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Opportunity, Challenge and Scope of Natural Products in Medicinal Chemistry, 2011: 283-311
ISBN: 978-81-308-0448-4

9. Natural products: Anti-fungal agents
derived from plants

Tasleem Arif, T. K. Mandal and Rajesh Dabur
National Research Institue of Basic Ayurvedic Sciences
Nehru Garden, Kothrud, Pune-411038, India

Abstract. As new spectrums of human fungal infections are
increasing due to increased cancer and AIDS patients. The
increased use of antifungal agents also resulted in the development
of resistance to these drugs. It makes necessary to discover new
classes of antifungal compounds to treat fungal infections. The
research on natural products and natural products derived
compounds has accelerated in recent years due to their importance
in drug discovery. Plants are rich source of bioactive secondary
metabolites of wide variety such as tannins, terpenoids, alkaloids,
and flavonoids, reported to have in vitro antifungal properties.
A series of molecules with antifungal activity against different
strains of fungus have been found in plants, which are of great
importance to humans and plants. These molecules may be used
directly or considered as a model for developing better molecules.
This review attempts to summarize the current status of reported
antifungal compounds from plants.

1. Introduction

The prevalence of resistance to antifungal agents significantly increased
in the past decade.

Resistance to antifungal agents has important implications
for morbidity, mortality and health care in the community. Until recently,



Correspondence/Reprint request: Dr. Rajesh Dabur, National Research Institue of Basic Ayurvedic Sciences
Nehru Garden, Kothrud, Pune, MH-411038, India. E-mail: rajeshdabur@yahoo.com
Tasleem Arif et al. 284
fungi were not recognized as important

pathogens because the annual
death rate due to candidiasis was steady from 1950

to 1970 [1, 2]. Since
1970, this rate increased significantly

due to more widespread use of
immunosuppressive therapies, indiscriminate use of broad-spectrum
antibacterial

agents, the common use of indwelling intravenous devices and

immunosuppressive viral infections such

as AIDS. These developments and
the associated increase in fungal

infections [3] necessitated the search for
new, safer, and more

potent agents to combat serious fungal

infections. For
nearly 30 years, amphotericin B, which causes significant nephrotoxicity,
was the sole drug available

to treat serious fungal infections. The imidazoles

and the triazoles in late 1980s and early 1990s were major advances in safe
and effective treatment of local and systemic

fungal infections. The high
safety profile of triazoles, in particular

fluconazole, has led to their extensive
use. Fluconazole

has been used to treat in excess of 16 million patients,
including

over 300,000 AIDS patients, in the United States alone since the

launch of this drug [4]. Due to selective pressure and widespread use of these
few antifungal drugs,

there have been increasing reports of antifungal
resistance [5].


Medicinal plants have been a source of wide variety of biologically
active compounds for many centuries and used extensively as crude material
or as pure compounds for treating various disease conditions. Relatively 1-10 %
of plants are used by humans out of estimated 250,000 to 500,000 species of
plants on Earth [6]. The plants are relatively cheap source of biological
material having a vast variety of metabolites, primary or secondary, available
in them for selecting the molecule of desired biological activity. Mainstream
medicine is increasingly receptive to the use of antimicrobial and other drugs
derived from plants, as traditional

antibiotics become ineffective. Another
driving factor for the

renewed interest in plant antimicrobials in the past
20 years

is due to

the rapid extinction rate of (plant) species [7].

The scientific
discipline, ethno botany, is utilizing the

impressive array of knowledge
assembled by indigenous peoples

about the plant and animal products they
have used to maintain

health [8,9]. Lastly, the ascendancy of the

human
immunodeficiency virus (HIV) has spurred intensive investigation

into the
plant derivatives, which may be effective, especially

for use in
underdeveloped nations. Few of the compounds isolated from plants such as
2-decanone, hydroxydihydrocornin-aglycones [10], various indole derivatives
[11] and isoflavanone are reported to have antifungal activities. However,
development of useful antifungal drugs from these compounds has not yet
been possible.
Plants derived anti-fungal agents
285
2. Major groups of antifungal compounds from plants

Plants have an almost limitless ability to synthesize aromatic substances
of different functional groups, most of which are phenols or their oxygen-
substituted

derivatives [12]. Most are secondary metabolites, of which at

least
13,000 have been isolated that is less

than 10% of the total [13]. In many
cases, these substances

serve as plant defense mechanisms against predation
by microorganisms,

insects, and herbivores. Some plants

used for their odors
(terpenoids), pigment, (quinones and tannins) and flavor

(terpenoid capsaicin
from chili peppers) were found to be endowed with medicinal properties.
Some of

the herbs and spices used by humans as season food yield

useful
medicinal compounds.

2.1. Simple phenols and phenolic acids

In recent years, numbers of studies have been reported on the antifungal
activity of phenolic compounds from natural sources. Some of the simplest
bioactive phytochemicals consist of a single substituted phenolic ring (Fig 1).
The common herbs tarragon and thyme both contain caffeic acid, a
representative of a wide group of phenylpropane-derived

compounds which is
effective against fungi [14]. The site(s) and number of hydroxyl groups

on
the phenol group are thought to be related to their relative

toxicity to
microorganisms, with evidence that increased hydroxylation

results in
increased toxicity [12]. In addition, it was also reported that more highly
oxidized phenols are more inhibitory [15, 16]. The mechanisms thought to be
responsible for phenolic

toxicity to microorganisms include enzyme inhibition
by the oxidized

compounds, possibly through reaction with sulfhydryl groups
or

through more nonspecific interactions with the proteins [17].

OH
OH O
OH
O
1
HO
HO
2
O
O HO
OH
HO
O
3

Tasleem Arif et al. 286
Tannins and salicylic acid are polyphenol compounds extracted from
Gaullher procumbens, Rhammus purshiand and Anacardum pulsatilla
showed antifungal activity [18,19]. Piper crassinervium, Piper aduncum,
Piper hostmannianum and Piper gaudichaudianum, contain phenolic
acid derivatives crassinervic acid (1), aduncumene, hostmaniane and
gaudichaudanic acid, respectively, were reported for fungitoxic activity [20].
Phenolic compound Eriosemaones AD (2, MIC 20 mg/mL) are reported to
have good antifungal activities [21]. Phenolic compound from Croton
hutchinsonianus [22],

and pinosylvin (3), a constituent of pine, showed growth-
inhibitory activity against C. albicans and Saccharomyces cerevisiae [23].
Four phenolic amides, dihydro-N-caffeoyltyramine, trans-N-
feruloyloctopamine, trans-N-caffeoyltyramine, and cis-N-caffeoyltyramine
isolated from Lycium chinense reported to have anti-fungal activity in a range of
5-10 g/mL [24a]. Three phenolic compounds, 1-galloyl--D-glucopyranosyl-(1-
->4)--D-galactopyranoside, 2-methoxy-5-(1,2,3'-trihydroxypropyl)-phenyl-1-
O-(6"-galloyl)--D-glucopyranoside and 2-methoxy-5-hydroxymethyl-phenyl-1-
O-(6"-galloyl)--D-glucopyranoside together with the known compounds from
the leaves of Baseonema acuminatum were reported for antifungal activity
against Candida albican strains with inhibitory concentration to 50% micro-
organism (IC50) values in the range of 25-100 g/mL [24b].

2.2. Flavonoids

Flavones are phenolic structures containing one carbonyl group and the

addition of a 3-hydroxyl group yields a flavonol (Fig 2). Flavonoids

are
hydroxylated phenolic substances synthesized

by plants in response to
microbial infection. They have been found to be effective

antimicrobial
substances against a wide array of microorganisms.

Their activity is probably
due to their ability to complex with

extracellular and soluble proteins and to
complex with fungal

cell walls. More lipophilic nature of flavonoids

may also
disrupt fungal membranes [25].
Flavonoids isolated from the stem bark of Erythrina burtii [26]

were
reported for antifungal activity. 4-methoxy-5,7-dihydroxyflavone 6-C-
glucoside (isocytisoside) from the leaves and stems of Aquilegia vulgaris
showed activity against the mould A. niger [27]. Pelalostemumol (4) from
Pelalostemium had strong antifungal activity against many pathogenic fungi
[28]. Galangin (5),

derived from the perennial herb Helichrysum aureonitens,
seems

to be a particularly useful compound, since it has shown activity

against wide range of fungi [29]. A flavonoid from rhizome of Alpinia
officinarum had strong antifungal activity against variety of pathogenic fungi.
Minimum inhibitory concentration (MIC) against the fungi varied from
Plants derived anti-fungal agents
287
3 g/mL [30,31]. A flavon 3,4',5,7-tetraacetyl quercetin isolated from
heartwood of Adina cordifolia exihibited moderate antifungal activity against
A. fumigatus and Cryptococcus neoformans [32]. Flavonoid derivative
phloretin from Malus sylvestris have antifungal properties [33].
Isopiscerythrone (6), allolicoisoflavone A (7), piscisoflavones A (8) and B (9)
from different plants were reported to be endowed with antifungal activity [34].

O
O
OH
OH
OH
HO
HO
4
O OH
HO
5
O
HO
OH
O
OH
HO
7
O
OH
O
O
OH
HO
8
O
O
O
HO
OHO
9
O OH
O OH
O
HO
OH
6

Heartwood extracts of Acasia auriculiformis and Acasia mangium
were reported to have antifungal activity due to the compounds 3,4',7,8-
tetrahydroxyflavanone and tetrracidin [35]. The four compounds
eupomatenoid-3, eupomatenoid-5, conocarpan and orientin, from Piper
solmsianum exhibited antifungal action against all the dermatophytes tested,
with MIC values in range of 2 to 60 g/mL and with a potency as high as
the standard antifungal drug ketoconazole [36]. Flavonoids, azulenes,
sesquiterpenes and essential oils from Inula viscosa were proved to have a
significant antifungal activity against dermatophytes even at low
concentrations (0.01 mg/mL). The high concentration of the sesquiterpene
Tasleem Arif et al. 288
(carboxyeudesmadiene), occurring in the leaf extracts, is reported to have
greater antifungal activity [37].
The 95% ethanol extract of the bark of Swartzia polyphylla afforded the
flavonoids biochanin A and dihydrobiochanin A as antifungal constituent and
another plant from the Fabaceae family Teramnus labialis was also reported
for antifungal flavonoid [38]. The antifungal activity of a series of prenylated
flavonoids purified from five different medicinal plants of moraceae family
was reported antifungal against C. albicans and S. cerevisiae [39]. These
results also support the use of prenylated flavonoids in traditional medicine to
treat fungal infections. A. nobilis furnished several flavonoids which showed
good fungicidal activity against C. cladosporioides [40]. Amentoflavone
from Selaginella tamariscina exhibited potent antifungal activity against
several pathogenic fungal strains but had a very low hemolytic effect on
human erythrocytes [41].

2.3. Coumarins

Coumarins have been reported to stimulate macrophages which could
have an indirect negative effect on infections. Coumarins are phenolic
substances made of fused benzene and -pyrone rings (Fig 3). Their fame has
come mainly from their antithrombotic50, anti-inflammatory [42] and
vasodilatory [43] activities and their use to prevent recurrences of cold sores
caused by HSV-1 in humans 48. Hydroxycoumarin scopoletin (10) was
isolated from seed kernels of Melia azedarach [44] reported to be antifungal
against Fusarium verticillioides.

N
H
HOOC
H
3
CO
OCH
3
O
O
O O
O
HO
OH
11
O O O
O
12
O O O
OH O
13 14
O O
O
HO
10

Plants derived anti-fungal agents
289
Tithoniamarin is a new isocoumarin dimer isolated from Tithonia
diversifolia [45] showed antifungal and herbicidal activities. Deng and
Nicholson [46] reported the antifungal properties of surangin B (11), a
coumarin from Mammea longifolia. Phytoalexins, which are hydroxylated
derivatives of coumarins,

are produced in carrots in response to fungal
infection and can

be presumed to have antifungal activity [47]. A coumarin
namely, 6,7-dimethoxycoumarin (12), isolated from P. digitatum-infected
Valencia fruit confers resistance against the mycotoxigenic fungi A. parasiticus
[48]. Clausenidin (13), dentatin, nor-dentatin, and carbazole alkaloid
clauszoline J (14) isolated from Clausena excavata showed antimycotic
activity (MIC 50 g/mL). Methylated clausenidin (MIC 50 g/mL), a
synthetic coumarin, also exhibited moderate antimycotic activity [50]. Data
about specific antibiotic properties

of coumarins are scarce, although many
reports give reason to

believe that some utility may reside in these
phytochemicals [51].

2.4. Quinones

Quinones are aromatic rings with two ketone substitutions and
characteristically

highly reactive. Fig 4 shows some of the important
antifungal quinones. They can switch between diphenol (or hydroquinone)

and diketone (or quinone) easily through oxidation and

reduction reactions.
These compounds, being colored, are responsible

for the browning reaction in
cut or injured fruits and vegetables

[52]. In addition to providing a source of
stable free radicals, quinones are known to complex irreversibly with
nucleophilic amino

acids in proteins [53]. Therefore the quinone inactivate
the

protein and impair there function. Quinones bind with surface-exposed
adhesins, cell wall polypeptides,

membrane-bound enzymes and form
complex which inactivate the enzymes.
In the anthraquinone group, there are only a few reports concerning their
antifungal activity. Schmidt

et al. [54] reported the antifungal activity of the
major anthraquinone aglycones, alizarin (15) and emodin (16) of Rubia
tinctorum and Rhamnus frangula. Hypericin (17),

from Hypericum
perforatum,

known as an

antidepressant and Duke reported in 1985 that it had
general

antimicrobial properties [14]. Examples of other antifungal
anthraquinones from medicinal species also included a new 1,3-dihydroxy-2-
methyl-5,6-dimethoxyanthraquinone (18) from the roots of Prismatomeris
fragrans [55]. The naphthoquinones kigelinone (19), isopinnatal, dehydro-
alpha-lapachone, and lapachol from Kigelia pinnata were reported for
antifungal activity [56].
Tasleem Arif et al. 290
O
O
HO
20
HO
O
O
OH
19
O
O
O
O
OH
OH
O OH
OH
OH
CH
3
OH
OH
CH
3
O OH
17
OH
OH
O
O
OH
CH
3
16
O
O
OH
OH
15
18


A novel compound 11-hydroxy-16-hentriacontanone isolated from
Annona squamosa was reported for its antifungal potential [57]. Hypericum
an anthraquinone extracted from Hypericum perforatum showed antifungal
activity

[58]. The 2-hydroxy-1,4-naphthoquinone (Lawsone) (20) from
Lawsonia inermis were found to exhibit strong fungitoxicity [59]. Emodin,
physcion and rheins were isolated from Cassia tora showed strong fungicidal
activity against the microorganism tested [60]. Hopeanolin MIC value range
0.1-22.5 g/mL, an unusual resveratral trimer with an O-quinone nucleus, from
the stem bark of Hopea exalata is reported to have antifungal activity [61].

2.5. Saponins

Saponins are secondary metabolites that occur in wide range of plant
species (Fig 5). They are stored in plant cells as inactive precursors but are
readily converted into biological active antibiotics by enzymes in response to
pathogen attack. Saponins are glycosylated compounds widely distributed in
plant kindom and can be divided into three major groups, a triterpenoid, a
steroid or a steroidal glycoalkaloid. CAY-1, a triterpene saponin from the
Capsicum frutescens was found to be active against sixteen different fungal
strains, including Candida spp, A. fumigatus and C. neoformans [62].
Importantly, CAY-1 appears to act by disrupting the membrane integrity of
fungal cells.
Recently, steroidal saponins ypsilandroside B, ypsilandroside A, iso
ypsilandroside A, iso ypsilandroside B and isoypsilandrogaine isolated from
Ypsilandra thebetica were reported for antimicrobial activities by [63]. Two
new spirostanol saponins were isolated from the roots of Smilax medica,
Plants derived anti-fungal agents
291
together with the known smilagenin 3-O--D-glucopyranoside (21)
exhibited antifungal activity against the human pathogenic yeasts C. albicans,
C. glabrata and C. tropicalis in a range of 6.25-50 g/mL [64]. Mollugo
pentaphylla, a tropical herb, contains an antifungal saponin, mollugogenol-A
(22) [65]. Phytolaccosides B (23) and E (24) from Phytolacca tetramera
showed antifungal activities against a panel of human pathogenic
opportunistic fungi [66]. Novel spirostanol saponins together with three
known saponins were reported for antimycotic activity. The most active
compound was found to be 6-O-[-D-xylopyranosyl-(13)--D-
quinovopyranosyl]-(25,S)-5-spirostan-3-ol, with IC
50
values of 25 g/mL
against T. mentagrophytes and T. rubrum [67]. From Solanum species,
Solanum chrysotrichum five new spirostan saponins showed antimycotic
activity against T. mentagrophytes, T. rubrum, A. niger and C. albicans.
Another compound isolated from same plant, 6--O--D-xylopyranosyl-
(1-->3)--D-quinovopyranosyl-(25R)-5-spirostan-3,23-ol was reported
to be active in a rage of 12.5 to 200 g/mL against T. mentagrophytes,
T. rubrum, A. niger and C. albicans [68]. Recently, saponins isolated from
Alternanthera tenella is reported to have strong antifungal in the range varied
from (MIC) 50-500 g/mL [69].
Bioassay-guided fractionation of the ethanol extracts of the aerial parts of
the Tibetan medicinal herb Clematides tangutica led to the isolation of two
new antifungal triterpene saponins 3-O--L-arabinopyranosyl hederagenin
28- O-- L-rhamnopyranosyl ester and 3-O--D-glucopyranosyl-(1-->4)--
L-arabinopyranosyl hederagenin 28-O--L-rhamnopyranosyl ester (MIA
2.5 g/disc) [70]. Two dammarane saponins from the stems of
Anomospermum grandifolium jujubogenin 3-O--l-arabinofuranosyl(1-->2)-
[-D-glucopyranosyl(1-->6)-D-glucopyranosyl(1-->3)]--l-arabinopyranoside,
ujubogenin 3-O--l-arabinofuranosyl(1-->2)-[6-O-[3-hydroxy-3-methylglutaryl]-
-D-glucopyranosyl(1-->3)]--l-arabinopyranoside and a new lupane saponin,
3-hydroxylup-20(29)-en-27,28-dioic acid 28-O--D-glucopyranosyl(1-->2)-[-
D-xylopyranosyl(1-->3)]--D-xylopyranosyl(1-->2)--D-glucopyranoside ester,
jujubogenin 3-O--l-arabinofuranosyl(1-->2)-[-D-glucopyranosyl(1-->3)]--l-
arabinopyranoside and 3-hydroxylup-20(29)-ene-27,28-dioic acid revealed
antifungal properties against C. albicans [71].
From the rhizomes of Dioscorea cayenensis, the dioscin (25) exhibited
antifungal activity against the human pathogenic yeasts C. albicans, C. glabrata
and C. tropicalis [72]. Three antifungal steroidal saponins were isolated from the
root of Smilax medica [73, 74]. Saponins, named minutoside A, minutoside B,
minutoside C, sapogenins, alliogenin and neoagigenin, were isolated from the
bulbs of Allium minutiflorum showed promised antifungal activity [75].
Tasleem Arif et al. 292
H
O
H
O
O
OH
OH
HO
O
HO
H
H
H
H
21
OH
OH
OH
OH
22
O
OH
O
O
HO
HO
HO
O
O
HO
HO
H
H
23
O
OH
O
O
HO
HO
O
O
O
O
HO
HO
HO OH
HO
HO
24


Nineteen saponins from Medicago sativa, M. murex, M. arabica and
M. hybrida, were were reported to be active against three dermatophytic
fungi Microsporum gypseum, T. interdigitale and T. tonsurans [76].

O
O
O
O
O O
O
O OH
OH
OH
HO
HO HO
HO
OH
25

Plants derived anti-fungal agents
293
Two saponins from Tribulus terrestris were reported for promised
antifungal activity against fluconazole resistant Candida strains
(MIC 0.15 mg/mL) [77,78]. Tigogenin-3-O--D-xylopyranosyl (1-->2)-[-D-
xylopyranosyl (1-->3)]--D-glucopyranosyl (1-->4)-[-L-rhamnopyranosyl
(1-->2)]--D-galactopyranoside was reported to have in vivo activity in
C. albicans vaginal infection model. Another saponin from same plant,
tigogenin-3-O--D-glucopyranosyl (1-->2)-[-D-xylopyranosyl (1-->3)]--
D-glucopyranosyl (1-->4)--D-galactopyranoside was found to be in vitro
very effective against several pathogenic Candida species (MIC
80
= 4.4, 9.4
g/mL), C. neoformans (MIC
80
=10.7, 18.7 g/mL) and inherently resistant
C. krusei (MIC
80
= 8.8, 18.4 g/mL [79]. The Avenacin obtained from the
Avena sativa showed varying degree of in vitro antifungal activity [80]. Other
antifungal saponins from medicinal plants also included Astragalus verrucosus
[81], A. suberi [82], A. auriculiformis [83] and Hedera taurica which possessed
in vitro antifungal activity against C. albicans, C. krusei and C. tropicalis [84].
Saponins from several plants i.e Hedera colchica [85], Kalopanax pictus [86],
Dracaena mannii and D. arborea [87], Trillium grandiflorum [88] and
Solidago virgaurea [89] were reported for antifungal activity.

2.6. Xanthones

Xanthones are a restricted group of plant polyphenols, biosynthetically
related to the flavonoids. These are planar-six carbon molecules in a
conjugated ring system consisting of a backbone molecule and various
chemical groups attached to it. Xanthone backbone consists of two benzene
rings attached through a carbonyl group and oxygen not allowing free
rotation about the carbonZcarbon bonds. The unique backbone along with
type and position of the attached chemical groups defines specific properties
of xanthones. Xanthones possess numerous bioactive capability including
antifungal properties (Figure 6).
Caledonixanthone E (26) isolated from the stem bark of Calophyllum
caledonicum was reported for strong antifungal activity (MIC80 8 mg/mL)
[90]. Isoprenylated xanthones, toxyloxanthone C (27), and wighteone (28)
showed antifungal activity against C. albicans with MIC values of 25 and
12.5 mg/mL, respectively [91]. The dichloromethane extract of Securidaca
longepedunculata yielded 1,7-dihydroxy- 4-methoxyxanthone (29) which
exhibited antibacterial activity against Staphylococcus aureus and antifungal
activity against A. niger, A. fumigatus, and a Penicillum species [92]. 1,3,6-
Trihydroxy-2,5-dimethoxyxanthone (30) isolated from the aerial part of
Monnina obtusifolia was reported to have antifungal potential [93]. Seven
xanthanolides from Xanthium macrocarpum were reported to be effective
Tasleem Arif et al. 294

O
OH
O
O
O
OH
26
O
OH O
OH
OH
O
27
O
OH
O OH
HO
28
O HO
O
O
HO
29
O
HO
HO
O
OH
O
30


against C. albicans, C. glabrata, and A. fumigatus [94,95]. Two new
2-hydroxy-3-methylbut-3-enyl-substituted xanthones, -caledol and -dicaledol,
were isolated from a dichloromethane extract of the leaves of Calophyllum
caledonicum and have been reported for antifungal activity against
A. fumigatus [96]. Xanthones from the green fruits of Garcinia mangostana
were reported to have strong antifungal activities [97]. Cudrania fruticosa
yielded an isoprenylated xanthone, cudrafrutixanthone which showed
antifungal activity against C. albicans [98, 98]. Xanthone analogues bearing
the basic chain of butenafine were reported for significant activity against
C. neoformans (1.5 mg/mL) [100].

2.7. Terpenoids and essential oils

A large number of studies have been done in recent years on the
antifungal activity of terpenoids of natural origin (Fig 7). These reports
concern mainly sesquiterpenes and sesquiterpene lactones. The fragrance of
plants is carried in essential oil fraction. These oils are secondary metabolites

that are highly enriched in compounds based on an isoprene structure. They
are called terpenes, their general chemical structure

is C
10
H
16
, and they occur
Plants derived anti-fungal agents
295
as diterpenes, triterpenes, and tetraterpenes

(C
20
, C
30
, and C
40
), as well as
hemiterpenes (C
5
) and sesquiterpenes

(C
15
). The mechanism of action of
terpenes

is not fully understood but is speculated to involve membrane

disruption by the lipophilic nature. Mendoza et al. [101] found that increasing
the hydrophilicity of kaurene

diterpenoids by addition of a methyl group
drastically reduced

their antimicrobial activity.
A number of terpenes or terpenoids are reported active against fungi

[102-104]. In 1977, it was reported

that 60% of essential oil derivatives
examined to date were inhibitory

to fungi while 30% inhibited bacteria [105].
The antifungal activities of the essential oil from Agastache rugosa and its
main component, estragole (31), combined with ketoconazole, were reported
to show significant synergistic effects [106]. A known sesquiterpene lactone,
encelin (32), isolated from the Mexican species Montanoa speciosa
has a determining action on growth and the morphogenetic process of
fungal cells [107]. The roots of Delphinium denudatum have yielded
8-acetylheterophyllisine, panicutine, and 3-hydroxy-2-methyl-4H-pyran-4-
one (33) has shown antifungal activity against a number of human pathogenic
fungi [108]. Khaya ivorensis afforded methyl angolensate and 1,3,7-
trideacetylkhivorin displayed antifungal activity, with 62.8 and 64% mycelial
growth inhibition at 1000 mg/L, respectively [109]. Estragole and the
essential oil of A. rugosa exhibited strong activities against the tested fungi
and showed synergism with ketoconazole against B. capitatus [110]. From
other Centaurea species, C. thessala and C. attica, two eudesmanolides,
4-epi-sonchucarpolide, 8-(3-hydroxy-4-acetoxy-2-methylene-butanoyloxy)
derivative and eudesmane derivative named atticin (35) showed a
considerable antifungal effect against nine fungal species [111]. Two new
dammarane type triterepenes, ailexcelone and ailexcelol from Ailantus
excelsa were reported to be endowed with antifungal activities [112].
Amesterol, isolated from Amaranthus viridis strongly inhibited a growth of
pathogenic fungus [113,]. Two diterpenes isolated by Batista et al. [114]
were

found to be active against Candida spp. Terpenoid isolated from Atrus
sinenisis, Armoracia rusticana, Metha peperita [115] and grapefruit showed
antifungal activity [116]. A. sativum oil exhibited the strongest inhibition of
growth of T. rubrum, T. erinacei, and T. soudanense with MIC of 4.0 g/mL,
while the activities of A. cepa and A. fistulosum were relatively mild [117].
The bark extract of Drimys brasiliensis led to the isolation of the
sesquiterpene polygodial, 1--(p-methoxycinnamoyl)-polygodial (36),
drimanial and 1--(p-cumaroyloxy)-polygodial which were selectively active
against fungi [118]. An antimicrobial diterpene 817-epoxylabd-12-ene-15,
16-dial from Alpinia galanga synergistically enhanced the antifungal activity
Tasleem Arif et al. 296
of quercetin and chalcone against C. albicans [119]. Triterpenoid glycosides
obtained from Solidago virgaurea and Bellis perennis inhibit the growth of
human-pathogenic yeasts (Candida and Cryptococcus species) [120].

O
O
H
O
O
HO
O
O
O
O
OH
HO
OH
H
O
O
O
O
O
O
O 34
O
31
O
O
O
O
O
HO
32
33
35
36


The oil from leaves of J. oxycedrus spp. oxycedrus was reported
antifungal with MIC and MLC values ranging from 0.08-0.16 M/L and
0.08-0.32 M/L, respectively. The chemical constituents of the essential oil
extracted from the fruits of Lindera glauca have epishyobunol acetate,
caryophyllene oxide and 3,6,6-trimethyl-2-norpinene exhibited more
manifest antifungal properties with MIC between 0.03-0.5 mL/L for
pathogenic fungi species [121]. The essential oil from the leaves of
Litsea cubeba have cis-ocimene,3,7-dimethyl-1,6-octadien-3-ol and n-
transnerolidol had manifest antifungal activities with MIC between 0.03-0.4
L/mL for utilized pathogenic fungi and 1.0-2.0 L/mL for moulds [122,].
The oil of the leaves, clemateol, and the alcohol from Calea clematidea
showed a moderate antifungal activity [123]. Daucus carota (Apiaceae),
afforded four sesquiterpene daucane esters [124] found to contain a range of
low antifungal activity against Fusarium oxysporum and A. niger. Carotol,
which was observed to be the main constituent of carrot seed, inhibited the
radial growth of fungi by 65%. The Vernonanthura tweedieana afforded one
Plants derived anti-fungal agents
297
antifungal active sesquiterpene, 6-cinnamoyloxy-1-hydroxyeudesm-4-en-3-
one [125]. Barrero et al. [126] investigated six Centaurea species:
C. bombycina, C. granatensis, C. monticola, C. incana, C. maroccana and
C. sulphurea of Astraceae family. The sesquiterpene lactones costunolide and
dehydrocostunolide showed noticeable IC
50
values. Other antifungal
sesquiterpene lactones from the Asteraceae family also included those
isolated from Ajania fruticulosa [127].
A fruit pulp extract of Detarium microcarpum endowed with four
new clerodane diterpenes which showed antifungal activity [128]. The
diterpenoids 16-hydroxy-cleroda-3,13-(14)-Z-diene-15,16-olide and 16-
oxo-cleroda-3,13-(14)-E-diene-15-oic acid isolated from the hexane
extract of the seeds of Polyalthia longifolia demonstrated significant
antifungal activity [129]. Five new diterpenoids from Casimirella namely,
humirianthone, 1-hydroxy-humirianthone, 15R-humirianthol, patagonol and
patagonal showed activity against pathogenic fungi [130]. Antifungal
activity of oxygenated pimarane diterpenes from Kaempferia marginata
was reported by Thongnest et al. [131]. The triterpenoids pristimerin and
celastrol isolated from the roots of Celastrus hypoleucus exhibited
inhibitory effects against diverse pathogenic fungi [132]. Oleanane
triterpenoid, triterpenetetrol isolated from the chloroform extract of the
aerial parts of Leontodon filii were reported to have antifungal prop [133].
Carvone, dinydrocarvone, limonene, dillapiole and dillapional from
Anethum sowa revealed antifungal activity at a concentration of 1:100 and
1:250 [134,135,136]. A derivative of dillapiole, isodilapiole tribromide
found to more active [137]. The steam distillate of fresh mature
leaves containing odorous oil rich in cyclic tri-and tetra-sulphides of C3,
C5 and C9 units exihibited antifungal activity at 125 g/mL in vitro [139].
The active compounds, 1'-acetoxychavicol acetate from Alpinia galanga
strong inhibitory affects at a MIC 0.024 g/mL against several fungal
pathogens [140 a,b]. Most of the species of Oscimum showed in vitro
antifungal activities against a broad range of fungi as well as bacteria.
An Indian chemotype Ocimum gratissimum, with a high level of ethyl
cinnamate, presents, in vitro, an interesting spectrum of antifungal
properties [141].

2.8. Alkaloids

Heterocyclic nitrogen compounds are called alkaloids (Fig 8 A-B). The
first medically useful example of an alkaloid was morphine; isolated

in
1805 from the opium poppy Papaver somniferum [142,], Codeine

and heroin
are both derivatives of morphine. Diterpenoid alkaloids,

commonly isolated
Tasleem Arif et al. 298
from the plants of the Ranunculaceae [143, 144]

are found to have
antimicrobial

properties [145]. While alkaloids have been found to have
microbiocidal

effects including against Giardia and Entamoeba species [146],

the major antidiarrheal effect is probably due to their effects

on transit time in
the small

intestine.
Recently, a novel alkaloid, 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-
1-methylethyl pentanoate (38) was isolated from the plant Datura metel
showed in vitro as well as in vivo activity against Aspergillus and Candida
species [147]. Another novel alkaloid, 6,8-didec-(1Z)-enyl-5,7-dimethyl-2,3-
dihydro-1H-indolizinium (37) from Aniba panurensis demonstrated the
activity against a drug-resistant strain of C. albicans [148]. The antifungal
alkaloids -carboline, a tryptamine- and two phenylethylamine-derived
alkaloids and N-methyl-N-formyl-4-hydroxy-beta-phenylethylamine (39)
from Cyathobasis fruticulosa [149]

and haloxylines A and B, new piperidine
from Haloxylon salicornium displayed antifungal potentials [150].
Jatrorrhizine (40) from Mahonia aquifolium was found to be the most
effective against all fungal species tested (MIC ranges from 62.5 to
125 g/mL), while the crude extract, berberine , and palmatine exhibited only
marginal activity (MIC 500 to >/= 1000 g/mL) [151].
Cocsoline (43), a bisbenzylisoquinoline alkaloid from the Epinetrum
villosum displayed antifungal activities [152]. The alkaloids N-methylhydrasteine
hydroxylactam and 1-methoxyberberine chloride from Corydalis longipes
showed high efficacy individually [153]. Four alkaloids, dicentrine (41), glaucine
(42), protopine, and alpha-allocryptopin (46) from Glaucium oxylobum
exhibited good activity against Microsporum gypseum, Microsporum canis,
T. mentagrophytes and Epidermophyton floccosum [154].

N
C
8
H
17
C
8
H
17
O
O
HN
N
OH
O
N
O
O
O
OH
N
O
O
O
O
N
O
O
O
O
42
41
40
39
37 38

Plants derived anti-fungal agents
299
Flindersine (45) and haplopine from Haplophyllum sieversii were
growth-inhibitory compounds against various fungi [155]. Canthin-6-one and
5-methoxy-canthin-6-one of Zanthoxylum chiloperone var. angustifolium
exhibited antifungal activity against C. albicans, A. fumigatus and
T. mentagrophytes [156]. Frangulanine, a cyclic peptide alkaloid and
waltherione A, a quinolinone alkaloid from leaves of Melochia odorata were
reported to exhibit antifungal activities against a broad spectrum of
pathogenic fungi [157].
The indole alkaloid venenatine exhibited antifungal activity against all
the 10 tested fungi, showed an especially high sensitivity towards this
compound, exhibiting germination levels below 10% [158]. From the root
bark of Dictamnus dasycarpus two antifungal furoquinoline alkaloids
were isolated. 3-methoxysampangine from Cleistopholis patens exhibited
significant antifungal activity against C. albicans, A. fumigatus, and
C. neoformans [159].

N
O
O
NH
O
O
HO
N
O
O
O
O
O
N
H
O
O
O
N
O
O
O
O
43
44
45 46


2.9. Lectins and polypeptides

Peptides, which are inhibitory to microorganisms, were first reported in
1942 [160]. They are often positively charged and

contain disulfide bonds
[161]. Their mechanism of action may

be the formation of ion channels in the
microbial membrane

[162] or competitive inhibition of adhesion of microbial
Tasleem Arif et al. 300
proteins

to host polysaccharide receptors [163]. Recent interest has been

focused mostly on studying fungi by these macromolecules,

such as that from
the herbaceous Amaranthus, has long been known [164]. Thionins are
peptides commonly found in barley and wheat and consist of 47 amino acid
residues. Thionins AX1 and AX2 from sugar beet were active against fungi

but not bacteria [165, 166].
Raw Allium Sativum extract showed antifungal activity beyond 48h in
extract stored at room temperature. Antifungal activity was stable upto 8h
under these conditions [167]. A novel lectin was isolated from the roots of
Astragalus mongholicus [168] and a protein with a novel N-terminal
sequence from ginger rhizomes exerted antifungal activity towards various
fungi [169]. An antifungal peptide was reported from fresh fruiting bodies of
the mushroom Agrocybe cylindracea [170]. Two antifungal peptides from
seeds of Pharbitis nil exhibited potent antifungal activity against both chitin-
containing and non-chitin-containing fungi in the cell wall. Concentrations
required for 50% inhibition of fungal growth were ranged from 3 to 26
micrograms/mL and from 0.6 to 75 g/mL [171].

From Phaseolus species, mung bean (Phaseolus mungo) seed, chitinase
with antifungal activity was isolated [172]. This species also yielded a novel
lysozyme exhibiting antifungal activity toward Botrytis cinerea [173].
Another Fabaceae species, Trigonella foenum-graecum, yielded defensins,
small cysteine rich peptides, which exhibited antifungal activity against the
broad host range fungi [174]. A novel antifungal peptide, cucurmoschin, was
isolated from the seeds of the black pumpkin inhibited mycelial growth in the
fungi [175]. A peptide designated cicerarin from seeds of the green chickpea
Cicer arietinum showed antifungal activity. The antifungal activity was
preserved after exposure to 100 degrees C for 15 min [176]. Two other
antifungal peptides cicerin and arietin were reported from seeds of the
chickpea (Cicer arietinum). Arietin manifested a higher antifungal potency
toward Mycosphaerella arachidicola, Fusarium oxysporum and Botrytis
cinerea [177]. An antifungal peptide designated angularin was isolated from
the adzuki bean exhibited antifungal activity against a variety of fungal
species [178]. Two novel antifungal peptides, designated alpha- and beta-
basrubrins, respectively, were isolated from seeds of the Ceylon spinach
Basella rubra [179].
An antifungal protein, AFP-J, was purified from potato tubers, Solanum
tuberosum strongly inhibited yeast fungal strains, including C. albicans,
Trichosporon beigelii and S. cerevisiae [180]. Pineapple leaf chitinase-B
from Ananas comosus exhibits strong antifungal activity toward Trichoderma
virida [181]. Another chitinase with antifungal activity was also purified
from the bulbs of the plant Urginea indica, known as Indian squill.

Plants derived anti-fungal agents
301
The protein was an active growth inhibitor of the fungal pathogens in an
in vitro assay [182]. A novel protein was isolated from the Chinese herb
Astragalus mongholicus Bunge. It exerted selective antifungal activity
against various fungi [183]. Recently, a new protein from E. coli, having
anti-Aspergillus activity was reported by Yadav et al. [184]. Antifungal
peptides and proteins from medicinal species also included two chitin-binding
proteins from spindle tree Evonymus europaeus [185], a thaumatin-like protein
from banana Musa acuminate [186], and a protein from ginger rhizomes
Zingiber officinalis (Zingiberaceae), which exerted antifungal activity toward
various fungi [187].

2.10. Other compounds

Many phytochemicals not mentioned above have been found to exert
antifungal properties. This review has attempted to focus

on reports of
chemicals, which are found in multiple instances

to be active. There are

reports of chemical having antifungal properties associated with several
different classes not covered above (Figure 9).

HO
O
O
O O
O
HO
O OH
48
49
50
O OH
HO
O
O
O
O
N
H
O
O
HO
HO
OH
47
51
52
53

Tasleem Arif et al. 302
N-trans-feruloyl-4-methyldopamine (47) recently isolated from
Achranthes ferruginea was reported to be active against a broad range of
fungi [188]. Leaves of Piper aduncum accumulate the anti-fungal
chromenes, methyl 2,2-dimethyl-2H-1-chromene-6-carboxylate and methyl
2,2-dimethyl-8-(3'-methyl-2'-butenyl)-2H-1-chromene-6-carboxylate [189].
Iridodial -monoenol acetate, from Nepeta leucophylla, and actinidine from
N. clarkei were found to be endowed with antifungal activities [190].
Anofinic acid and fomannoxin acid (48) from Gentiana algida were found
to be active against fungi [191]. The antifungal activity of Artemisia
herba-alba was found to be associated with two major volatile compounds
as carvone and piperitone [192]. The phenylpropanoids p-coumaric acid
and ferulic acid from Kigelia pinnata were observed to have antifungal
activity [193]. Piper cubeba afforded the compounds (8R,8'R,9'S)-5-
methoxyclusin, (-)-clusin, (-)-yatein, ethoxyclusin, and (-)-dihydroclusin
showed very potent and selective inhibitory activity against CYP3A4 with
IC
50
values (0.44-1.0 M) identical to that of the positive control,
ketoconazole (IC
50
, 0.72 M)

[194].
Demethoxyageratochromene (49) from Ageratum conyzoides showed
antifungal activity [195,196] at a concentration of 2000 ppm. The leaf
extract was found to be active and showed strong toxicity against the fungi
causing ringworm [197]. 2,4-Dihydroxy-3-methoxychalcone (50) and
2,4-dihydroxychalcone (51) in the dichloromethane extracts of Zuccagnia
punetata was found to have antifungal properties [198]. Plumbagin from
Plumbago zeylanica was also reported to inhibit the fungel species viz.
Trichophyton, Epidermophyton, Microsporum in a range of 30-40 g/mL
[199]. Hexane extracts of the stem bark as well as (-)-kaur-16-en-19-oic
acid of Annona glabra revealed antifungal activity [200]. Isoalantolactone
(52) and alantolactone (53), the major constituents of the roots of Inula
racemosa showed in vitro antifungal activity againest T. mentagrophytes
and Microsporum canis [201]. Withafarin A and amemonine isolated from
Withania somniferm and Anemone pulsatillea, salicin a phenolic glucoside
compound from Salix alba showed antifungal activity [202]. The psoralen,
8-methoxypsoralen and imperatorin in extracts of leaf, fruit, stem, bark and
root of Zanthoxylum americanum demonstrated a broad spectrum of
antifungal activity and inhibited fungal species in a disk diffusion assay
[203]. Myrothecium roridum contains macrocyclic trichothecenes of the
verrucarin type, 16-hydroxyverrucarin A and verrucarin X exhibited
moderate antifungal activity. Both compounds were reported to
preferentially inhibit in vivo protein biosynthesis [204].
Plants derived anti-fungal agents
303
3. Conclusion

Phytomedicines are major component of traditional system of healing in
developing countries, which have been an integral part of their history and
culture. Besides wide spread use of botanicals as medicinal products in
developing countries, such products are becoming part of the integrative
healthcare system of industrialized nations, known as complementary and
alternative system of medicines (CAM).
Existing costly therapy is not affordable well for the millions of
individuals particularly in the developing world. Plant extracts are the cheap
and easily available source to poor people. Plants are great source of
thousands new useful phytochemicals of great diversity,

which have
inhibitory effects on all types of microorganisms in

vitro. Till date more than
600 plants have been reported for their antifungal properties, however a few
of them were explored for the active components. The current pharmaceutical
armoury of antifungal is a clear cause for satisfaction, not from gloom.
However, we still do not have agents that fulfil every one of the criteria that a
physician would set as desiterata for antifungal drugs. They need to be active
against those fungai causing infections which we cant yet depend on
eradacting. They need to be formaluted for both oral and parenteral
administration, they need to be extremly safe and as cheep as possible. The
search for new antifungal agents therefore must go on.
Identification of new chemotypes for drug development remains an
urgent need in antifungal therapeutics. Simultaneously, a number of
antifungal compounds reported till date, are tested for their in vitro activities
not for in vivo acitivities. In vivo and in vitro activities of a compound may be
different and a very small number of plants extracts or components have been
studied for their in vivo activity. Therefore these should be subjected to
animal and

human studies to determine their effectiveness in whole-organism

systems. Also in vitro testing and method of extraction should be
standardized so that the search could be more systematic.
The current set of clinically available antifungal agents includes three
classes of natural product and four classes of synthetic chemicals. We
therefor cant abandon intrest in biodiversity as a source of natural antifungal
products. Furthermore, the inactive plant extracts may be subjected to
chemical diversification of their components to increase the activity. The
transformation of chemical groups in natural products into rare chemical
groups is possible which are rarely produced by secondary metabolism.
Therefore, biosynthesis machinery can be complemented to produce a whole
range of new semisynthetic compounds in one step which may become an
alternative source of compounds to feed the discovery process for new
intresting compounds.
Tasleem Arif et al. 304
The study of alternative

mechanisms of infection prevention and
treatment is essential. Plant products furthermore may be structurally
modified to increase their in vivo activity. For example isodilapiole
tribromide, a derivative of dillapiole was found to more active. Another
example include echnicandin type peptide FR901379, chemical modification
of which lead toward more active FK463 compound. Therefore, attention
toward the plant derived principles, their chemical modification and
chemotherapeuitic potential is needed.

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