Natural products – antifungal agents derived from - Encognitive.com

19 Pages·2009·0.17 MB·English

JournalofAsianNaturalProductsResearch
Vol.11,No.7,July2009,621–638
Natural products – antifungal agents derived from plants
TasleemArifa,J.D.Bhosalea,NareshKumara,T.K.Mandala,R.S.Bendreb,G.S.Lavekara
and Rajesh Dabura*
aRegionalResearchInstitute(Ay),CentralCouncilforResearchinAyurvedaandSiddha,Nehru
Garden,Kothrud,Pune411038,India;bSchoolofChemicalSciences,NorthMaharashtra
University,Jalgaon425001,India
(Received1December2008;finalversionreceived1April2009)
A new spectrum of human fungal infections is increasing due to increased cancer,
AIDS,andimmunocompromisedpatients.Theincreaseduseofantifungalagentsalso
resultedinthedevelopmentofresistancetothepresentdrugs.Itmakesnecessaryto
discovernewclassesofantifungalcompoundstocurefungalinfections.Plantsarerich
sourceofbioactivesecondarymetabolitesofwidevarietysuchastannins,terpenoids,
saponins, alkaloids, flavonoids, and other compounds, reported to have in vitro
antifungal properties. Since the plant kingdom provides a useful source of lead
compoundsof novelstructure,a wide-scale investigation ofspecies from thetropics
has been considered. Therefore, the research on natural products and compounds
derivedfromnaturalproductshasacceleratedinrecentyearsduetotheirimportancein
drugdiscovery.Aseriesofmoleculeswithantifungalactivityagainstdifferentstrains
offungushavebeenfoundinplants,whichareofgreatimportancetohumans.These
molecules may be used directly or considered as a precursor for developing better
molecules. This review attempts to summarize the current status of important
antifungalcompoundsfromplants.
Keywords:antifungal;tannins;saponins;alkaloids;flavonoids;bioactivemetabolites
1. Introduction fungal infections have serious drawbacks
The prevalence ofresistance to antifungal such as the development of fungal
agents significantly increased in the resistance and toxic side effects. The
broad-spectrum drug amphotericin B was
past decade. Resistance to antifungal
the soledrugfor nearly30 years, andit is
agents has important implications for
one of the few drugs that actually kill
morbidity, mortality, and healthcare in
fungal cells, but can cause significant
the community. Humans and fungi share
nephrotoxicity in the patients. The imida-
some of the same molecular processes;
therefore,thereisalwaystheriskthatwhat zoles and the triazoles in late 1980s and
istoxictothefungalcells willbetoxic to early 1990s, respectively, were major
the host cells. Patients with AIDS, organ advanceswhichactbyinhibitingprocesses
transplant patients, patients receiving ofthefungalcell,buttheyhavebeenfound
chemotherapy, and diabetes patients toresultinrecurrenceoftheinfectionand
represent current medical challenges [1]. the development of resistance to the drug
The drugs currently available to treat [2].Therefore,thereisneedtosearchnew,
*Correspondingauthor. Email:[email protected]
ISSN1028-6020print/ISSN1477-2213online
q2009Taylor&Francis
DOI:10.1080/10286020902942350
http://www.informaworld.com
622 T. Arif et al.
safer, and more potent agents to combat havebeenisolatedthatislessthan10%of
serious fungalinfections. the total. In many cases, these substances
There is already a rich history of serveasplantdefensemechanismsagainst
researchthathasbeencarriedouttoverify predationbymicroorganisms,insects,and
folk medicine practices. Medicinal plants herbivores. Some plants used for their
have been a source of wide variety of odors(terpenoids),pigment(quinonesand
biologically active compounds for many tannins), and flavor (terpenoid capsaicin
centuries and used extensively as crude from chili peppers) were found to be
materialoraspurecompoundsfortreating endowedwithmedicinalproperties.Some
various disease conditions. Relatively 1– of the herbs and spices used by humans
10% of plants are used by humans out of as season food yield useful medicinal
theestimated250,000–500,000speciesof compounds.
plantsonearth[3].Thechemicaldiversity
of natural products is complementary to
the diversity found in synthetic libraries. 2.1 Phenols
However, natural products are sterically In recent years, a number of studies have
more complex and have greater ring beenreportedontheantifungalactivityof
system diversity because of the long phenolic compounds from natural sources
evolutionary selection process. Therefore, (Figure 1). The site(s) and number of
strategiestoexploitthenaturalsourcesand hydroxyl groups on the phenol group are
to develop methodologies for the prep- thought to be related to their relative
aration of natural product like libraries toxicitytomicroorganisms,withevidence
through the diversification of natural that increased hydroxylation results in
product mixtures by combinatorial bio- increased toxicity. The mechanisms
synthesis and related techniques are thought to be responsible for phenolic
possible. Mainstream medicine is increas- toxicity to microorganisms include
inglyreceptive tothe useofantimicrobial enzyme inhibition by the oxidized com-
and other drugs derived from plants, as pounds, possibly through reaction with
traditional antibiotics become ineffective sulfhydryl groups or through more
[4].Anumberofcompoundsisolatedfrom nonspecific interactions with the proteins.
plants such as dimethyl pyrrole, hydro- Anotherstudiesonmechanismofactionof
xydihydrocornin-aglycones,indolederiva- the diterpenic and phenolic compounds
tives, etc., are reported to have antifungal isolated from Euphorbia species showed
activities [5]. However, development of
useful antifungal drugs from these com-
pounds has not yet been possible. This O
review is an attempt to cover important O
O
antifungal compounds isolated from H
OH O
higher plants.
O
2. Majorgroupsof antifungal 1 2
compounds from plants
OH O
Plants have an almost limitless ability to
synthesize aromatic substances of differ-
ent functional groups, most of which are OH O
OH O
phenolsortheiroxygen-substitutedderiva-
3
tives.Maximumcompoundsaresecondary
metabolites, of which more than 13,000 Figure1. Structuresofphenols1–3.
JournalofAsian Natural Products Research 623
that these compounds modulate to a antifungal activity against variety of
differentextentazoleantifungalresistance pathogenic fungi and MIC was reported
mediatedbyPdr5p,Snq2p,andCdr1p[6]. to up to 3.0mg/ml [14]. Isopiscerythrone
Tannins and salicylic acid are poly- (8), allolicoisoflavone A (9), piscisofla-
phenol compounds extracted from Gaull- vones A (10) and B (11) [15], and
herprocumbens,Rhammuspurshiand,and quercetin-3,7-dimethyl ether [16] from
Anacardum pulsatilla showed antifungal different plants were reported to be
activity [5]. Geranylated biphenyl deriva- endowedwith antifungal activity.
tive 3-hydroxy-4-geranyl-5-methoxybi- Inula viscose is currently used as a
phenyl (1) from the green fruits of popular medicine for its therapeutic
Garcinia mangostana has strong antifun- effects. Flavonoids, azulenes, sesquiter-
gal and a number of other biological penes, and essential oils of the plant were
activities [7]. A novel polyisoprenylated proved to have a significant antifungal
benzophenone (2) from an ethanolextract activity against dermatophytes even at
of Cuban propolis showed significant low concentrations (10mg/ml). The high
antimicrobial and antifungal activities concentrations of the sesquiterpene
against a variety of bacteria and yeasts (carboxyeudesmadiene), occurring in the
[8]. 4-Hydroxyphenyl-6-O-[(3R)-3,4- leaf extracts, may explain its greater
dihydroxy-2-methylenebutanoyl]-D-glu- antifungal activity [17].
copyranoside isolated from foliage of An isoflavan, 2-hydroxy maackiain
Toronia toru was the main antimicrobial from the root extract of Hildegardia
component of the crude extract [9]. Some barteri was observed to have antifungal
of the prenylindoles isolated from Mono- activity [18]. Flavonoid derivatives, scan-
doraangolensisandIsolonacauliflorahad denone, tiliroside, quercetin-3,7-O-a-L-
antifungalandantimalarialactivities[10]. dirhamnoside (12), and kaempferol-3,7-
Eriosemaones A–D (3; MIC¼20mg/ml) O-a-L-dirhamnoside (13), were reported
are reported to have good antifungal to have antifungal activities against C.
activities [11]. albicans at 1.0mg/ml as potent as
ketoconazole [19]. The flavones hispidu-
lin and belamcanidin from Artemisia
2.2 Flavonoids giraldii were shown to inhibit the growth
Flavones (Figure 2(A) and (B)) are of the broad range of human pathogenic
phenolic structures containing one carbo- fungi [20]. In addition, 3-O-(100,800,1400-
nylgroupandtheadditionofa3-hydroxyl trimethylhexadecanyl)naringenin[21]was
groupyieldsaflavonol.Amentoflavone(4) reported to be endowed with antifungal
from Selaginella tamariscina exhibited properties.
potent antifungal activity (IC value of
50
18.3mg/ml) against several pathogenic
2.3 Coumarins
fungalstrainsandhasaverylowhemolytic
effectonhumanerythrocytes[12]. Coumarinshavebeenreportedtostimulate
The four compounds eupomatenoid-3, macrophageswhichcouldhaveanindirect
eupomatenoid-5 (5), conocarpan (6), and negative effect on infections. Coumarins
orientin (7), from Piper solmsianum are phenolic substances made of fused
exhibited antifungal action against all the benzene and a-pyrone rings (Figure 3).
dermatophytes tested, with MIC values in Their fame has come mainly from their
the range of 2.0–60.0mg/ml and with a antithrombotic, anti-inflammatory, and
potencyashighasthestandardantifungal vasodilatory activities and their use to
drug ketoconazole [13]. A flavonoid from prevent recurrences of cold sores caused
rhizomeofAlpiniaofficinarumhadstrong by HSV-1 inhumans [22].
624 T. Arif et al.
(a)
OH
OH
O OH
OH O O
O
O
5
OH OH
OH O
4 OH OH
HO
O
HO
OH
O HO O
6
OH O
O
7
HO
O OH
OH
O OH
8
(b)
HO
O HO O
OH
OH
HO
O O
OH OH
O
9
O 10
O
O
HO
OHO
11
OH OH
CH3 OH CH3
HO
OH OH
O HO O
O O O O
OH OH
O O
OH O OH O
O CH3 HO O CH3
HO HO OH HO
OH
12 13
Figure2. (a)Structuresofflavonoids4–8.(b)Structuresofflavonoids9–13.
JournalofAsian Natural Products Research 625
O OH activity against the dermatophytes, 5,8-
COOH dihydroxyumbelliprenin being most
MeO active with MIC of 10mM [29]. Data
OMe
O O O about the antifungal properties of cou-
N
marins are limited but many reports give
H
14 reason to believe in the utility of these
15
phytochemicals[30].
O O O
O 2.4 Quinones
16 O 17
Quinones (Figure 4) are aromatic rings
with two ketone substitutions and charac-
Figure3. Structuresofcoumarins14–17.
teristically highly reactive. They can
switch between diphenol and diketone
Clausenidin (14), dentatin, nor-denta-
easily through oxidation and reduction
tin,andcarbazolederivatives,andclauszo-
reactions. These compounds, being
line J (15) isolated from Clausena
excavata showed antimycotic activity
(MIC¼50mg/ml). O-Methylated clause-
nidin (MIC¼50mg/ml), a synthetic cou-
OH
marin,alsoexhibitedmoderateantimycotic O
activity[23].Abioactiveeremophilanolide
(16), 1-tigloyloxy-8bH,10bH-eremophil- 18
7(11)-en-8a,12-olideisolatedfromSenecio
O
poepigiishowedantifungalproperties[24].
A prenylated coumarin was isolated from
the dichloromethane leaf extract of Bac-
charis pedunculata and identified to be
O Cl
responsible for the antifungal activity
againstsomehumanpathogenicfungi[25]. 19
Angelicin (17), a naturally occurring
HO
furanocoumarin, showed antifungal
O OH
activity LD 2.0mg/ml. Synthetic cou-
50
H
marinsandangelicinderivativeswerealso
HO
reported to be active against C. albicans, H H H OH
H
C.neoformans,S.cerevisiae,andA.niger.
H
Simultaneously, angelicin and several O
O
potent antifungals were reported to be O
nontoxic [26]. An antifungal dihydrofur- O
anocoumarin, 20(S),30(R)-20-acetoxyiso- HO
20
propyl-30-acetoxy-20,30-dihydroangelicin,
was reported from the aerial parts of HO
Tordyliumapulum[27].Acoumarinalong O
withtwonewphenolicglycosidesfromthe O
stem bark of Amburana cearensis was
O
HO
found to be endowed with in vitro
O
antifungalandantibacterialactivities[28].
21
Fsafetida foetida yields prenylated
coumarins exhibiting strong antifungal Figure4. Structuresofquinines18–21.
626 T. Arif et al.
colored, are responsible for the browning attack. Saponins are glycosylated com-
reaction in cut or injured fruits and pounds widely distributed in the plant
vegetables.Inadditiontoprovidingasource kingdom and can be divided into three
ofstablefreeradicals,quinonesareknown majorgroups;atriterpenoid,asteroid,ora
to complex irreversibly with nucleophilic steroidal glycoalkaloid. Saponins appear
amino acids in proteins. Therefore, the to act by disrupting the membrane
quinones inactivate the protein and impair integrity offungalcells.
theirfunction.Quinonesbindwithsurface- Spirostanol steroidal saponins were
exposed adhesins, cell wall polypeptides, isolated from the roots of Smilax medica,
membrane-boundenzymes,andformcom- together with the smilagenin 3-O-b-D-
plexwhichinactivatetheenzymes. glucopyranoside (22) and disporoside A
In the anthraquinone group, there are exhibited antifungal activity against the
only a few reports concerning their human pathogenic yeasts C. albicans,
antifungal activity. The naphthoquinones C. glabrata, and C. tropicalis with MIC
kigelinone, isopinnatal, dihydro-a-lapa- valueinthe rangeof6.25–50mg/ml [37].
chone, and lapachol from Kigelia pinnata Two new steroidal saponins isolated from
were reported for antifungal activity [31]. the roots of Smilax aspera subsp.
A compound, 11-hydroxy-16-hentriacon- mauritanica exhibited antifungal activity
tanone (18), isolated from Annona squa- against the human pathogenic yeasts,
mosa was reported for its antifungal Candida albicans, C. glabrata, and
potential[32].Astudyoftheantimicrobial C. tropicalis in the range of 25–
compounds from Moneses uniflora 50mg/ml [38]. Phytolaccosides B (23)
resulted in the isolation of a 8-chloro- and E from Phytolacca tetramera showed
2,7-dimethyl-1,4-naphthoquinone (8- antifungal activities against a panel of
chlorochimaphilin) (19), together with human pathogenic opportunistic fungi
chimaphilin and 3-hydroxychimaphilin as [39]. Tigogenin-3-O-b-D-xylopyranosyl-
the antimicrobial components [33]. Hope- (1!2)-[b-D-xylopyranosyl-(1!3)]-b-
anolin (20), an unusual resveratral trimer D-glucopyranosyl-(1!4)-[a-L-rhamno-
with an o-quinone nucleus, from the stem pyranosyl-(1! 2)]-b-D-galactopyrano-
bark of Hopea exalata demonstrated side was found to have in vivo activity in
antifungal activity in the MIC value C. albicans vaginal infection model.
range of 0.1–22.5mg/ml [34]. 2,6- Another saponin from same plant, tigo-
Dimethoxy-p-benzoquinone (MIC¼50 genin-3-O-b-D-glucopyranosyl-(1!2)-
mg/ml)fromtheheartwoodofRhizophora [b-D-xylopyranosyl-(1!3)]-b-D-gluco-
apiculata exhibited activity against fungi pyranosyl-(1!4)-b-D-galactopyranoside
[35].Exampleofantifungalanthraquinone was found to be in vitro very effective
from medicinal species includes a new against several pathogenic Candida
1,3-dihydroxy-2-methyl-5,6-dimethox- species (MIC ¼4.4–9.4mg/ml) and C.
80
yanthraquinone (21) from the roots of neoformans (MIC ¼10.7–18.7mg/ml)
80
Prismatomeris fragrans [36]. [40].
Recently, steroidal saponins ypsilan-
droside B, ypsilandroside A, isoypsilan-
2.5 Saponins
droside A, isoypsilandroside B, and
Saponins are secondary metabolites that isoypsilandrogaine isolated from Ypsilan-
occur in a wide range of plant species drathebeticawerereportedforantimicro-
(Figure5).Theyarestoredinplantcellsas bial activities [41]. Eight saponins from
inactive precursors but are readily con- Tribulus terrestris were reported, out of
verted into biologically active antibiotics which two compounds showed promised
by enzymes in response to pathogen antifungal activity against fluconazole-
JournalofAsian Natural Products Research 627
H
O
OH O
H
HO OH
H
H H
HO
O O
H
22
HO
O
HO O HO O
HO O
O
HO HO
23
COOH
COOH
OH OO
OH OH OO
OH
H OH
OH OO H
OO OH
OH
H
OHOH OH H
24 25
Figure5. Structuresofsaponins22–25.
resistant Candida strains (MIC ¼4.4 designated sansevierin A, sansevistatin 1,
80
mg/ml), C. neoformans (MIC ¼10.7 and sansevistatin 2 and three steroidal
80
mg/ml),andC.krusei(MIC ¼8.8mg/ml) saponins isolated from the Sansevieria
80
[40]. Saponins from Solanum chrysotri- ehrenbergii exhibited antimicrobial
chum showed promising activity having activity,particularlyagainstthepathogenic
lowMIC12.5mg/mlagainstseveralfungal fungiC.albicansandC.neoformans[43].
pathogens[42].Threespirostanolsaponins Kalopanaxsaponins A (24) and I (25)
628 T. Arif et al.
showed antifungal activity against 4-methoxyxanthone (29) which exhibited
C. albicans and C. neoformans at a antibacterial activity against Staphylococ-
concentration of (MIC) 25mg/ml [44]. cus aureus and antifungal activity against
Spirostanol saponin (25R),5a-spirostan- A. niger, A. fumigatus, and a Penicillum
3b,6b-diol 3-O-{b-D-glucopyranosyl- species[50].
(1!2)-O-[b-D-xylopyranosyl-(1!3)]- 1,3,6-Trihydroxy-2,5-dimethoxyxan-
O-b-D-glucopyranosyl-(1 ! 4)-b-D- thone (30) isolated from the aerial part of
galactopyranoside} from the flower of Monnina obtusifolia was reported to have
Allium leucanthum was reported to have antifungalpotential[51].Sevenxanthano-
antifungal activity with a MCF ranging lides from Xanthium macrocarpum were
from6.25to12.5mg/mlonthemostyeast reportedtobeeffectiveagainstC.albicans,
stains tested [45]. C. glabrata, and A. fumigatus [52]. Two
Several saponins from A. suberi new 2-hydroxy-3-methylbut-3-enyl-sub-
were reported to have considerable MIC stituted xanthones, (^)-caledol and (^)-
values ranging from 25 to 50mg/ml [46]. dicaledol, were isolated from a dichlor-
SaponinsfromMedicagosativa,M.murex, omethane extract of the leaves of Calo-
M.Arabica,andM.hybridawerereportedto phyllum caledonicum and have been
beactiveagainstthreedermatophyticfungi reported for antifungal activity against
Microsporumgypseum,T.interdigitale,and A. fumigatus [53]. Xanthones from the
T.tonsurans(MIC,0.09mg)[47]. greenfruitsofGarciniamangostanawere
reported to have strong antifungal activi-
ties [54]. Cudrania fruticosa yielded an
2.6 Xanthones isoprenylated xanthone, cudrafruti-
Xanthones are a restricted group of plant xanthonewhichshowedantifungalactivity
polyphenols, biosynthetically related to against C. albicans [55]. Xanthone ana-
theflavonoids.Theseareplanar-sixcarbon logues bearing the basic chain of butena-
molecules in a conjugated ring system fine were reported for significant activity
consisting of a backbone molecule and againstC.neoformans(1.5mg/ml)[56].
various chemical groups attached to it.
Xanthone backbone consists of two
2.7 Alkaloids
benzeneringsattachedthroughacarbonyl
group and oxygen not allowing free Heterocyclic nitrogen compounds are
rotation about the carbonZcarbon bonds. called alkaloids (Figure 7). The first
Theuniquebackbonealongwithtypeand medically useful example of an alkaloid
position of the attached chemical groups was morphine, isolated in 1805 from the
defines specific properties of xanthones. opium poppy Papaver somniferum[57].
Xanthones possess numerous bioactive Recently, an alkaloid, 2-(3,4-dimethyl-
capability including antifungal properties 2,5-dihydro-1H-pyrrol-2-yl)-1-methylethyl
(Figure 6). pentanoate(31),hasbeenisolatedfromthe
CaledonixanthoneE(26)isolatedfrom plant Datura metel and showed in vitro as
thestembarkofCalophyllumcaledonicum wellasinvivoactivitiesagainstAspergillus
wasreportedforstrongantifungalactivity andCandidaspecies[58].Anotheralkaloid,
(MIC ¼8mg/ml) [48]. Isoprenylated 6,8-didec-(1Z)-enyl-5,7-dimethyl-2,3-
80
xanthones, toxyloxanthone C (27), and dihydro-1H-indolizinium (32) from
wighteone(28)showedantifungalactivity Aniba panurensis demonstrated the
againstC.albicanswithMICvaluesof25 activity against drug-resistant strains of
and 12.5mg/ml, respectively [49]. The C. albicans [59]. Bromo-8-n-hexylberber-
dichloromethane extract of Securidaca ine,aderivativeofberberine,wasreported
longepedunculata yielded 1,7-dihydroxy- to be 32 times more active against
JournalofAsian Natural Products Research 629
O OH OH
O O O OH
O O
OH OH O
26 27
O OH
HO O
HO
O
OH O
OH O
28 29
O
HO O OH
O
HO O
30
Figure6. Structuresofxanthones26–30.
C.albicansincomparisontotheclinically dermatitideshavingMIC23.4mg/ml[63].
usedberberine[60]. The indole alkaloid venenatine from
The alkaloids N-methylhydrasteine Alstonia venenata exhibited antifungal
hydroxylactam(33)and1-methoxyberber- activity against all the 10 tested fungi,
ine chloride from Corydalis longipes exhibiting germination levels below 10%
showed high efficacy individually [61]. [64]. 3-Methoxysampangine (36) from
Frangulanine, a cyclic peptide alkaloid, Cleistopholis patens exhibited significant
andwaltherioneA,aquinolinonealkaloid antifungal activity (MIC¼3.12mg/ml)
from leaves of Melochia odorata, were against C. albicans, A. fumigatus, and
reported to exhibit antifungal activities C.neoformans[65].Isoquinolinealkaloids
against a broad spectrum of pathogenic from Fumaria and Corydalis species
fungi [62]. growing in Turkey had significant anti-
Cinnamodial(34)andcinnamosmolide fungal activity at 8.0mg/ml concentration
(35) from Pleodendron costaricense [66].
showedahighactivityagainstC.albicans Antofine [67] from Ficus septica,
azole-resistant strain D10 and Wangiella sampangine (Figure 1) from the stem
630 T. Arif et al.
O
O
H N N+
31 32
O O
O
O O O HO
O
O
O H
O
O
O
O H OH O
O
N
33 34 35
N
N O
N
N
N
O
36 37
Figure7. Structuresofalkaloids31–37.
barkofCanangaodorata,[68]cycleanine, A lectin and a polypeptide isolated
cocsoline, and N-desmethylcycleanine from the roots of Astragalus mongholicus
from Albertisia villosa [69] are the other exertedantifungalactivitytowardsvarious
antifungal alkaloids reported from higher fungi [73]. An antifungal peptide was
plants. reported from fresh fruiting bodies of the
mushroom Agrocybe cylindracea [74].
Fabaceae species, Trigonella foenum-
2.8 Lectins and polypeptides graecum,yieldeddefensins,smallcysteine
Peptides,whichare inhibitory tomicroor- rich peptides, which exhibited antifungal
ganisms, were first reported in 1942 [70]. activityagainstthebroadhostrangefungi
They are often positively charged and [75]. A novel antifungal peptide, cucur-
contain disulfide bonds. Their mechanism moschin, isolated from the seeds of the
of action may be the formation of ion black pumpkin inhibited mycelial growth
channels in the microbial membrane [71] in the fungi [76]. A peptide designated
or competitive inhibition of adhesion of cicerarin from the seeds of the green
microbial proteins to host polysaccharide chickpea Cicer arietinum showed anti-
receptors[72]. fungalactivity.Theantifungalactivitywas