lip
id(1
10)
Su
lfo
gly
coli
pid
An
tiH
IVIs
rael
Res
hef
etal
.(1
99
7)
Scy
ton
ema
ho
fma
nn
iC
yan
ob
acte
rin
(15)
Aro
mat
icla
cto
ne
An
tim
icro
bia
lU
SA
Mas
on
etal
.(1
98
2)
All
elo
pat
hic
US
AG
leas
on
and
Cas
e(1
98
6),
Pig
nat
ello
etal
.(1
98
3)
Scy
ton
ema
mir
ab
ile
To
lyto
xin
(99
)M
acro
lid
eA
nti
fun
gal
Cy
toto
xic
Kir
ibat
iC
arm
eli
etal
.( 1
99
0),
Pat
ters
on
and
Car
mel
i(1
99
2)
Scy
ton
ema
pse
ud
oh
ofm
an
ni
Scy
top
hy
cin
sA
(94
),B
(95)
C–
E(9
6–
98)
Mac
roli
de
Cy
toto
xic
An
tifu
ng
al
US
AIs
hib
ash
iet
al.
(19
86
)
Scy
ton
ema
vari
um
Scy
tov
irin
Pro
tein
An
tiH
IVU
SA
Bo
kes
chet
al.
(20
03
)
Scy
ton
ema
sp.
Su
lfo
gly
coli
pid
(11
1)
Su
lfo
gly
coli
pid
An
tiH
IVS
eych
elle
sR
esh
efet
al.
(19
97)
Scy
ton
ema
sp.
Scy
tosc
alar
ol
(10
0)
Ses
tert
erp
ene
An
tim
icro
bia
lU
SA
Mo
etal
.(2
00
9b
)
Sp
iro
gyr
ava
ria
ns
Pen
tag
allo
yl-
glu
cose
(10
5)
Tan
nin
An
tim
icro
bia
l
a-G
luco
sid
ase
inh
ibit
or
UK
Can
nel
let
al.
(19
88
)
Phytochem Rev
123
Page 6
peptide structure showing potent biological properties
at lM or lg/ml levels; spiroidesin (1) (Anabaena
spiroides) with activity against toxic cyanobacteria
Microcystis aeruginosa (IC50 = 1.6 9 10-6 M)
(Kaya et al. 2002). In contrast, M. aeruginosa
produced kasumigamide (2) (Ishida and Murakami
2000); other peptides are nostocyclamide (3) and
nostocyclamide M (4) (Nostoc sp. 31) with inhibitory
properties (IC50 = 0.1 lM) against Anabaena
(Todorova et al. 1995; Juttner et al. 2001); and
pahayakolide A (5) (Lyngbya sp.) which showed
effect against Chlamydomonas Ev-29 green algae at
6.8 lM (Berry et al. 2004).
Nostocine A (6) is an unusual pirazolo triazine
isolated from Nostoc spongiaeforme with toxic effect
comparable to paraquat against Anabaena, Nostoc
commune, Oscillatoria and green algae Chlorella and
Dunaliella at MIC values of 5–30 lM (Hirata et al.
1996, 2003). More algaecidal alkaloids are fischell-
erin A (7) (Gross et al. 1991; Hagmann and Juttner
1996; Papke et al. 1997; Etchegaray et al. 2004),
fischellerin B (8) (Papke et al. 1997), and nostocarb-
oline (9) (Nostoc 78-12a) (Blom et al. 2006).
Metabolite 4 has shown toxicity to algae and higher
plants at nM concentrations while 9 was toxic at lM
concentrations against Kirchneriella, Microcystis,
and Synechococcus (Blom et al. 2006). Hapalindoles
are indole alkaloids produced by Fischerella or
Hapalosiphon genus with several biological activities
such as antimicrobial (Moore et al. 1987b), insecti-
cidal (Becher et al. 2007) and algicidal (Etchegaray
et al. 2004). One example of active hapalindole is
12-epi-hapalindole F (10), this was isolated from a
Fischerella strain, with ability to inhibit the Micro-
cystis and Synechococcus growth (Etchegaray et al.
2004).
4,40-dihydroxybiphenyl (11) (Nostoc insulare) was
algaecidal at B18 lg/ml concentrations as were the
alkaloids norharmane (12) and norharmalane (13)
(Nodularia harveyana) (Volk 2005, 2006). Recently,
the euglenophycin (14) alkaloid from Euglena san-
guinea showed algaecidal activity against M. aeru-
ginosa and Planktothrix sp. at concentrations
\300 ppb, additionally 14 showed ichthyotoxic and
anticancer activities (Zimba et al. 2010) (Fig. 1).
Scytonema genus has also shown algaecidal activity,
displaying cyanobacterin (15) (Scytonema hofmanni)
that inhibited the growth of algae and angiosperms at
B5 lM dosis (Gleason and Case 1986).Ta
ble
1co
nti
nu
ed
Sp
ecie
sM
etab
oli
teT
yp
eo
fco
mp
ou
nd
Act
ivit
yF
rom
Ref
eren
ce
Wes
tiel
lain
trin
cata
N-M
eth
ylw
elw
itin
do
lin
on
e
Cis
oci
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e(9
3)
Ind
ole
alk
alo
idA
nti
fun
gal
Mic
ron
esia
Str
atm
ann
etal
.(1
99
4)
Wes
tiel
lop
sis
pro
lifi
caA
mb
igu
ine
iso
nit
rile
D(5
0)
E(5
1)
Ind
ol
alk
alo
idA
nti
fun
gal
Haw
aii
Sm
itk
aet
al.
(19
92
)
Phytochem Rev
123
Page 7
NH
NH
OH
O
HO
O
NH
O
HO
O
HN
OHHN
HN
ON
NO
O
O
O
O
HO
O CH2OH O
O
OO
OH
O
NH3COC
CONH2
NH
O
HN
NH
HN
NH
HN
5 Pahayokolide A
N N
S
N
O
N
O
O
OH3C
H H
H
SN
N
R
3 Nostocyclamide R = CH(CH3)24 Nostocyclamide M: R = CH2CH2SCH3
NN
N
NH
N
O
NH2
OH
NH
NH
O
HN
NH
COOH
O O O
HO
NH
NH
NH
2 Kasumigamide
6 Nostocine A
1 Spiroidesin
O
OCH3
H3C
CH3
OO
O
Cl H
HO
OHHO
NH
N
NH
NCl+
I-
NH
NCS
Cl
NH
N
N
H H
H
OH
H
N
N
O
O
O
H
N
10 12-epi-hapalindole F
12 Norharmane11 4,4´-Dihydroxybiphenyl 13 Norharmalane
14 Euglenophycin 15 Cyanobacterin
9 Nostocarboline8 Fischellerin B
7 Fischellerin A
Fig. 1 Chemical structures of metabolites isolated from freshwater aquatic microalgae with pesticidal activities
Phytochem Rev
123
Page 8
NCl N
HN
Cl
NH
linker
X-+
X-+
O
O
O
N
H
N
Cl
O
Cl Cl
Cl
O
OH
Cl Cl
N
NH
ON
S
HN
R2
OR
O
NH
HO
N
S
H
R1
N
OR
H
N
S
H
R1
NHO
N
R2
HN
O
NH
HO
Aerucyclamide20
B: R = (S)-CH(CH3)CH2CH3; R1 = H; R2 = S21
C: R = CH3; R1 = CH(CH3)2; R2 = O
linker =
23 24 25 26
27 28
16 Calothrixin A: 2N = N-oxide17 Calothrixin B
12
18 Ambigol C
Aerucyclamide19
A: R = (S)-CH(CH3)CH2CH3; R1 = βH,R2 = α (S)CH(CH3)CH2CH3
22D: R = CH2C6H5; R1 = αH, R2 = βCH2CH2SCH3
29
Synthetic dimers of Nostocarboline
O
OH
HN
HOOH
HO
H
NC
R
NHNH
H
NCH
R
34 Eremophilone
352R,5R-bis(hydroxymethyl)-3R,4R-
dihydroxypyrrolidine
12-epi-Hapalindole isonitrile:30 C: R = H31 E: R = Cl
12-epi-Hapalindole isonitrile:32 J : R = HHapalindole33 L: R = Cl
Fig. 1 continued
Phytochem Rev
123
Page 9
OH
O
R
O
N
HN
HN
HN
NH OO
HN
NH
O
O
NH
O
O
HNNH
OO CH2OH
OH
CH2OH
HN OO
O
NHHOH
O
H
H
O
O
H3C
H3C
H
O
OH
N
O
NH
HO
HN NH
HN
NH
O
HN
N O
O
H
O OH
HN
CONH2H
H
HO
NH
OH
OH
CONH2
NH
O
Cl
Cl
OH
Cl
Cl
ClOH
Cl
O
OH
Cl Cl Cl
Cl
O
Cl
Cl
OOOO
O
O
**
CO2H
OH
CO2H CO2H
OH
CO2H
39 Coriolic acid38 α-Dimorphecolic acid
42 Propanoic acid: R = H43 Butanoic acid: R = CH3
36 Laxaphycin A 37 Laxaphycin B
45 Ambigol A 46 Ambigol B
8
44 Parsiguine41 γ-Linolenic acid
40 Linoleic acid
N
HO NC
H OOH
R
NH
R1
R
NCH
Cl
NH
HO NC
H O
51Ambiguine E isonitrile
Ambiguine isonitrileR R1
47 A: Cl H48 B: Cl OH49 C: H OH53 H: H H
Ambiguine isonitrileR
50 D: Cl54 I: H
Fig. 1 continued
Phytochem Rev
123
Page 10
H
H
CO2H
OHHO
NH
OHNC
OH
H
R
R1
NH
OHNC
H
R
NH
HO NC
O
H
Cl
OHO
HO
HO
OH
OH
R R1
H H
CO2H
Ambiguine isonitrileR R1
52 F: Cl OH57 M: Cl H58 N: H H
59Ambiguine O isonitrile
Ambiguine isonitrileR
55 K: Cl56 L: H
ComnostinR R1
62 A: CH2OH CH363 B: CHO CH364 C: COOH CH365 D: CH(OCH3)2 CH366 E: CH3 CO H
604-[(5-carboxy-2-hydroxy)-
benzyl]-1,10-dihydroxy-3,4,7,11,11-pentamethyloctahydrocyclopenta<a>naphthalene 61 Noscomin
O
HO
H H H
HOCO2H
O
O
O NH2R2
OH2N Cl
RHO OH
OHHOR1
O
O
OH OHO
OH
O
N
ON
OH
NH
O
OH
OH
H
H
HO
H
HO
H2N
O
OH
H2N
O
OH
H
HON
N
O
O
NN
OH
HN
68 1,8-Dihydroxy-4-methylanthraquinone
694-Hydroxy-7-
methylindan-1-one
70 Nostofungicidine
678-[(5-carboxy-2,9-epoxy)benzyl]-2,5- dihydroxy-1,1,4a,7,8-pentamethyl-1,2,3,4,4a,6,7,8,9,10,10a
dodecahydrophenanthrene
CarbaimidocyclophaneR R1 R2
71 A: Cl Cl Cl71 B: Cl Cl H73 C: Cl H H
Fig. 1 continued
Phytochem Rev
123
Page 11
NH
H
Cl
NC
HO
O
NH
H
Cl
NC
O
74 Fontonamide 75 Anhydrohapaloxindole A
NH
H
R
R1
NH
Cl
NC
R2
H
R
R1
NH
NH
H
Cl
NHS
ONH
O
H
H
Cl
NC
N
CH3
O
O
Cl
NCS
NH
O
Cl
CN
1015
12
HapalindoleR R1 R2
80 G: Cl NC αH, 10-epimer81 H: H NC βH82 J: H NC αH84 M: H NCS αH86 O: OH NCS αH90 U: H NC αH 10-epimer91 V: Cl NC αH 10 βOH
10
HapalindoleR R1
76 C: H NC77 D: H, NCS78 E: Cl NC79 F: Cl NCS88 Q: H NCS, 10, 15-diepimer
83 Hapalindole K
Hapalindole85 N 20R87 P 20S 89 Hapalindole T
15
20
93N-Methylwelwitindolinone
C isocianate92
Welwitindolinone A isonitrile
OCH3
OH OH
R
O
O
O OCH3 OCH3
O OH O H3CO CHO
N
OOH
OCH3
O
OH
OCH3
OH
OH OH
OH
HN NH2
H
OH
H H
NH
OH
OH
RO
O
OR
ORRO
OR
OH
OH
OH
CO
76
1026-Hydroxy-
7-O-methylscytophycin E
16and
100 Scytoscalarol
95 Scytophycin B
16
99Tolytoxin
10320-Nor-3a-acetoxy-abieta-5,7,9,11,13-
pentaene R = H104
20-Nor-3a-acetoxy-abieta-5,7,9,11,12-hydroxy-13-pentaene R = OH
1
27
277
7
16
16 16
94 Scytophycin A 96 Scytophycin C
97Scytophycin D
76
and
6
76
98Scytophycin E 101 6-Hydroxy-scytophycin B
R =
105 Pentagalloyl-glucose
Fig. 1 continued
Phytochem Rev
123
Page 12
Antiprotozoal metabolites
There are only six (9, 16–18, 21, 22; Fig. 1)
antiprotozoal metabolites reported from freshwater
microalgae. Antiplasmodial indol [3,2-j]phenanthri-
dines named calothrixins A (16) and B (17)
(Calothrix sp.) inhibited Plasmodium falciparum
FAF6 growth at IC50 = 58 and 180 nM while
chloroquine used at the same assay displayed
growth inhibition at 83 nM (Rickards et al. 1999).
Other natural product from freshwater algae with
moderate antiprotozoal activity against P. falcipa-
rum clone KI (IC50 = 1.5 lg/ml) and NF54
(IC50 = 2.4 lg/ml) is ambigol C (18), which was
isolated from Fischerella ambigua (Wright et al.
2005). Furthermore, aerucyclamides A–D (19–22)
(M. aeruginosa) were reported from microalgae
between 2005 and 2008 (Portmann et al. 2008a, b;
Gademann and Kobylinska 2009), but only aerucy-
clamides C (21) and D (22) exhibited antiplasmodial
properties. Metabolite 21 was the most selective,
and active compound with 0.7, 15.9 and 120 lM
IC50 values for chloroquine-resistant strain K1 of P.
falciparum, Trypanosoma brucei rhodesiense STIB
900 and cytotoxic activity in rat myoblast L6 cells,
respectively (Portmann et al. 2008b). On another
hand, 9 and its synthetic dimers (23–29; Barbaras
et al. 2008) were evaluated against T. brucei
rhodesiense STIB 900, Trypanosoma cruzi Tulahuen
C2C4, Leishmania donovani MHOM-ET-67/L82
axenic amastigotes, and Plasmodium K1. The nat-
ural product 9 showed a pronounced inhibition
against P. falciparum (IC50 = 194 nM) and it was
selective (600 fold) over rat myoblast L6 cells
(IC50 = 120.9 nM), IC50 values of the other para-
sites tested were between 34 and 88 lM. Dimer 29
with longer linker displayed the best antiplasmodial
effect against P. falciparum with IC50 of 14 nM
with a selectivity over rat myoblast L6 cells of 575
(Barbaras et al. 2008).
Insecticidal and larvicidal metabolites
There are some examples of natural products from
freshwater microalgae with insecticidal activity (30–
35; Fig. 1), most important being those isolated from
Fischerella genus: 12-epi-hapalindole C isonitrile
(30), 12-epi-hapalindole E isonitrile (31), 12-epi-
hapalindole J isonitrile (32), and hapalindol L (33)
These compounds killed 100% of the larvae of the
dipteran Chironomus riparius within 48 h at\37 lM
(Becher et al. 2007). A sesquiterpene with activity
against the same dipteran was eremophilone (34),
from Calothrix sp. PCC 7507, which showed acute
toxicity (LC50) against insects at 29 lM, and Tham-
nocephalus platyurus (crustacea) at 22 lM, the
compound was not toxic for Plectus cirratus (nem-
atoda) (Hockelmann et al. 2009). Another alkaloid
with insecticidal properties is 2(R),5(R)-bis(hydroxy-
methyl)-3(R),4(R)-dihydroxypyrrolidine (DMDP,
35), isolated from Cylindrospermum licheniforme
and higher plants, it showed be a glucosidase
digestive inhibitor of aquatic insects and crustacean
grazers (Thamnocephalus platyurus) (Juttner and
Wessel 2003). One example of an antifeedant
metabolite from microalgae is 6, which was active
against cotton ballworm (Heliotis armigera) at
EC50 = 3.4 lg/cm2 and total inhibiton of feeding
was at 10 lg/cm2 (Hirata et al. 2003), however its
potential is reduced because 6 is considered a
dangerous poison.
In general, many microalgae have effects in the
development and survival of mosquito larvae; there
are several reports about the potential in the vectors
control of disease such as malaria, dengue, enceph-
alitides, and filariasis through the use of microalgae
O
HO2CHO
HO
OHO
OHO
O
CH2OHHO
OH OH
O
HO
OH
HO
R2O H
HO
SO3Na
R3OR3O
O
O OR1HO
OO
OHHO
OH
O
HOH2C
HO
OHN
N
CH3
Cl
R
106 Bauerine A R = H107 Bauerine B R = Cl
108 Oscillatoria raoi; R1 = linoleoyl; R2= palmitoyl; R3 = H109 O. raoi: R1 = palmitoyl; R2 = palmitoyl; R3 = H110 O. trichoides: R1 = oleoyl; R2 = palmitoyl; R3 = H111 Scytonema sp.: R1 = linoleoyl; R2 = palmitoyl; R3 = palmitoyl 112 Sugar composition of Nostoflan
Fig. 1 continued
Phytochem Rev
123
Page 13
and algae. Effects of them could be the toxicity to
aquatic stages of mosquitoes, reduction of population
by algae’s indigestibility or modification of the
reproductive cycles (Marten 1986; Rao et al. 1999;
Ahmad et al. 2001; Tuno et al. 2006; Marten 2007;
Rey et al. 2009). The use of microalgal hepato and
neurotoxins as mosquito control agents is not recom-
mended for environmental implications. However
there are larvicides from cyanobacteria, which are not
hepato and neurotoxic, an example was a compound
partially purified from O. agardhii, which was highly
toxic in larvae of Aedes aegypti (Kiviranta and
Abdel-Hameed 1994). Studies in the same species of
microalgae revealed a toxic mixture to larvae of
Aedes albopictus, unsaturated (oleic, linoleic and
c-linoleic acids) and saturated (myristic, palmitic,
stearic acids) fatty acids were found in the mixture
(Harada et al. 2000).
Antimicrobial metabolites
There are several chemical groups of microalgae’s
metabolites with antimicrobial activity including
fatty acids, alkaloids, aromatics, macrolides, peptides
and terpenes. Laxaphicins B (36) and C (37;
Anabaena laxa) are lipopeptides that showed inhib-
itory activity against Aspergillus oryzae, Candida
albicans, Penicillum notatum, Saccharomyces cervi-
siae and Trichophython mentagrophytes. The test was
made by disk assay (50 lg/disk) and these com-
pounds showed also significant cytotoxic property
(Frankmolle et al. 1992).
Pahayokolide A (5) (Lyngbya sp.) is a peptide with
antimicrobial activity which inhibited the growth of
Bacillus megaterium (MIC = 5 lg/ml) and Bacillus
subtilis (MIC = 5 lg/ml), and showed cytotoxicity
over six cell lines (IC50 \ 6 lM) (Berry et al. 2004).
Fatty acids such as a-dimorphecolic (38), coriolic
(39), and linoleic (40) acids from Oscillatoria redekei
were capable of inhibiting the growth of the Gram-
positive bacteria B. subtilis, Micrococcus flavus and
Staphylococcus aureus, although their activities were
moderate with MIC values of 75–100 lg/ml (Mundt
et al. 2003). A more active fatty acid was c-linolenic
acid (41), produced by Fischerella sp., which also
demostrated growth inhibition of Escherichia coli,
Enterobacter aerogenes, Pseudomonas aeruginosa,
Salmonella typhi and S. aureus with MIC values of
4–16 lg/ml (Asthana et al. 2006). More non polar
antimicrobial compounds were propanoic (42) and
butanoic acids (43) as major components of an active
mixture (MIC = 3–16 mg/ml) against Aspergillus
niger, C. albicans, E. coli, and S. aureus, this was
obtained from Haematococcus pluvialis (Rodrıguez-
Meizoso et al. 2010).
From Fischerella genus was isolated parsiguine
(44), a non polar cyclic polimer with activity against
Staphylococcus epidermidis (MIC = 40 lg/ml) and
Candida krusei (MIC = 20 lg/ml) (Ghasemi et al.
2004). Other antimicrobials isolated from the same
genus were fischellerin A (7) (Gross et al. 1991;
Hagmann and Juttner 1996), ambigols A (45), B (46)
(Falch et al. 1993) and ambiguine A–F (47–52), H–I
(53, 54), K–O (55–59) isonitriles (Smitka et al. 1992;
Raveh and Carmeli 2007; Mo et al. 2009a). The most
active compounds amongst these alkaloids were 47, 55
and 57 with activities (MIC) against Bacillus anthracis
of 1, 6.6 and 7.5 lM respectively, while 54 displayed
selectivity against Mycobacterium tuberculosis
(13.1 lM) over B. anthracis (MIC [ 128 lM) and
Vero cell assay (no detectable cytotoxicity) (Mo et al.
2009a). Moderate antimicrobial activity is attributed to
(45), which showed inhibition against M. tuberculosis
at IC50 = 64 lg/ml (Falch et al. 1993).
Many substances with antimicrobial potential have
been isolated from Nostoc genus (Piccardi et al. 2000;
Svirtec et al. 2008), some of them are diterpenoids with
important activities. For example, 4-[(5-carboxy-2-
hydroxy)-benzyl]-1,10-dihydroxy-3,4,7,11,11-pentame-
thyloctahydrocyclopenta\a[naphthalene (60) showed
growth inhibition of E. coli, E. aerogenes, P. aerugin-
osa, S. aureus, S. typhi (MIC = 0.5–16 lg/ml), and
M. tuberculosis H37Rv (MIC = 2.5 lg/ml) (Asthana
et al. 2009). Other significant antimicrobial compounds
are noscomin (61) (Jaki et al. 1999), comnostins
A–E (62–66) (Jaki et al. 2000b), and 8-[(5-carboxy-
2,9-epoxy)benzyl]-2,5- dihydroxy-1,1,4a,7,8-pentamethyl-
1,2,3,4,4a,6,7,8,9,10,10a dodecahydrophenanthrene
(67), 1,8-dihydroxy-4-methylanthraquinone (68) 4-
hydroxy-7-methylindan-1-one (69) (Jaki et al. 2000a).
Several of these compounds 61, 64, 66 and 67 showed
selective and potent antibacterial properties,
which were equal to chloramphenicol and tetra-
cycline when were tested S. epidermis and E. coli,
respectively (Jaki et al. 1999, 2000a, b). More antimi-
crobials from Nostoc genus are nostofungicidine
(70) with activity against Aspergillus candidus
(MIC = 1.6 lg/ml) (Kajiyama et al. 1998) and
Phytochem Rev
123
Page 14
carbaimidocyclophanes A–C (71–73), which dis-
played more cytotoxicity than antimicrobial properties
(Bui et al. 2007).
Hapalosiphon fontinalis is recognized as producer
of fungicidal compounds, some of them being
fontonamide (74), anhydrohapaloxindole A (75),
hapalindoles C–H (76–81), J–K (82–83), L (33),
M–Q (84–88), and T–V (89–91) (Moore et al. 1987a,
b). In the same way, welwitindolinone A isonitrile
(92) and N-methylwelwitindolinone C isocianate (93)
have been isolated from H. welwitschii and Westiella
genus (Stratmann et al. 1994).
Antimicrobials identified from Scytonema genus
are cyanobacterin (15) (Mason et al. 1982; Pignatello
et al. 1983), scytophycins A–E (94–98) (Ishibashi
et al. 1986), tolytoxin (99) (Carmeli et al. 1990) and
scytoscalarol (100), a guanidine-bearing sesterterpene
(Mo et al. 2009b). Macrolide 99 showed selective and
potent fungicidal activity against two yeast and twelve
filamentous fungi, their MIC values were between
0.25 and 8 nM (Patterson and Carmeli 1992), while
100 displayed a significant antimicrobial activity
against B. anthracis (MIC = 6 lM), C. albicans
(MIC = 4 lM) and S. aureus (MIC = 2 lM), in
adition it was weakly cytotoxic in a Vero cell assay
(Mo et al. 2009b). Metabolites 95 and 98 were isolated
from Cylindrospermum muscicola together with their
also fungicidal derivates 6-hydroxyscytophycin B
(101) and 6-hydroxy-7-methoxy-scytophycin E (102;
Nostocaceae family) (Jung et al. 1991). Furthermore,
95 and 98 were cytotoxic agents with potential for
killing drug-resistant tumor cells (Smith et al. 1993).
Active compounds against S. typhi were isolated
from cyanobacteria Microcoleus lacustris, 20-nor-
3a-acetoxy-abieta-5,7,9,11,13-pentaene (103) and 20-
nor-3a-acetoxy-12-hydroxy-abieta-5,7,9,11,13-pentaene
(104) whose MIC values were 61.4 and 46.2 lg/ml,
respectively (Perez-Gutierrez et al. 2008). Moderate
antimicrobial activity has been observed for green
microalgae such as Euglena viridis (Das et al. 2005)
and Spirogyra varians (Cannell et al. 1988). From
S. varians was identified pentagalloylglucose (105)
as responsible of its antimicrobial effect against
B. subtilis and Micrococcus flavus.
Compounds with other activities
The nematicidal properties of the microalgae against
Meloidogyne species have been reported with extracts or
direct application of organisms such as Aulosira fertil-
issima (Chandel 2009), Microcoleus vaginatus (Khan
and Park 1999) and Oscillatoria chorina (Khan et al.
2007). Antiviral substances originating from microalgae
are bauerines A (106) and B (107) (b-carbolines)
(Fig. 1), which have been isolated from a species of
Dichothrix baueriana (Larsen et al. 1994). Ambigol A
(45) (F. ambigua) (Falch et al. 1993), glycolipids
isolated from Oscillatoria raoi, O. trichoides, and
Scytonema sp. (108–111) (Reshef et al. 1997), and the
95 aminoacids containing protein named scytovirin
(Scytonema varium) (Bokesch et al. 2003) which
exhibited inhibition of the HIV-1 reverse transcriptase,
while the polisacaride nostoflan (112, MW 2.11 9
105 Da) (Nostoc flagelliforme) exhibited a potent and
selective antiherpes simplex virus type 1 activity
(Kanekiyo et al. 2005). Therefore is probable that the
study of macro molecules derived from freshwater
microalgae can reveal a greater number of antiviral
compounds, given that the sulfated polysaccharides
obtained from the marine microalgae have resulted to be
highly promising as antivirals (Harden et al. 2009).
Freshwater fungi
There are more than 600 species of freshwater fungi
between ascomycetes and mitosporic fungi, where a
greater number are known from temperate, as com-
pared to tropical regions (Wong et al. 1998). Despite
this, there are few studies focused on chemical and
biological properties of fungi from freshwater aquatic
ecosystems. This indicates that this important group of
microorganisms has been scarcely explored for their
pharmaceutical and pesticidal potential. Table 2 pre-
sents a compilation of freshwater species of fungi that
have been explored in terms of their chemical content
and biological properties, which belong to different
fungal genus. These include Anguillospora, Annula-
tascus, Astrosphaerilla, Camposporium, Caryospora,
Clavariopsis, Decaisnella, Dendrospora, Glarea,
Helicodendron, Helicoon, Kirshchsteiniothelia, Mass-
arina, Mortierella, Ophioceras, Paraniesslia, Pseudo-
halonectria, Stachybotrys, and Vaginatispora genera.
The contributions made to the species studied have
been directed mainly to the search for antimicrobial
and nematicidal agents. Therefore, the following
paragraphs, and in the Fig. 2 (113–191), documented
those freshwater fungal metabolites thus far identified.
Phytochem Rev
123
Page 15
Table 2 Metabolites with pesticidal properties isolated from fungi found in freshwater systems
Fungal species Metabolite Type of compound Activity From Reference
Anguillosporalongissima
Anguillosporal (120) Polyketide Antimicrobial USA Harrigan et al. (1995)
Annulatascustriseptatus
Annularins A–H (140–147) a-pyrone Antibacterial USA Li et al. (2003)
Astrosphaeriellapapuana
Astropaquinones A–C (168–170)
6-hydroxyl-2-4-dimethoxy-7-
methylanthraquinone (171)
Naphthoquinone Antibacterial China Wang et al. (2009)
CamposporiumquercicolaYMF1.01300
Quercilolin (162)
Tenellic acid A (116)
20,40-dihydroxyacetophenone (163)
Diphenyl ether Antibacterial China Wang et al. (2008)
CaryosporacallicarpaYMF1.01026
Caryospomycins A-C (172–174)
4,8-Dihydroxy-3.4-
dihydronaphthalen-1(2H)-one (175)a
4,6-Dihydroxy-3.4-
dihydronaphthalen-1(2H)-one (176)a
4,6,8-Trihydroxy-3.4-
dihydronaphthalen-1(2H)-one (177)a
3,4,6,8-Tetrahydroxy-3.4-
dihydronaphthalen-1(2H)-one
(cis-4-hydroxyscytalone) (178)a
Macrolactone
Naphtahlene
Nematicidal
Nematicidal
China
China
Dong et al. (2007)
Zhu et al. (2008)
Clavariopsisaquatica
Clavariopsin A–B (158–159) Cyclic depsipeptide Antifungal Japan Kaida et al. (2001)
Decaisnellathyridioides
Decaspirones A–E (121–125) Spirodioxynaphthalenes Antimicrobial USA Jiao et al. (2006a)
Dendrosporatenella
Tenellic acids A–D (116–119) Diphenyl ether Antibacterial USA Oh et al. (1999)
Glarea lozoyensis Pneumocandin B0 (160)
Pneumocandin A0 (161)a
Cyclic lipopeptide Antifungal Spain Bills et al. (1999),
Schmatz et al.
(1992a, b)
Helicodendrongiganteum
Heliconols A–C (126–128) Polyketide Antimicrobial USA Mudur et al. (2006)
Kirschsteiniotheliasp. C-76-1
Kirschsteinin (113)
2,6-Dichloro, 3-hydroxy, 5-methyl-
(20chloro, 30-hydroxy, 50-methyl)phenoxy bencene (114)
2,6-Dichloro, 3-hydroxy, 5-methyl-
(20, 60-dichloro,
30-hydroxy, 50- methyl)phenoxy
bencene (115)
Napthoquinone
Diphenyl ether
Antimicrobial
Cytotoxic
Antimicrobial
Antimicrobial
Chile Poch et al. (1992)
Massarina tunicate Massarinolins A–C (129–131) Sesquiterpenlactone Antibacterial USA Oh et al. (1999)
Massarilactones A–B (132–133) Sesquiterpenlactone Antibacterial USA Oh et al. (2001)
Massarigenins A–D (134–137)
Massarinins A–B (138–139)
Polyketide Antibacterial USA Oh et al. (2003)
Paraniesslia sp.
YMF1.01400
(2S,20R,3R,30E,4E,8E)-1-O-(b-D-
Glucopyranosyl)-3-hydroxyl-2-
[N-20-hydroxyl-30 Eicosadecenoyl]
amino-9-methyl-4,8-octadecadiene
(190)
Cerebroside C (191)a
Sphingolipid Nematicidal China Bills et al. (1999)
Phytochem Rev
123
Page 16
Antimicrobial metabolites
Following different strategies, researchers have iden-
tified antimicrobial metabolites with unusual and
varied structures from freshwater fungi. Specifically,
the studies by the Gloer’s group had described most
freshwater aquatic fungal metabolites reported in the
literature (Gloer 2007). Among those, one of the first
fungi studied was Kirschsteiniothelia sp., which was
collected from a thermal stream in Puyehue, Chile.
The chemical studied guided to isolate kirschsteinin
(113), a naphthoquinone dimer, together with two
chlorinated diphenyl ethers (114–115). All com-
pounds displayed a good antimicrobial activity
against B. subtilis (1–5 lg/ml) and S. aureus
(1–5 lg/ml), using the disk assays. Also, 113 showed
cytotoxic properties towards three different carci-
noma cells (Poch et al. 1992). Other diphenyl ethers
were the tenellic acids A–E (116–119) which were
isolated from the fungus Dendrospora tenella, and
with activity against Gram-positive bacteria (Oh et al.
1999). Anguillosporal (120) is a polyketide isolated
by antimicrobial assay-guided from Ingold Anguil-
lospora longissima. This compound exhibited good
antibacterial activity against S. aureus (4 lg/disk)
and C. albicans (58 lg/disk) (Harrigan et al. 1995).
Furthermore, another freshwater fungus identified as
Decaisnella thyridioides produced decaspirones A–E
(121–125), which were novel metabolites belonging
to spirodioxynaphthalenes chemical family. One of
them, 121 displayed wide activity spectrum against
C. albicans (MIC = 10 lg/ml), Aspergillus flavus
(MIC = 10 lg/ml), Fusarium verticillioides
(MIC = 5 lg/ml), and S. aureus (MIC = 10 lg/ml)
(Jiao et al. 2006a). Other species like Helicodendron
giganteum and Massarina tunicate were highly
prolific in the production of metabolites with unusual
chemical structures and antibacterial properties.
H. giganteum biosynthetized unusually reduced fur-
anocyclopentanes named heliconols A–C (126–128)
(Mudur et al. 2006) while M. tunicate produced
massarinolins A–C (129–131), massarilactones A–B
(132–133), massarigenins A–D (134–137) and mas-
sarinins A–B (138–139) (Oh et al. 1999, 2001, 2003).
Table 2 continued
Fungal species Metabolite Type of compound Activity From Reference
Pseudohalonectriaadversaria YMF1.01019
Pseudohalonectrin A–B (179–180) Pyrone-quinone Nematicidal China Dong et al.
(2006)
Stachybotrys sp. (CS-710-1) Stachybotrins A and B (155–156) Alkaloid Antimicrobial USA Xu et al.
(1992)
Unknown A-00471 Dihydroaltenuenes A–B (148–149)
Dehydroaltenuenes A–B (150–151)
Isoaltenuene (152)a
Altenuene (153)a
50epi-Altenuene (154)a
Dibenzopyrone Antibacterial USA Jiao et al.
(2006b)
YMF 1.01029 Ymf 1029 A–E (181–185) Bisnaphthospiroketal Nematicidal China Dong et al.
(2008)
Preussomerin C (186)a, D (187)a Bisnaphthospiroketal Nematicidal
(4RS)- 4,8-Dihydroxy-3,4-
dihydronaphthalen-1(2H)-one (188)a
4,6,8-Trihydroxy-3,4-
dihydronaphthalen-1(2H)-
one (189)a
Napththalene Nematicidal
Colomitides A, B (164–165) Bicyclic ketal Antimicrobial China Dong et al.
(2009a)
Colelomycerones A–B (166–167) Naphthalene Antimicrobial China Dong et al.
(2009b)
Vaginatispora aquatica Oxasetin (157)a Polyketide Antibacterial Hong
Kong
He et al.
(2002)
a Also found in other source
Phytochem Rev
123
Page 17
CHO
OH
OH
O
OH OH
R
HO
HO
OH
OCH3
O
HO
O OH O
OOH3COH
O
O OR
OR1
O O
H
HOO O
HHO OAc
OH
OCH3O
CHO COOH
OR
O
Cl R
OHClClHO
O
OH
O
OCO2H
OH
CO2H
OH
HO
122 Decaspirone B
120 Anguillosporal
HeliconolR
126 A: CH3126 B: CH2OH128 C: COOH
113 Kirschsteinin
DecaspironeR R1
121 A: H H124 D: H Ac125 E: Ac H
1142,6-dichloro, 3-hydroxy, 5-methyl-(2´chloro,
3´-hydroxy, 5´- methyl)phenoxy bencene R = H115
2,6-dichloro, 3-hydroxy, 5-methyl-(2 , 6´-dichloro,3´-hydroxy, 5´- methyl)phenoxy bencene R = Cl
Tenellic acidR
116 A: CH3117 B: H118 C: COCH3119 D: CH2CH(CH3)2
129 Massarinolin A 130 Massarinolin B 131 Massarinolin C
O OH
OH1
O O
H
123 Decaspirone C
OOHO
OH
HO
OO
O
HO
OH
O
O
HO
OH
O
132 Massarilactone A 133 Massarilactone B 134 Massarigenin A
Fig. 2 Chemical structures of metabolites with pesticidal properties isolated from fungi found in freshwater systems
Phytochem Rev
123
Page 18
OO
H3COOH
OO
H3COO
O O
OCH3
R1
R
O O
OCH3
O
OH
OHO
O
O
OH
OHO
O
O
OOH
O
OH
O
O
OO
H3CO
O
O
O OCH3
HO
OH
O
OH
OHO
O
147 Annularin H
AnnularinR R1
140 A: H OH141 B: OH H142 C: OH OH143 D: H H
146 Annularin G144 Annularin E
137 Massarigenin D136 Massarigenin C
139 Massarinin B
135 Massarigenin B
145 Annularin F
138 Massarinin A
N N
O
O
N
OCH3
O
N N NR
O
O
OHN N
O O
HO2C
NHO
O
O
NO O
H
H
H
O OH
O
H
R
R1
OOH
OCH3
O
R
OOH
OCH3
O
O
H
HO
OOH
OCH3
HO
O
R
R1
OOH
OCH3
HN
R
HO
OH
O
O
DihydroaltenueneR R1
148 A: βOH βOH149 B: βOH αOH
Dehydroaltenuene150 A: R = αOH151 B: R = βOH
158 Clavariopsin A: R = CH3159 Clavariopsin B: R = H157 Oxasetin
152 Isoaltenuene
R R1153 Altenuene: βOH αOH
154 5´Epi-altenuene: βOH βOH155 Stachybotrin A: R = OH156 Stachybotrin B: R = H
Fig. 2 continued
Phytochem Rev
123
Page 19
OO
HO
O
O
OCH3
OCH3
HO
OCH3OO
O
O
H3CO
OH3CO
CH3O
H3CO
O
OAc
O
H3CO
OCH3O
O
O
H3CO
OCH3O
O
R
OHO OH
OCH3
HO OH
O
NH
HO
OH
N
O
OH
H OH
HO
HO
H2NOC
HOH
HN
NH
HN
O
HO OHO
OH
H
NHO
O
HN
O
R
Colomitide164 A: 3β, 4β, 5β165 B: 3α, 4α, 5α
1
3
4
5
167 Colelomycerone B166 Colelomycerone A
Astropaquinone169 B: R = OCH3170 C: R = OH
1718-Hydroxy-2,4-dimethoxy-7-methylanthraquinone168 Astropaquinone A
162 Quercilolin
163 2', 4'-Dihydroxyacetophenone160 Pneumocandin Bo: R = H161 Pneumocandin Ao: R =CH3
O
H3CO
OH O
O
O
OH
OCH3 OH
OHOH
O
O
OH
R1
R2R3
O
O
O
O
OH OH
OO
O
OOH
HO
O OH
OO
O
OOH
HO
179 Pseudohalonectrin A
172 Caryospomycin A
7´
6´5´
6´5´
173 Caryospomycin B
6´5´
174 Caryospomycin C
1754,8-Dihydroxy-3,4-dihydronaphthalen-1(2H)-one:
R1 = OH, R2 = H: R3 = H176
4,6-Dihydroxy-3,4-dihydronaphthalen-1(2H)-one:R1 = H, R2 = OH, R3 = H
1774, 6, 8-Trihydroxy-3,4-dihydronaphthalen-1(2H)-one:
R1 = R2 = OH, R3 = H178
3 (R), 4(S), 3, 4, 6, 8-Tetrahydroxy-3,4-dihydronaphthalen-1(2H)-one: R1 = R2 = R3 = OH
180 Pseudohalonectrin B
181 Ymf 1029 A 182 Ymf 1029 B
Fig. 2 continued
Phytochem Rev
123
Page 20
The most active of these were 132, 138 and 139 in
disk assay against B. subtillis and S. aureus (Oh et al.
2001, 2003).
Metabolites with a-pyrone ring are also produced
by freshwater fungi, for example the annularins A–H
(140–147) isolated from Annulatascus triseptatus. In
this case, the antibacterial activity was exhibited for
140–142 and 145 (Li et al. 2003). A group of lactones
corresponding to the altenuenes was isolated from an
unknown freshwater fungus belonging the family
Tubeufiaceae. These were the novel dihydroaltenu-
enes A–B (148–149), dehydroaltenuenes A–B (150–
151) and the previously reported isoaltenuene (152),
altenuene (153) and 50epi-altenuene (154), where
only the compounds 148, 150 to 153 displayed
antibacterial activity against at least one of the strains
tested (Li et al. 2003; Jiao et al. 2006b). To date, the
unique alkaloids reported from freshwater fungi are
OH OH
OO
O
O
O
OCH3
OH OH
OO
O
OR
O
OH OH
OO
O
O
O
H
OH
183 Ymf 1029 C: R = OH184 Ymf 1029 D: R = H 185 Ymf 1029 E
186Preussomerin C
OO
(CH2)7CH3HOHO
OH
NH
O
(CH2)nCH3
OHOH
OH
OH OH
OO
O
O
O
OH
OH
O
OH
OOH
OH
190(2S,2’R,3R,3’E,4E,8E)-1-O-(β-D-
glucopyranosyl)-3-hydroxy-2-[N-2’-hydroxy-3’-eicosadecenoyl]amino-9-methyl-4,8-octadecadiene: n = 14
191Cerebroside C: n = 12
187Preussomerin D
1884, 6, 8-trihydroxy-3,
4-dihydronaphthalen-1(2H)-one
1896, 8-dihydroxy-3,
4-dihydronaphthalen-1(2H)-one
Fig. 2 continued
Phytochem Rev
123
Page 21
the stachybotrins A–B (155–156), both isolated from
the fungus Stachybotrys sp. CS-710-01, a strain
collected from brackish water in Florida. Both
compounds were able to inhibit to B. subtillis
(10 lg/disk), and to filamentous fungi Ascobolus
furfuraceus and Sordaria fimicola at concentrations
of 20 lg/disk (Xu et al. 1992).
Oxasetin (157) is an interesting antibacterial
polyketide produced by Vaginatispora aquatica, a
fungus isolated from Hong Kong. It displayed
activity against yeast C. albicans, and bacteria
E. coli, vancomycin-resistant Enterococcus faecalis
(MIC = 16 lg/ml), methicillin-resistant S. aureus
(MIC = 16 lg/ml), and Streptococcus pneumoniae
(MIC = 16–32 lg/ml) (He et al. 2002). Clavariopsis
aquatica was isolated from submerged decaying
leaves in Japan, an aquatic fungus which produced
two cyclic depsipeptide, clavariopsin A–B (158–
159). Both metabolites were antagonistic to C. albi-
cans (MIC = 8 lg/ml), A. niger (MIC = 4 lg/ml)
and A. fumigatus (MIC = 2–4 lg/ml). Interestingly,
159 induced hyphae swelling of A. niger after 24 h
incubation (Kaida et al. 2001).
Undoubtedly, one of the most important antifungal
agents discovered in recent decades was pneumocan-
din B0, a cyclic lipopeptide (160). This compound
together with pneumocandin A0 (161) and other
derivatives were produced by Glarea lozoyensis, a
dematiaceous hyphomycete isolated from filtrate pond
water in Spain (Bills et al. 1999; Schmatz et al. 1992a,
b). The in vitro assays showed the enormous potential
of pneumocandins where 160 was the best, at very low
concentrations against C. albicans (MIC = 0.06 lg/
ml), in the assay with the enzyme 1,3-b-D-glucan
(IC50 = 0.06 lg/ll) and in vivo efficiency against
Pneumocystis carinni in mice showed a ED50 between
0.15 and 2.5 mg/kg (Schmatz et al. 1992b). Caspo-
fungin (Cancidas�) is a synthetic derivative of the
chemical class member of pneumocandin/equinocan-
din, available on the market and the first systemic
antifungal agent (Keating and Figgitt 2003).
Recently, Dong0s group have made interesting
contributions in the exploration of freshwater fungal
metabolites from China, where after a screening with
30 aquatic fungi, Camposporium quercicola was
selected for its antibacterial activity. This fungus was
cultured and using the bioassay identified quercilolin
(162), a new diphenyl ether with moderate activity
against Bacillus cereus, Bacillus laterosporus and
S. aureus. Also isolated were 116 and dihydroxyace-
tophenone (163), known metabolites reported with
antibacterial and antifungal activities (Wang et al.
2008). Then, an unidentified freshwater fungus YMF
1.01029 led to the isolation of antimicrobial metabolites
identified as colomitides A–B (164–65) and colelomy-
cerones A–B (166–67), with moderate antibacterial and
antifungal activity. In these cases, the antimicrobial
activity was evaluated using standard disk assays
(50 lg/disk) against seven phytopathogenic fungi and
four pathogenic bacteria. Biological profile showed
very similar behavior to colomitides and colelomyce-
rones metabolites, all being active against B. subtilis
B. laterosporus, Bipolaris maydis, Cochliobolus sati-
vus, Fusarium verticillioides and S. aureus. Interest-
ingly, these compounds have in common a ketal carbon
in their structures (Dong et al. 2009a, b). Another
species analyzed by the same authors was Astrosphae-
riella papauna, isolated from submerged wood and
producer of four nahpthoquinones called astropaqui-
nones A–C (168–170) and 6-hydroxyl-2-4-dimethoxy-
7-methylanthraquinone (171). All compounds exhibited
moderate activity against Alternaria sp., B. cereus,
B. laterosporus, and S. aureus. Also 169 displayed
antagonist action against, Phyllosticta sp. and Esche-
richia coli; further, 170 was active against Colletotri-
chum sp., Fusarium sp., Giberella saubinetii, and
Phyllosticta sp. (Wang et al. 2009).
Nematicidal metabolites
As for the search of nematicidal metabolites produced
by freshwater fungi micromycetes, the contributions
found in the literature corresponded to the research
conducted by Dong’s group. These were made for
alternatives to control Bursaphelenchus xylophilus, a
very economically important nematode devastating
pine wood. During this search the fungus Caryospora
callicarpa was detected which produces seven com-
pounds belonging to two groups of chemical families,
macrolactons (caryospomycins A–C) (172–174) and
naphthalenes (175–178). All exhibited moderate
activity against B. xylophilus (LC50 = 100–229 lg/
ml) (Dong et al. 2007; Zhu et al. 2008). Other
nematicidals identified were pseudohalonectrin A–B
(179–180), recognized as azaphilone derivatives and
isolated from Pseudohalonectria adversaria (Dong
et al. 2006). From YMF 1.01029 strain were detected
several compounds with nematicidal activity against
Phytochem Rev
123
Page 22
B. xylophilus (IC50 = 100–200 lg/ml) (18–89), 187
being the most active (Dong et al. 2008). This strain
showed its ability to biosynthesize several metabolites
with properties toward different targets, as antimicro-
bials as mentioned in previous subsections. Finally,
the fungus Paraniesslia sp. was able to produce
two glycosphingolipids, (2S,20R,3R,30E,4E,8E)-1-O-
(b-D-glucopyranosyl)-3-hydroxyl-2-[N-20-hydroxyl-
30eicosadecenoyl] amino-9-methyl-4,8-octadecadiene
(190) and cerebroside C (191), both showed weaker
(LC50 = 110 lg/ml) nematicidal activities against
B. xylophilus (Dong et al. 2005). This scenario shows
the enormous potential of chemical cocktails in our
microbial reserves that still remain unkown.
Conclusions and perspectives
The diversity of MNP reported from freshwater
aquatic algae and fungi are examples of the structural
diversity of their metabolic ability, where many of
them were novel contributions to the chemistry of
natural products. This shows the ability to respond to
the extremely high and competitive interactions that
exists in the microbial communities. In particular, it
seems that the secondary metabolites of green
microalgae show great potential in the search for
compounds with plaguicidal application, because
they are not common producers of hepatic or
neurotoxins like cyanobacteria, examples are
Euglena (Zimba et al. 2010; Das et al. 2005) or
Haematococcus (Rodrıguez-Meizoso et al. 2010).
Furthermore, some cyanobacteria have proven to be
important producers of non peptide compounds,
whose toxicity is not comparable to the hepato or
neurotoxins as bioactive fatty acids from species of
Oscillatoria (Kiviranta and Abdel-Hameed 1994;
Tellez et al. 2001). In the research of freshwater
fungal metabolites with pesticidal properties from
microscopic fungi we found that the existing litera-
ture is very poor. This is probably due to the
increased awareness that cyanobacteria are organisms
responsible for that cause problems in the quality of
freshwater.
In general, the mechanisms and mode of action of
much of the freshwater fungal and microalgae
metabolites have not been explored yet. In any case,
we need more studies of the biological activity of
MNP, as there are a large number of reports on
isolation of compounds, but without enough biological
assays to evaluate them as potential pesticide agents.
There is now a huge and urgent demand for new
agrochemical agents that are eco-friendly to the
environment and humans. This is the challenge to
researchers, to develop new effective agents with novel
sites of action eliminating the undesirable side effects
of many synthetic products. Therefore, it is important
to develop new in vitro and in vivo bioassays to detect
metabolites with new modes of action.
Also, as with the other organisms, it is extremely
important to generate information on the knowledge
of different types of microorganisms from unexplored
habitats to create more opportunities to find new
isolates, or with a different metabolism, and therefore
more probabilities to discover new bioactive MNP
with a profitable biotechnological potential. So the
efforts must increase to continue cataloging, classi-
fying and describing microbial diversity. Therefore,
the MNP from freshwater aquatic species represent
appealing opportunities to find natural alternatives to
develop commercial antimicrobial, algaecide, insec-
ticide, herbicide and nematicide products, all with
high probabilities to be eco-friendly to the environ-
ment and humans.
Acknowledgments The authors thank Sergio Perez (CICY)
and Clara Blanco (CCMA) for their valuable technical
assistance.
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