Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
Active antifungal substances from natural sources
Maria José Abad, María Ansuategui, and Paulina Bermejo*
Department of Pharmacology, Faculty of Pharmacy, University Complutense, Avda.
Complutense s/n, 28040, Madrid, Spain
E-mail: naber@farm.ucm.es
Dedicated to Professor Atta-ur-Rahman on the Occasion of his 65th Birthday
Abstract
The spread of multidrug-resistant strains of fungus and the reduced number of drugs available,
makes it necessary to discover new classes of antifungals and compounds that inhibit these
resistant mechanisms. This has led to a search for therapeutic alternatives, particularly among
medicinal plants and compounds isolated from them used for their empirically antifungal
properties. In these natural sources, a series of molecules with antifungal activity against
different strains of fungus have been found, which are of great importance to humans and plants.
In this article, we review the main sources of molecules with antimycotic activity obtained from
the natural environment.
Keywords: Fungus, antifungals, medicinal plants
Contents
Introduction
1.
Crude extracts
2.
Essential oils
3.
Terpenoids
4.
Saponins
5.
Phenolic compounds
6.
Alkaloids
7.
Peptides and proteins
ISSN 1424-6376
Page 116
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
Introduction
In the past few decades, a worldwide increase in the incidence of fungal infections has been
observed as well as a rise in the resistance of some species of fungus to different fungicidals used
in medicinal practice. Fungi are one of the most neglected pathogens, as demonstrated by the fact
that the amphotericin B, a polyene antibiotic discovered as long ago as 1956, is still used as a
“gold standard” for antifungal therapy. The last two decades have witnessed a dramatic rise in
the incidence of life threatening systemic fungal infections. The challenge has been to develop
effective strategies for the treatment of candidiasis and other fungal diseases, considering the
increase in opportunistic fungal infections in human immunodeficiency virus-positive patients
and in others who are immunocompromised due to cancer chemotherapy and the indiscriminate
use of antibiotics. The majority of clinically used antifungals have various drawbacks in terms of
toxicity, efficacy and cost, and their frequent use has led to the emergence of resistant strains.
Additionally, in recent years public pressure to reduce the use of synthetic fungicides in
agriculture has increased. Concerns have been raised about both the environmental impact and
the potential health risk related to the use of these compounds.
Hence, there is a great demand for novel antifungals belonging to a wide range of
structural classes, selectively acting on new targets with fewer side effects. One approach might
be the testing of plants traditionally used for their antifungal activities as potential sources for
drug development. Medicinal plants are not only important to the millions of people for whom
traditional medicine is the only opportunity for health care and to those who use plants for
various purposes in their daily lives, but also as a source of new pharmaceuticals. Natural
products, either as pure compounds or as standardised plant extracts, provide unlimited
opportunities for new drug leads because of the matchedless availability of chemical diversity.
This review aims to examine the recent efforts (1995 to date) towards discovering novel
antifungal drugs of natural origin. The information has been organised into easily accessible and
comparable sections, with reference to the crude extracts or isolated constituents studied.
1. Crude extracts
A review of the literature on the evaluation of medicinal plant extracts shows that many studies
into their antifungal activities have been carried out in recent years. Various research group have
initiated antifungal screening programmes for plants used all over the world as anti-infectious
agents in traditional medicine.
Nineteen plant species from fourteen families used in traditional North American Indian
medicine were tested for their fungicidal (Cladosporium cucumerinum and Candida albicans)
activity.1 Of the species investigated, nine were active against Cladosporium cucumerinum and
nine against Candida albicans. A programme was designed for the pharmacological screening of
ISSN 1424-6376
Page 117
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
species used by the Mayan people in the highlands of Chiapas in southern Mexico to treat
gastrointestinal and respiratory diseases.2 It demonstrated that 63% of the botanical species
showed antifungal properties against Candida albicans.
Verastegui et al.3 investigated the antifungal activity of several widely distributed plants in
the vegetation of northern Mexico and the southern U.S.A. The plants were evaluated on the
growth of yeasts and moulds: Candida albicans, Candida krusei, Candida rugosa, Cryptococcus
neoformans, Cryptococcus laurentis, Cryptococcus albidus, Microsporum canis, Microsporum
gypseum, Trichophyton tonsurans, Epidermophyton flocosum and Sporotrix schenckii. The
extracts analysed showed good antifungal activity against more than one organism.
Another screening for antifungal agents was done on medicinal and fruit bearing plants
used against skin diseases by the Brazilian population.4 The results, evaluated by the diameter of
the inhibition zone of fungal growth, indicate that six plant species, among the sixteen
investigated, showed significant activity against three fungi: Candida albicans, Trichophyton
rubrum and Cryptococcus neoformans. Ethanol extracts from the leaves and/or roots of thirty
five medicinal plants commonly used in Brazil were also screened for anti-Candida albicans
activity.5 Extracts from thirteen plants showed activity.
Methanol extracts from eleven traditionally-used Argentine medicinal plants were assayed
in vitro for antifungal activity against yeasts, hialohypomycetes as well as dermatophytes with
the microbroth dilution method.6 Of these, the most pronounced effect was presented by
Eupatorium bunifolium H.B.K. (Asteraceae) and Terminalia triflora (Griseb.) Lillo
(Combretaceae).
As part of a European screening aimed at the selection of novel antimycotic compounds of
vegetable origin, leaf extracts of Camelia sinensis L. (Theaceae), Cupressus sempervivens L.
(Cupressaceae) and Pistacia lentiscus L. (Anacardiaceae), and the seed extract of Glycine soja
Sieb. et Zucc. (Papilonaceae) were tested against yeast and yeast-like species implicated in
human mycoses.7 Only extracts of C. sinensis exhibited widespread activity.
In recent years, there has also been a large number of antifungal screening programmes of
medicinal plants used in the traditional medicine of Eastern Europe and Africa. Tadeg et al.8
investigated the antifungal activities of some selected traditional Ethiopian medicinal plants used
in the treatment of skin disorders. Hydroalcohol extracts of Acokanthera schimperi (D.C.) Benth.
et Hook. (Apocynaceae), Calpurna aurea L. (Leguminoseae), Kalanchoe petitiana (Engl.)
Cufod. (Crassulaceae), Lippia adonensis Hochst. (Verbenaceae), Malva parviflora L.
(Malvaceae), Olinia rochetiana L. (Oliniaceae), Phytolacca dodecandra L’Herit
(Phytolaccaceae) and Verbascum sinaiticum Bentham (Scrophulariaceae) were screened for
antifungal activity against different strains of fungi which are known to cause different types of
skin infections. Of all the plants tested, L. adoensis and O. rochetiana were found to be the most
active species against fungal strains.
Seventy seven crude extracts from leaves and stem barks of fifteen Gabonese plants used
in traditional medicine were evaluated for their antifungal activities.9 The methanol extract of
Polyalthia suaveolens Engler & Diels (Polygonaceae) displayed good antifungal activity on all
ISSN 1424-6376
Page 118
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
the strains tested with IC50 values (inhibitory concentration required for 50% inhibition) of 1
mg/ml. During interviews with the Pare people from north-eastern Tanzania, twenty nine plants
used for medicinal purposes as well as fourty-one plants used for non-medicinal purposes were
screened for antifungal activity.10 All plants showed activity against several test organisms.
Zaidi and Crow11 reported the antifungal activity of the following four important medicinal
plants from Balochistan, Pakistan: Grewia erythraea Schwein f. (Tiliaceae), Hymenocrater
sessilifolius Fisch. (Lamiaceae), Vincetoxicum stocksii Ali & Khatoon (Asclepidaceae) and
Zygophyllum fabago L. (Zygophyllaceae). The extracts of Z. fabago and V. stocksii showed good
activity against Candida albicans. In an antifungal screening programme, thirty six extracts
derived from ten plant species used by traditional Thai healers were assayed for their antifungal
activity against clinical isolates of Candida albicans, Cryptococcus neoformans and
Microsporum gypseum.12 The chloroform extract of Alpinia galanga (L.) Willd. (Zingiberaceae)
and Boesenbergia pandurata (Robx.) Schltr. (Zingiberaceae) had pronounced antifungal activity
against Cryptococcus neoformans and Microsporum gypseum, but exhibited weak activity
against Candida albicans. Both plants are excellent candidates for the development of a remedy
for opportunistic fungal infections in acquired immunodeficiency syndrome patients. Examples
of other antifungal crude extracts of traditional medicinal plants also included those of plants
used against venereal diseases in South Africa,13 and some medicinal plants from the Soqotra
island in Yemen.14
Besides antifungal screening programmes, a review of the literature on the
pharmacological evaluation of plant extracts shows that many studies into their antifungal
activity have been carried out in recent years. These reports concern mainly the Asteraceae and
Liliaceae families.
Members of the genus Echinops in the Asteraceae family are widely used in Ethiopian
herbal medicine for the treatment of various diseases and illnesses such as migraine, diarrhoea,
different forms of infections, intestinal worm infestation and haemorrhoids. Hydroalcohol
extracts of the root, flower head, leaf and stem of Echinops ellenbeckii O. Hoffm. and Echinops
longisetus A. Rich were investigated for their antifungal activity.15 The flower extract of E.
ellenbeckii showed strong inhibitory activity against Candida albicans.
Plants from the genus Pterocaulon (Asteraceae), known as quitoco, are used to treat
problems popularly diagnosed as mycoses, which may have a fungic etiology. In order to
validate this traditional practice, the crude methanol extracts from the aerial parts of three species
of Pterocaulon, Pterocaulon alopecuroides (Lam.) D.C., Pterocaulon balansae Chodat. and
Pterocaulon polystachyum D.C., grown in southern Brazil were analysed for the in vitro
antifungal activity against a panel of standardised and clinical opportunistic pathogenic yeasts
and filamentous fungi, including dermatophytes.16 The crude methanol extract of P.
polystachyum was the most active.
Extracts from roots of the common vegetable Cichorium intybus L. (Asteraceae), highly
appreciated for its bitter taste, were studied to investigate their possible biological activity on
fungi from a variety of ecological environments.17 The extracts were ineffective on geophilic
ISSN 1424-6376
Page 119
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
species and on tested phytopathogens, with the exception of Pythium ultimum, whereas they
inhibited the growth of zoophilic and anthropophilic dermatophytes, in particular Trichophyton
tonsurans var. sulfureum.
Loizzo et al.18 investigated the antifungal activity of methanol, ethyl acetate,
dichloromethane, n-hexane, n-butanol and chloroform extracts of Senecio inaequidens D.C. and
Senecio vulgaris L. (Asteraceae). The hexane extract of S. vulgaris showed significant activity
against Trichophyton tonsurans (IC50 of 0.031 mg/ml). Examples of other antifungal crude
extracts from the Asteraceae family also included Cynara scolymus L. extracts,19 the
dichloromethane extract of the aerial part of Blumea gariepina D.C. which was shown to be
active against the phytopathogenic fungus Cladosporium cucumerinum,20 and aqueous and
petroleum ether extracts of Spilanthes calva D.C. which were active towards Fusarium
oxysporum and Trichophyton mentagrophytes.21
In the Liliaceae family, reports on the antifungal activity concern mainly the Allium genus.
By using an agar dilution assay, the antifungal activity of aqueous extracts prepared from Allium
cepa L. (onion) and Allium sativum L. (garlic) were evaluated against Malassezia furfur,
Candida albicans as well as several strains of various dermatophyte species.22 The results
indicate that onion and garlic might be promising sources of drugs for the treatment of fungalassociated diseases from the important pathogenic genera Candida, Malassezia and the
dermatophytes. The antifungal activity of onion and garlic was also investigated on two
important dermatophytes, Trichophyton rubrum and Trichophyton mentagrophytes.23,24 From
another Allium species, Allium ascalonicum O. Fedtsch, Amin and Kapadnis25 investigated the
antifungal activity against twenty three strains of fungi. Among them, Aureobasidium pullulans
and Microsporum gypseum were the most sensitive (IC50 of 0.15 mg/ml).
Other antifungal medicinal plants belong to the Leguminoseae, Rutaceae, Myrtaceae and
Lamiaceae families. The effect of heartwood extracts from two Leguminoseae species, Acacia
mangium Willd and Acacia auriculiformis A. Cunn., was examined on the growth of woodrotting fungi in in vitro assays.26 A. auriculiformis heartwood extracts had higher antifungal
activity that A. mangium. The extracts of leaf, root, stem and the callus obtained from another
Leguminoseae species, Pseudarthria viscida (L.) Wight & Arn., showed significant inhibitory
activity against some fungal pathogens causing major diseases in crop plants and stored food
grains.27
Antifungal activity of ethanol extracts of grapefruit, Citrus paradisis Macf. (Rutaceae)
seed and pulp was examined against ten yeast strains.28 Yeasts were sensitive to extract
concentrations ranging from 4.13 to 16.50%. Leaf, fruit, stem, bark and root of another Rutaceae
species, Zanthoxylum americanum Mill., were investigated for antifungal activity with eleven
strains of fungi representing diverse opportunistic and systemic pathogens, including Candida
albicans, Cryptococcus neoformans and Aspergillus fumigatus.29 All extracts demonstrated a
broad spectrum of antifungal activity and inhibited at least eight fungal species in a disk
diffusion assay. The results provide a pharmacological basis for the very widespread use of this
ISSN 1424-6376
Page 120
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
plant in the indigenous North American ethnomedical tradition for conditions that may be related
to fungal infections.
Reports on the antifungal activity of medicinal species belonging to the Myrtaceae family
include the herbal food clove Syzygium aromaticum L. (Merr. & Perry),30 and extracts of
Eucalyptus globulus Labill., Eucalyptus maculata Hook. and Eucalyptus viminalis Labill. which
significantly inhibited the growth of the fungus Trichophyton mentagrophytes.31
Ocimum gratissimum L. (Lamiaceae), a plant known as alfavaca, has been reported as
having in vitro activity against the dermatophytes Microsporum canis, Microsporum gypseum,
Trichophyton rubrum and Trichophyton mentagrophytes.32 Trichophyton rubrum, the most
common etiological agent of dermatophytosis in Goiania, state of Goias, Brazil, was the most
susceptible dermatophyte. The plant was also active towards twenty five isolates of
Cryptococcus neoformans, the etiological fungus responsible for cryptococcal infections.33
Another Lamiaceae species, Satureja khuzistanica Jamzad was also active against Candida
albicans.34
Other antifungal medicinal plants belong to the Combretaceae, Zingiberaceae,
Amaryllidaceae and Euphorbiaceae families. Masoko et al.35 investigated the antifungal
activities of six South African Terminalia species (Combretaceae), Terminalia prunioides M.A.
Lawson, Terminalia brachystemma Welw. ex Hiern, Terminalia sericea Burch ex D.C.,
Terminalia gazensis Bak. f., Terminalia mollis Laws and Terminalia sambesiaca Engl. & Diels.
against five fungal animal pathogens (Candida albicans, Cryptococcus neoformans, Aspergillus
fumigatus, Microsporus canis and Sporothrix schenkii). T. sericea extracts were the most active
against nearly all the microorganisms tested. Five species of Combretaceae growing in Togo
were also investigated for their antifungal activity against twenty pathogenic fungi in order to
confirm the traditional therapeutic properties of these plants.36 The hydroethanol extracts of
Terminalia glaucescens Planch. ex Benth. (L.) and Anogeissus leiocarpus (D.C.) Guill. et Perr.
(L.) appeared to be the most active, with IC50 values ranging from 0.25 to 4 mg/ml.
In the Zingiberaceae family, the ethanol extract of Curcuma longa L. and A. galanga were
also found to possess good antifungal activities against Trichophyton longifusus.37 Other
Curcuma species from the Zingiberaceae family, Curcuma zedoaria Rosc. and Curcuma
malabarica Vel., also presented antifungal activity which supports the use of their tubers in
traditional medicine for the treatment of bacterial and fungal infections.38
One member of the Amaryllidaceae family, Polianthes tuberosa L., was evaluated against
the mycelial growth of Colletotrichum gloeosporioides on potato-dextrose-agar medium.39
Examples of other antifungal crude extracts from the Amaryllidaceae family also included
Sternbergia sicula Tineo ex Guss. and Sternbergia lutea (L.) Ker-Gawl. ex Spreng.40
Based on an ethnobotanical approach, the dragon’s blood collected from Croton urucurana
Baill. (Euphorbiaceae) bark was tested for antifungal activity against five dermatophytes by the
paper disk diffusion method.41 The test dermatophytes were Trichophyton tonsurans,
Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis and Epidermophyton
floccossum. The dragon’s blood (0.175-3 mg/ml) exhibited an inhibition zone range of 7.6-26.9
ISSN 1424-6376
Page 121
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
mm against all the tested fungi, with IC50 of 1.25-2.5 mg/ml. Another member of the
Euphorbiaceae family, Phyllanthus amarus Schumach & Thonn., was also tested against the
dermatophytic fungus Microsporum gypseum.42 The chloroform extract of the aerial part of the
plant showed a significant inhibitory effect against this dermatophytic fungus.
Reports on the antifungal activity of the extracts of several medicinal species belonging to
other botanical families have also been found in the literature. Some of these plants have been
reported to be used in folk medicine as anti-infectious agents.
Pycnogenol, a standardised extract of Pinus pinaster Ait. (Pinaceae), was tested for its
antifungal activity towards twenty three different yeast and fungi microorganisms.43 Pycnogenol
inhibited the growth of all the tested microorganisms in minimum concentrations ranging from
20 to 250 µg/ml. These results conform with clinical oral healthcare studies describing the
prevention of plaque formation and the clearance of candidiasis by pycnogenol. Zizyphus lotus
(L.) Desf. (Rhamnaceae) is one of the traditional drugs commonly used in folk medicine in
Morocco. Extracts obtained from the successive exhaustion in petroleum ether, chloroform, ethyl
acetate and methanol were found active in vitro against nine pathogenic fungi.44 The chloroform
extract in particular appeared to be the most interesting in antifungal tests at lower
concentrations.
De Campos et al.45 investigated the crude methanol extract and some fractions (hexane,
dichloromethane and ethyl acetate) from Piper solmsianum C. D.C. var. solmsianum
(Piperaceae) for possible antifungal activity against twelve pathogenic fungi. The experiments
showed that the crude extract exhibited antifungal action against all the dermatophytes tested,
with IC50 values of between 20 to 60 µg/ml. Similar activity was also verified for the hexane,
dichloromethane and ethyl acetate fractions. The antifungal activity of Nigella sativa L.
(Ranunculaceae) seed was tested against eight species of dermatophytes: four species of
Trichophyton rubrum and one each of Trichophyton interdigitale, Trichophyton mentagrophytes,
Epidermophyton floccosum and Microsporum canis.46 These results denote the potentiality of N.
sativa as a source for antidermatophyte drugs, and support its use in folk medicine for the
treatment of fungal skin infections.
The antifungal activity of a crude extract from Yucca gloriosa L. (Agavaceae) flowers,
named alexin, was investigated in vitro against a panel of human pathogenic fungi and yeasts, as
well as dermatophytes and filamentous species.47 Alexin had a broad spectrum of antifungal
activity for all the tested yeast strains, except for Candida lusitaniae and Candida kefyr. It was
also active against several clinical Candida isolates known to be resistant to the usual antifungal
agents. One member of the Nyctaginaceae family, Boerhavia diffusa L., was active against the
dermatophytic species of Microsporum gypseum, Microsporum fulvum and Microsporum
canis.48,49
Crude methanol extracts and fractions from the aerial parts of seven species of Hypericum
(Gutiferaceae) growing in southern Brazil were analysed for their in vitro antifungal activity
against a panel of standardised and clinical opportunistic pathogenic yeasts and filamentous
fungi, including dermatophytes.50 Chloroform and hexane extract of Hypericum ternum A. St.-
ISSN 1424-6376
Page 122
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
Hill. showed the greatest activity among the extracts tested. Rojas et al.51 investigated the
antifungal activity of Gentianella nitida Griseb. (Gentianaceae). The most susceptible
microorganisms were Candida albicans, Trichophyton mentagrophytes and Microsporum
gypseum. The antifungal activity was concentrated in the 90% methanol and non-soluble
fractions.
The n-butanol soluble part and four fractions of the aqueous ethanol extract of the leaves of
Daniellia oliveri (Rolfe) Hutch & Dalziel (Fabaceae) were active against the fungus
Trichophyton rubrum,52 while the aqueous extract from the plant P. dodecandra
(Phytolaccaceae) showed fungicidal activity against dermatophytes.53 The seeds of two Apiaceae
species, Ligusticum hultenii Fernald and Lomatium californicum (Nutt.) Math. & Const. were
investigated for antifungal activity.54 Preliminary bioassays indicated that the methylene chloride
extracts of the seeds of both species had antifungal activity against Colletotrichum fragariae.
Examples of other antifungal crude extracts from medicinal species also included Bauhinia
racemosa L. (Caesalpiniceae) stem bark,55 the latex of gazyumaru (Ficus microcarpus L.,
Moraceae),56 Larrea divaricata Cav. (Zygophyllaceae) which presented fungitoxic activity
against yeasts and fungi,57 and leaf extracts of Tapinanthus sessilifolius (P. Beauv) Van Tiegh.
(Loranthaceae) which was active towards Candida albicans.58
2. Essential oils
The increasing resistance to antifungal compounds and the reduced number of available drugs
led us to search for therapeutic alternatives among aromatic plants and their essential oils, used
for their empirically antifungal properties. In recent years, these reports have involved mainly the
Lamiaceae and Asteraceae families.
The antifungal effect on Candida albicans growth of the essential oils from several species
of the Lamiaceae family, Satureja montana L., Lavandula angustifolia Mill., Lavandula hybrida
Reverchon, Origanum vulgare L., Rosmarinus officinalis L. and six chemotypes of Thymus
vulgaris L. were studied.59 The greatest efficiency was obtained with the essential oil from the T.
vulgaris thymol chemotype (IC50 of 0.016 µg/ml). From two of these genera, Lavandula and
Rosmarinus, extensive works on the antifungal activity of their essential oils have been reported.
Figure 1. Structure of limonene
ISSN 1424-6376
Page 123
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
The antifungal activity of the essential oil of L. angustifolia (lavender oil) and its main
components, linalool and linalyl acetate, was investigated against fifty clinical isolates of
Candida albicans (oropharyngeal and vaginal strains).60 Linalool was more effective than
essential oil, although linalyl acetate was almost ineffective. Angioni et al.61 investigated the
chemical composition and antifungal activity of the essential oil from the stems/leaves and
flowers of another Lavandula species growing wild in southern Sardinia, Italy, Lavandula
stoechas L. ssp. stoechas. The essential oils tested were effective on the inactivation of
Rhizoctonia solani and Fusarium oxysporum, and less effective against Aspergillus flavus.
Among the single components tested, fenchone, limonene (Figure 1) and myrtenol appeared to
be the most effective on the inhibition of Rhizoctonia solani growth. The chemical composition
of the essential oil of the Sardinian R. officinalis obtained by hydro-distillation was also
studied.62 The major compounds in the essential oil were α-pinene, borneol (Figure 2),
camphene, camphor, verbenone and bornyl acetate. An inhibitory effect on fungal growth,
especially toward Fusarium graminearum, was observed.
OH
Figure 2. Structure of borneol
Other antifungal essential oils from the Lamiaceae family are those from species of the
genera Ocimum, Nepeta and Thymbra. The in vitro antifungal activity of the essential oil of O.
gratissimum was investigated in order to evaluate its efficacy against Candida albicans, Candida
krusei, Candida parapsilosis and Candida tropicalis.63 These results demonstrated that the
essential oil showed fungicidal activity against all of the Candida species studied. Analysis of
the ultrastructure of the yeast cells revealed changes in the cell wall and in the morphology of
some subcellular organelles. The essential oil from another species of the Ocimum genus, the
wild Amazonian basil Ocimum micranthum Willd., showed a dose-dependent antifungal activity
against pathogenic and food spoiling yeasts.64
The composition and antifungal activity of the essential oil of Nepeta crispa Willd.
(Lamiaceae), an endemic species from Iran, was studied.65 The oil exhibited a noticeable
antifungal activity against all the tested fungi. Twenty three compounds, accounting for 99.8% of
the total oil, were identified. The main constituents were 1,8-cineole and 4α,7αabetanepetalactone. The composition and the antifungal activity of the essential oil of Thymbra
capitata (L.) Cav. (Lamiaceae) on Candida, Aspergillus and dermatophyte strains were also
studied.66 The oil exhibited antifungal activity for all the strains tested, particularly for
dermatophytes, with IC50 values ranging from 0.08 to 0.32 µg/ml. All samples are of the
ISSN 1424-6376
Page 124
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
carvacrol type, with a high content of carvacrol and its biogenetic precursors, γ-terpinene and pcymene.
Reports on the antifungal activity and chemical composition of the essential oils from
aromatic plants belonging to the Asteraceae family have also been found in the literature. The
antifungal activity of the essential oil of flowerheads of garland chrysanthemum Chrysanthemum
coronarium L. (Asteraceae) was evaluated against twelve agricultural pathogens.67 Flowerhead
oil was active both in contact and headspace in vitro assays and produced hyphal growth
inhibition, although there was less activity on faster growing fungi. The main compounds in the
oil were camphor, α- and β-pinene and lyratyl acetate.
Kordali et al.68 investigated the chemical composition and antifungal activity of the
essential oils from three Turkish Artemisia species (Asteraceae): Artemisia absinthium L.,
Artemisia santonicum L. and Artemisia spicigera C. Koch. The results showed that all the oils
had potent inhibitory effects over a very broad spectrum against all the fungi tested. Pure
camphor and 1,8-cineole, which are the major components of the oils, were also tested for
antifungal activity against the same fungal species. Compounds showed antifungal activity
against some of the fungal species.
The composition of the leaf oils, obtained by hydro-distillation, of five endemic Psiadia
species of the Asteraceae family from Mauritius, were also studied.69 In vitro antifungal assays,
using the agar-well diffusion method, revealed that most of the oils were not very active against
the tested microorganisms, except for that of Psiadia lithospermifolia Lam., which significantly
inhibited the growth of Aspergillus ochraceus, Candida pseudotropicalis and Fusarium
moniliforme. This activity has been attributed to the presence of δ-elemene, farnesene, αcurcumene, selina-4,7(11)-diene and β-bisabolene, some of which have established antifungal
profiles.
The essential oil extracted by steam distillation from the capitula of Indian Tagetes patula
L. (Asteraceae) was evaluated for its antifungal properties.70 The oil exerted good antifungal
activity against two phytopathogenic fungi, Botrytis cinerea and Penicillium digitatum,
providing complete growth inhibition at 10 and 1.25 µg/ml, respectively. The contribution of the
two main compounds, piperitone and piperitenone, to the antifungal efficacy was also evaluated,
and structural modifications in mycelia were observed via electron microscopy, displaying
considerable alterations in hyphal morphology and a multi-site action mechanism. Examples of
other antifungal essential oils from the Asteraceae family also included the essential oil of
Chrysactinia mexicana Grag, which completely inhibited Aspergillus flavus growth,71 and
Helichrysum italicum (Roth) Don growing wild in Calabria and Sardinia, Italy, which was active
against the phytopathogenic fungus Pythium ultimum.72
Other antifungal essential oils from medicinal plants belong to the Verbenaceae, Rutaceae,
Lauraceae and Cupressaceae families. Some of these medicinal and aromatic plants have been
reported to be anti-infectious agents.
Mexican oregano, Lippia berlandieri Shauer (Verbenaceae) grows wild in the desert zone
of Mexico and is commonly added to regional foods. Portillo et al.73 initiated studies to evaluate
ISSN 1424-6376
Page 125
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
the antifungal activity of Mexican oregano versus food-contaminant fungi. The oregano essential
oil was inhibitory to all fungal strains tested, but there were differences in the extent of the
effect. Although the antifungal effect of oregano is strongly established, there was a differential
effect with the fungal strains studied. Another species from the genus Lippia, Lippia javanica
(Burm. f.) Spreng, is widely distributed throughout South Africa, where it is used extensively in
traditional herbal preparations. An infusion of the leaves is commonly used as a decongestant for
colds and coughs. Recently, Viljoen et al.74 reported the antimicrobial activity of L. javanica leaf
essential oil against some fungi. The essential oils of two members of the Verbenaceae family,
Aloysia triphylla (Ort.) H.B.K. and Aloysia polystachya (Gris.) Mol., were also active towards
Fusarium verticillioides.75
In the Rutaceae family, the essential oil extracted from the epicarp of Citrus sinensis (L.)
Osbeck exhibited absolute fungitoxicity against ten post-harvest pathogens.76 The chemical
composition and antifungal activity of the essential oil of Haplophyllum tuberculatum (Forsskal)
A. Juss (Rutaceae) was also analysed.77 The oil affected the mycelial growth of Curvularia
lunata and Fusarium oxysporium in a dose-dependent manner, but had no effect on the
germination of their spores. Thirty compounds, constituting about 99.7% of the total oil, were
identified. The most abundant oil components were α- and β-phellandrene, limonene (Figure 1),
β-ocimene, β-caryophyllene and myrcene.
The antifungal activity of the essential oils from several aromatic species from the
Lauraceae family, Aniba rosaedora Ducke, Laurus nobilis L., Sassafras albidum (Nutt.) Nees
and Cinnamomum zeylanicum Blume were investigated against seventeen micromycetes.78
Among the fungal species tested were food poisoning and food spoilage fungi, and plant and
animal pathogens. Linalool was the main component in the essential oil of A. rosaedora, while
1,8-cineole was dominant in L. nobilis. Safrole was the major component in S. albidum essential
oil, and the main component of the oil of C. zeylanicum was trans-cinnamaldehyde. The
essential oil of C. zeylanicum showed the strongest antifungal activity. Another antifungal
Cinnamomum species is Cinnamomum osmophloeum Kaneh, a hardwood species indigenous to
Taiwan, which has significant antifungal activity against wood decay fungi.79
From the Cupressaceae family, Calocedrus formosana Florin is an endemic tree species in
Taiwan. Its timber is recognised for its natural resistance to decay. Cheng et al.80 investigated the
antifungal activity of its essential oil. Leaf oil constituents displayed activity against four fungi:
Lenzites betulina, Pycnoporus coccineus, Trametes versicolor and Laetiporus sulphurous. Two
compounds, α-cadinol and muurolol, exhibited the strongest antifungal activity. The antifungal
activity of the essential oil from another coniferous tree, Chamaecyparis obtusa (Siebold &
Zucc.) Siebold & Zucc. ex Endl. was also reported.81 The oil had antifungal effects and the main
component was bornyl acetate. Examples of other antifungal essential oils from the
Cupressaceae family also included Juniperus comunis L. essential oil which was active against
the dermatophyte Aspergillus and Candida strains.82
Reports on the antifungal activity of essential oils from aromatic medicinal plants
belonging to other botanical families have also been found in the literature. In an attempt to
ISSN 1424-6376
Page 126
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
develop stable and antifungal agents from natural products (daily food stuffs in particular), the
activity of essential oils from Allium fistulosum L., A. sativum and A. cepa (Liliaceae) were
investigated against three Trichophyton species responsible for severe mycoses in humans.83
Among the oils tested, A. sativum oil exhibited the strongest inhibition of growth of
Trichophyton rubrum with an IC50 value of 61 µg/ml, while the activities of A. cepa and A.
fistulosum were relatively mild.
Singh et al.84 investigated the chemical constituents and antifungal effects of ajwain
essential oil, Trachyspermum ammi (L.) Sprague (Apiaceae). The oil exhibited a broad spectrum
of fungitoxic behaviour against all tested fungi, such as Aspergillus niger, Fusarium moniliforme
and Curvularia lunata, as absolute mycelial zone inhibition was obtained at a 6 µl dose of the
oil. Analysis of ajwain essential oil showed the presence of twenty six identified components,
which account for 96.3% of the total amount. Thymol was found to be a major component along
with p-cymene, γ-terpinene, β-pinene and terpinen-4-ol. The essential oils from different tissues
of Japanese cedar, Cryptomeria japonica D. Don (Taxodiaceae) were active against four wood
decay fungi and six tree pathogenic fungi,85 while essential oil isolated by hydro-distillation from
the aerial parts of Chenopodium botrys L. (Chenopodiaceae) showed significant fungicidal
activity.86
Examples of other antifungal essential oils from medicinal plants also included those from
C. sinensis (Theaceae),87 Croton cajucara Benth (Euphorbiaceae) linalool-rich essential oil,88 the
essential oil of Pelargonium graveolens L’Herit ex Aiton (Geraniaceae) which was active against
Trichophyton spp.,89 and the aerial parts of Bupleurum gibraltaricum Lamarck (Umbeliferae),
which yielded an antifungal essential oil active towards Plasmopara halstedii in sunflower.90
The main compounds in this oil were sabinene, α-pinene and 2,3,4-trimethylbenzaldehyde.
3. Terpenoids
A large number of studies have been done in recent years on the antifungal activity of terpenoids
of natural origin. These reports concern mainly sesquiterpenes and sesquiterpene lactones. Some
of these compounds were isolated by bioassay-guided fractionation, after previously detecting
antifungal activity on the part of the plant.
ISSN 1424-6376
Page 127
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
O
O
OH
Figure 3. Structure of 6-cinnamoyloxy-1-hydroxyeudesm-4-en-3-one
Phytochemical and biological investigation of the roots of the wild carrot, Daucus carota
L. ssp. carota (Apiaceae), afforded four sesquiterpene daucane esters.91 Based on an agar
diffusion assay, compounds were screened and found to contain a range of low antifungal
activity against Fusarium oxysporum and Aspergillus niger. This species also yielded the
sesquiterpenes carotol, daucol and β-caryophyllene.92 Carotol, which was observed to be the
main constituent of carrot seed, inhibited the radial growth of fungi by 65%. The bioassayguided fractionation of the antifungal dichloromethane extract from the roots of Vernonanthura
tweedieana (Baker) H. Rob. (Asteraceae), allowed the isolation of one active sesquiterpene,
identified as 6-cinnamoyloxy-1-hydroxyeudesm-4-en-3-one (Figure 3).93 Trichophyton
mentagrophytes was the most sensitive strain.
A dichloromethame and a methanol extract of the liverwort Bazzania trilobata (L.) S.F.
Gray (Lepidoziaceae) showed antifungal activity against the phytopathogenic fungi Botrytis
cinerea, Cladosporium cucumerinum, Phythophthora infestans, Pyricularia oryzae and Septoria
tritici. From these extracts, Scher et al.94 isolated six antifungal sesquiterpenes: 5- and 7hydroxycalamenene, drimenol (Figure 4), drimenal, viridiflorol, gymnomitrol and
chloroisopiagiochin D. Polygodial, a sesquiterpene isolated from Polygonum punctatum Elliot.
(Polygonaceae), was found to exhibit a fungicidal activity against a food spoilage yeast,
Zygosaccharomyces bailii.95 The time-kill curve study showed that polygodial was fungicidal at
any growth stage.
CH2 OH
Figure 4. Structure of drimenol
ISSN 1424-6376
Page 128
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
Examples of other antifungal sesquiterpenes from medicinal species also included those
isolated from Juniperus thurifera L. (Cupressaceae) wood,96 and antifungal sesquiterpenes from
the root exudates of Solanum abutiloides (Griseb.) Bitter & Lillo (Solanaceae) which inhibited
the spore germination of Fusarium oxysporum.97
Reports on antifungal sesquiterpene lactones from natural sources mainly concern those
isolated from medicinal species of the Asteraceae family. In the search for new sources of
sesquiterpene lactones, Barrero et al.98 investigated six Centaurea species: Centaurea bombycina
Boiss ex D.C., Centaurea granatensis Boiss, Centaurea monticola Boiss, Centaurea incana
Desf., Centaurea maroccana Ball. and Centaurea sulphurea Willd. The activity of the
sesquiterpene lactones isolated from the Centaurea plants against the fungus Cunninghamella
echinulata was evaluated. Of these, costunolide (Figure 5) and dehydrocostunolide showed
noticeable IC50 values, whilst more polar lactones were inactive. These results suggest that a
relatively low polarity is one of the molecular requirements for the antifungal activity of
sesquiterpene lactones. From other Centaurea species, Centaurea thessala Hausskn. and
Centaurea attica Nym., two new eudesmanolides, 4-epi-sonchucarpolide and their 8-(3hydroxy-4-acetoxy-2-methylene-butanoyloxy) derivative, and one new eudesmane derivative
named atticin, were isolated.99 The in vitro antifungal activity of these sesquiterpene lactones
was tested against nine fungal species using the micro-dilution method. All the compounds
showed a considerable antifungal effect.
O
O
Figure 5. Structure of costunolide
Examples of other antifungal sesquiterpene lactones from the Asteraceae family also
included those isolated from Ajania fruticulosa (Lebeb.) Poljak,100 and seven xanthanolides from
Xanthium macrocarpum D.C. which were effective against Candida albicans, Candida glabrata
and Aspergillus fumigatus.101
Besides sesquiterpenes and sesquiterpene lactones, studies into other antifungal terpenoids
from medicinal species also included diterpenoids and triterpenoids. Some of these compounds
were isolated by bioassay-guided fractionation after previously detecting antifungal activity on
the part of the plant.
A fruit pulp extract of Detarium microcarpum Guill. et Perr. (Leguminoseae) showed
inhibition of the growth of the plant pathogenic fungus Cladosporium cucumerinum.102
Fractionation of this extract led to the isolation of four new clerodane diterpenes which showed
ISSN 1424-6376
Page 129
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
antifungal activity. The diterpenoids 16α-hydroxy-cleroda-3,13-(14)-Z-diene-15,16-olide and
16-oxo-cleroda-3,13-(14)-E-diene-15-oic acid (Figure 6) isolated from the hexane extract of the
seeds of Polyalthia longifolia (Som.) Thw (Annonaceae) also demonstrated significant
antifungal activity.103
CHO
HOOC
Figure 6. Structure of 16-oxo-cleroda-3,13-(14)-E-diene-15-oic acid
Bioassay-guided fractionation of the methanol and ethyl acetate extracts of two lianas from
the genus Casimirella (Miers) RA Howard (Icacinaceae) collected in the Suriname rainforest,
has led to the isolation of five new diterpenoids: humirianthone, 1-hydroxy-humirianthone, 15Rhumirianthol, patagonol and patagonal.104 All the diterpenoids showed activity against
phytopathogenic fungi. Examples of other antifungal diterpenoids from medicinal species also
included oxygenated pimarane diterpenes from Kaempferia marginata Caney ex Roscoe
(Zingiberaceae).105
COOH
HO
H
Figure 7. Structure of oleanolic acid
Chemical investigation of the diethyl ether extract of the stem bark of Khaya ivorensis A
Chev (Meliaceae) afforded ten highly oxygenated triterpenes.106 These compounds were
evaluated for their antifungal activity against the plant pathogenic fungus Botrytis cinerea.
Methyl angolensate and 1,3,7-trideacetylkhivorin displayed the highest antifungal activity, with
ISSN 1424-6376
Page 130
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
62.8 and 64% mycelial growth inhibition at 1000 mg/l, respectively. Lythrum salicaria L.
(Lytraceae) extracts showed activity against the phytopathogenic fungus Cladosporium
cucumerinum. Becker et al.107 isolated the two antifungal triterpenoids, oleanolic acid (Figure 7)
and ursolic acid.
The triterpenoids pristimerin and celastrol isolated from the roots of Celastrus hypoleucus (Oliv)
Warb f. Argurtior Loes (Celastraceae) exhibited inhibitory effects against diverse
phytopathogenic fungi such as Rhizoctonia solani and Glomerelia cinguiata.108 Examples of
other triterpenes from medicinal plants also included a novel oleanane triterpenoid,
triterpenetetrol (Figure 8), isolated from the chloroform extract of the aerial parts of Leontodon
filii (Hochst. ex Seub.) Paiva et Orm (Asteraceae).109
OH
H
H
HO
HO
H
Figure 8. Structure of triterpenetetrol
4. Saponins
Compounds chemically related to the triterpenoid group, such as triterpene saponins, together
with steroidal saponins, were also isolated as antifungal constituents from medicinal plants.
These reports concern mainly members of the Solanaceae family.
CAY-1, a novel triterpene saponin from the Capsicum frutescens L. (Solanaceae) plant
commercially known as cayenne pepper, was investigated to determine its in vitro antifungal
activity.110 CAY-1 was active against sixteen different fungal strains, including Candida spp. and
Aspergillus fumigatus, and was especially active against Cryptococcus neoformans. Importantly,
CAY-1 appears to act by disrupting the membrane integrity of fungal cells.
A novel spirostanol saponin, together with three known saponins, were isolated from the
leaves of Solanum hispidum Pers. (Solanaceae).111 All the isolated compounds showed
antimycotic activity. The most active compound was 6α-O-[β-D-xylopyranosyl-(1→3)-β-Dquinovopyranosyl]-(25,S)-5α-spirostan-3β-ol, with IC50 values of 25 µg/ml against both
Trichophyton mentagrophytes and Trichophyton rubrum. From another Solanum species,
Solanum chrysotrichum Schltdl., five new spirostan saponins were isolated using bioactivity-
ISSN 1424-6376
Page 131
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
directed isolation procedures.112 These compounds showed antimycotic activity against
Trichophyton mentagrophytes, Trichophyton rubrum, Aspergillus niger and Candida albicans.
Bioassay-guided fractionation of the ethanol extract of the aerial parts of the Tibetan
medicinal herb Clematides tangutica Skill. (Ranunculaceae), led to the isolation of two new
antifungal triterpene saponins.113 Inhibitory activities of the two saponins against seven fungal
strains were reported. Two new dammarane saponins were also isolated from the methanol
extract of the stems of Anomospermum grandifolium Eichler (Menispermaceae).114 Activity
screening of the compounds revealed antifungal properties against Candida albicans.
From the rhizomes of Dioscorea cayenensis Lam. Holl (Dioscoreaceae), new steroid
saponins with antifungal activity against the human pathogenic yeasts Candida albicans,
Candida glabrata and Candida tropicalis have been isolated,115,116 while three new antifungal
steroidal saponins were isolated from the root of Smilax medica L. (Liliaceae).117 Examples of
other antifungal saponins from medicinal plants also included those isolated from Astragalus
verrucosus Moris (Leguminoseae),118 from A. auriculiformis (Fabaceae),119 and the saponins
from Hedera taurica Carr. (Araliaceae) which possessed antifungal activity in vitro against
Candida albicans, Candida krusei and Candida tropicalis.120
5. Phenolic compounds
In recent years, a large number of studies have been done on the antifungal activity of phenolic
compounds of natural origin. This section deals mainly with those phenolic classes with
antifungal properties found in medicinal plants, namely simple phenolic compounds, flavones
and related flavonoid glycosides, coumarins and derivatives, and anthraquinones. Some of these
compounds were isolated by bioassay-guided fractionation, after previously detecting antifungal
activity on the part of the plant.
Antifungal activity-guided fractionation of the n-butanol extract of the stem bark of
Artocarpus nobilis Thw (Moraceae) furnished two stilbene derivatives.121 Both compounds
showed strong antifungal activity against Cladosporium cladosporioides. Four Piper species
(Magnoliaceae) collected in the state of Sao Paulo, Brazil, Piper crassinervium Kunth, Piper
aduncum L., Piper hostmannianum (Miquel) C. D.C. and Piper gaudichaudianum Kunth,
contain the new phenolic acid derivatives crassinervic acid (Figure 9), aduncumene, hostmaniane
and gaudichaudanic acid, respectively, as major secondary metabolites.122 The fungitoxic activity
of these compounds was reported against Cladosporium cladosporioides and Cladosporium
sphaerospermum.
ISSN 1424-6376
Page 132
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
O
OH
OH
O
OH
Figure 9. Structure of crassinervic acid
Three new phenolic compounds were isolated from the leaves of Baseonema acuminatum
P. Choux (Asclepiadaceae).123 The compounds showed antifungal activity against two clinically
isolated Candida albicans strains with IC50 values in the range of 25-100 µg/ml. Four phenolic
acid derivatives were isolated from an ethyl acetate extract of the root bark of Lycium chinense
Miller (Solanaceae).124 All had antifungal effect and impeded the dimorphic transition of the
pathogen Candida albicans.
Examples of other antifungal simple phenolic acid derivatives from medicinal herbs also
included two phenolic compounds from Pulicaria odora L. (Asteraceae),125 those isolated from
Croton hutchinsonianus Hosseus (Euphorbiaceae),126 and pinosylvin, a constituent of pine, P.
pinaster (Pinaceae), with growth-inhibitory activity against Candida albicans and
Saccharomyces cerevisiae.127
In the flavonoid group, reports on antifungal compounds from natural sources mainly
concern those isolated from species of the Fabaceae and Moraceae families. Some of these
flavonoids were isolated by bioassay-guided fractionation, after previously detecting antifungal
activity on the part of the plant.
The crude methanol extract of Zuccagnia punctata Cav. (Fabaceae) was active against the
fungal pathogens of soybean Phomopsis longicolla and Colletotrichum truncatum.128 Assayguided fractionation led to the isolation of two chalcones and one flavanone as the compounds
responsible for the antifungal activity. The 95% ethanol extract of the bark of Swartzia
polyphylla D.C. (Fabaceae) possesses important antimycobacterial and antifungal activities in
vitro.129 Bioassay-guided studies performed on the crude extract afforded the flavonoids
biochanin A and dihydrobiochanin A as antifungal constituents. Examples of another antifungal
flavonoid from the Fabaceae family also included a novel biologically active flavonol glycoside
from the ethanol extract of the stems of Teramnus labialis (L.) Spreng.130
The antifungal activity of a series of prenylated flavonoids which were purified from five
different medicinal plants from the Moraceae family was evaluated by determination of IC50
using the broth microdilution method against two fungal microorganisms (Candida albicans and
Saccharomyces cerevisiae).131 These results support the use of prenylated flavonoids in Asian
traditional medicine to treat fungal infections. Antifungal activity-guided fractionation of the nbutanol extract of the leaves of A. nobilis (Moraceae) furnished several flavonoids which showed
ISSN 1424-6376
Page 133
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
good fungicidal activity against Cladosporium cladosporioides,132 while Cudrania fruticosa
(Roxburgh) Corner (Moraceae) yielded a new isoprenylated xanthone, cudrafrutixanthone, which
showed antifungal activity against Candida albicans.133
OH
HO
O
OH
OH
OH
O
Figure 10. Structure of luteolin
Reports on the antifungal activity of flavonoids of several medicinal plants belonging to
other botanical families have also been found in the literature. The leaves of Blumea balsamifera
(L.) (D.C.) (Asteraceae) afforded the flavonoid luteolin (Figure 10).134 Antifungal tests indicated
that luteolin had moderate activity against the fungi Aspergillus niger, Trichophyton
mentagrophytes and Candida albicans. The flavonoids trifolin and hyperoside (Figure 11)
isolated from Camptotheca acuminata Decne (Nyssaceae) effectively control fungal pathogens
in vitro, including Alternaria alternata, Epicoccum nigrum, Pestalotia guepinii, Drechslera spp.
and Fusarium avenaceum.135
OH
HO
O
OH
OGalac
OH
O
Figure 11. Structure of hyperoside
Examples of other antifungal flavonoids from medicinal species also included those
isolated from the stem bark of Erythrina burtii Ball. (Leguminoseae),136 and the main flavonoid
4’-methoxy-5,7-dihydroxyflavone 6-C-glucoside (isocytisoside) from the leaves and stems of
Aquilegia vulgaris L. (Ranunculaceae), which showed activity against the mould Aspergillus
niger.137
In addition to simple phenolic derivatives and flavonoids, studies into other antifungal
phenolic compounds from natural sources also included coumarins and anthraquinones. Some of
ISSN 1424-6376
Page 134
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
these compounds were isolated by bioassay-guided fractionation, after previously detecting
antifungal activity on the part of the plant.
In the continuous search for antifungal compounds from plants, the hydroxycoumarin
scopoletin (Figure 12) was isolated from seed kernels of Melia azedarach L. (Meliaceae).138
Guided-fractionation using Fusarium verticillioides as test organisms led to the isolation of
scopoletin, which had a IC50 value of 1.5 mg/ml in the microbroth dilution method. The
methanol extract of the aerial parts of the shrub Mutisia friesiana Cabrera (Asteraceae) afforded
two new 5-methylcoumarins, mutisicoumarones C and D.139 The compounds showed antifungal
effect against the phytopathogenic fungus Cladosporium cucumerinum.
CH3O
O
HO
O
Figure 12. Structure of scopoletin
Tithoniamarin is a new isocoumarin dimer isolated from Tithonia diversifolia (Hemsl)
Gray (Asteraceae).140 Preliminary studies showed that tithoniamarin has antifungal and
herbicidal activities against Microbotryum violaceum and Chlorella fusca. Deng and
Nicholson141 reported the antifungal properties of surangin B, a coumarin from Mammea
longifolia (Wight ex Wall.) Planch. & Triana (Guttiferae). As an inhibitor of mycelial growth,
surangin B showed the strongest activity against Rhizoctonia solani (IC50 of 3,8 µM) and
Botrytis cinerea (IC50 of 11.2 µM). Inhibitory effects was less pronounced in Alternaria dauci
and Fusarium oxysporum (IC50 values > of 30 µM) and absent in Trichoderma harzianum.
In the anthraquinone group, there are only a few reports concerning their antifungal
activity. Manojlovic et al.142 reported the antifungal activity of the methanol extracts and the
major anthraquinone aglycones, alizarin and emodin (Figure 13), of Rubia tinctorum L.
(Rubiaceae) and Rhamnus frangula L. (Rhamnaceae).
OH
O
HO
OH
CH 3
O
Figure 13. Structure of emodin
The fungicidal activities of Cassia tora L. (Leguminoseae) and its active principles were
determined against Botrytis cinerea, Erysiphe graminis, Phytophora infestans, Puccinia
recondita, Pyricularia grisea and Rhizoctonia solani.143 Emodin (Figure 13), physcion and rhein
ISSN 1424-6376
Page 135
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
(Figure 14) were isolated from the chloroform extract and showed strong fungicidal activity
against the microorganisms tested. Furthermore, aloe-emodin showed strong and moderate
fungicidal activity against Botrytis cinerea and Phytophthora infestans, respectively. Examples
of other antifungal anthraquinones from medicinal species also included a new 1,3-dihydroxy-2methyl-5,6-dimethoxyanthraquinone from the roots of Prismatomeris fragrans Wall
(Rubiaceae).144
OH
O
OH
COOH
O
Figure 14. Structure of rhein
6. Alkaloids
Reports of antifungal alkaloids from medicinal species have also been found in the literature.
Some of these plants have been reported to be used in folk medicine as anti-infectious agents.
O
O
N
+
CH3O
CH3O
Figure 15. Structure of berberine
Bioassay-guided fractionation of the hexane/ethyl acetate/water crude extract of the aerial
parts of Haplophyllum sieversii Lincz et Wed. (Rutaceae) was performed after preliminary
screening data indicated the presence of growth-inhibitory compounds against Colletotrichum
fragariae, Colletotrichum gloeosporioides and Colletotrichum acutatum.145 Fractionation
resulted in the isolation of the bioactive alkaloids, flindersine, anhydroevoxine and haplamine.
Of them, flindersine and haplamine demonstrated the highest level of antifungal activity. The
crude extract of Mahonia aquifolium (Pursh) Nutt. (Berberidaceae) stem bark and its two main
ISSN 1424-6376
Page 136
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
protoberberine alkaloids, berberine (Figure 15) and jatorrhizine, were tested for their in vitro
antifungal activity.146 Twenty strains of Candida spp. isolated from chronic vulvovaginal
candidoses were tested for their susceptibility to crude extracts and two isolated alkaloids. The
results indicate a rational basis for the traditional use of M. aquifolium for localised skin and
mucosal infection therapy, as well as for the possible development of a preparation for
supportive therapy of these diseases.
A novel alkaloid, 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1-methylethyl pentanoate
was isolated from the plant Datura metel L. (Solanaceae).147 The in vitro activity of this
dihydropyrrole derivative against Aspergillus and Candida species was evaluated. The
compound was found to be active against all the species tested, namely Candida albicans,
Candida tropicalis, Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. Activityguided fractionation of an Aniba panurensis (Meissn) Mez (Lauraceae) organic extract has led to
the isolation of the novel alkaloid, 6,8-didec-(1Z)-enyl-5,7-dimethyl-2,3-dihydro-1Hindolizinium.148 Bioassays performed in vitro demonstrated the toxicity of this alkaloid to a drugresistant strain of Candida albicans.
Examples of other antifungal alkaloids from medicinal species also included a β-carboline, a tryptamine- and two phenylethylamine-derived alkaloids from the aerial parts and roots of
Cyathobasis fruticulosa (Bunge) Aellen (Chenopodiaceae),149 and haloxylines A and B, new
piperidine alkaloids from the chloroform extract of Haloxylon salicornium L. (Chenopodiaceae),
which displayed antifungal potentials.150
7. Peptides and proteins
In the last years, reports on the antifungal activity of peptides and proteins isolated from
medicinal plants have mainly concerned species of the Fabaceae family. From the seeds of
haricot beans, Phaseolus vulgaris L. (Fabaceae), Wong and Ng151 purified an antifungal peptide.
This peptide, named vulgarinin, displayed antifungal activity toward fungal species such as
Fusarium oxysporum, Mycosphaerella arachidicola, Physalospora piricola and Botrytis cinerea.
From another Phaseolus species, mung bean (Phaseolus mungo L.) seeds, a chitinase with
antifungal activity was isolated.152 This protein exerted antifungal action toward Fusarium
solani, Fusarium oxysporum, Mycosphaerella arachidicola, Pythium aphanidermatum and
Sclerotium rolfsii. This species also yielded a novel lysozyme exhibiting antifungal activity
toward Botrytis cinerea.153 Another Fabaceae species, Trigonella foenum-graecum L., yielded
defensins, small cysteine rich peptides, which exhibited antifungal activity against the broad host
range fungus Rhizoctonia solani and the peanut leaf spot fungus Phaeoisariopsis personata.154
Reports on the antifungal activity of peptides and proteins isolated from medicinal plants
belonging to other botanical families have also been found in the literature. An antifungal
protein, AFP-J, was purified from potato tubers, Solanum tuberosum cv L. Jopung
(Solanaceae).155 AFP-J strongly inhibited yeast fungal strains, including Candida albicans,
ISSN 1424-6376
Page 137
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
Trichosporon beigelii and Saccharomyces cerevisiae, whereas it exhibited no activity against
crop fungal pathogens. Taira et al.156 purified three proteins, designated pineapple leaf chitinaseA, -B and –C, from the leaves of pineapple, Ananas comosus L. (Bromeliaceae). Pineapple leaf
chitinase-B exhibits strong antifungal activity toward Trichoderma virida, but the others do not.
Another chitinase with antifungal activity was also purified from the bulbs of the plant
Urginea indica L. (Liliaceae), known as Indian squill.157 The protein was an active growth
inhibitor of the fungal pathogens Fusarium oxysporum and Rhizoctonia solani in an in vitro
assay. A novel protein was isolated from the Chinese herb Astragalus mongholicus Bunge
(Leguminoseae).158 It exerted antifungal activity against Botrytis cinerea, Fusarium oxysporum,
Colletotrichum spp. and Drechslera turcia, but not against Rhizoctonia solani and
Mycosphaerella arachidicola.
Examples of other antifungal peptides and proteins from medicinal species also included
two chitin-binding proteins from spindle tree Evonymus europaeus L. (Celastraceae),159 a
thaumatin-like protein from banana Musa acuminata Colla (Musaceae),160 and a protein from
ginger rhizomes Zingiber officinalis L. (Zingiberaceae), which exerted antifungal activity toward
various fungi, including Botrytis cinerea, Fusarium oxysporum, Mycosphaerella arachidicola
and Physalospora piricola.161
Acknowledgements
The technical assistance of Ms. P. Brooke-Turner is gratefully acknowledged.
References
1.
2.
3.
4.
5.
6.
7.
8.
Bergeron, C.; Marston, A.; Gauthier, R.; Hostettmann, K. Int. J. Pharmacog. 1996, 34, 233.
Meckes, M.; Villasreal, M. L.; Tortoriello, J.; Berlin, B.; Berlin, E. A. Phytother. Res. 1995,
9, 244.
Verastegui, M. A.; Sanchez, C. A.; Heredia, N. L.; Garcia-Alvarado, J. S. J.
Ethnopharmacol. 1996, 52, 175.
Schmourlo, G.; Mendonca, R. R.; Alviano, C. S.; Costa, S. S. J. Ethnopharmacol. 2005, 96,
563.
Duarte, M. C.; Figueira, G. M.; Sartoratto, A.; Rehder, V. L.; Delarmelina, C. J.
Ethnopharmacol. 2005, 97, 305.
Muschietti, L.; Derita, M.; Sulsen, V.; De Dios, J.; Ferrero, G.; Zacchino, S.; Martino, V. J.
Ethnopharmacol. 2005, 102, 233.
Turchetti, B.; Pinelli, P.; Buzzini, P.; Romani, A.; Heimler, D.; Franconi, F.; Martini, A.
Phytother. Res. 2005, 19, 44.
Tadeg, H.; Mohammed, E.; Asres, K.; Gebre, T. J. Ethnopharmacol. 2005, 100, 168.
ISSN 1424-6376
Page 138
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
ARKIVOC 2007 (vii) 116-145
Lamidi, M.; Digiorgio, C.; Delmas, F.; Favel, A.; Egele, C.; Rondi, M. L.; Ollivier, E.; Uze,
L.; Balansard, G. J. Ethnopharmacol. 2005, 102, 185.
De Boer, H. J.; Kool, A.; Broberg, A.; Mzirov, W. R.; Hedberg, I.; Levenfors, J. J. J.
Ethnopharmacol. 2005, 96, 461.
Zaidi, M. A.; Crow, S. A., Jr. J. Ethnopharmacol. 2005, 96, 331.
Phongpaichit, S.; Subhadhirasakul, S.; Wattanapiromsakul, C. Mycoses 2005, 48, 333.
Buwa, L. V.; Van Staden, J. J. Ethnopharmacol. 2006, 103, 139.
Mothana, R. A.; Lindequist, V. J. Ethnopharmacol. 2005, 96, 177.
Hymete, A.; Iversen, T. H.; Rohloff, J.; Erko, B. Phytomedicine 2005, 12, 675.
Stein, A. C.; Sortino, M.; Avancini, C.; Zacchino, S.; Von Poser, G. J. Ethnopharmacol.
2005, 99, 211.
Mares, D.; Romagnoli, C.; Tosi, B.; Andreotti, E.; Chillemi, G.; Poli, F. Mycopathologia
2005, 160, 85.
Loizzo, M. R.; Statti, G. A.; Tundis, R.; Conforti, F.; Bonesi, M.; Autelitano, G.; Houghton,
P. J.; Miljkovic, A.; Menichini, F. Phytother. Res. 2004, 18, 777.
Zhu, X. F.; Zhang, H. X.; Lo, R. Fitoterapia 2005, 76, 108.
Queiroz, E. F.; Ioset, J. R.; Ndjoko, K.; Guntern, A.; Foggin, C. M.; Hostettmann, K.
Phytochem. Anal. 2005, 16, 166.
Rai, M. K.; Varma, A.; Pandev, A. K. Mycoses 2004, 47, 479.
Shams, M.; Shokoohamiri, M. R.; Amirrajab, N.; Moghadasi, B.; Ghajari, A.; Zeini, F.;
Sadeghi, G. Fitoterapia 2006, 77, 321.
Ghahfarakhi, M. S.; Goodarzi, M.; Abvaneh, M. R.; Al Tiraihi, T.; Sevedipovr, G.
Fitoterapia 2004, 75, 645.
Iwalokun, B. A.; Ogunledun, A.; Ogbolu, D. O.; Bamiro, S. B.; Jimi, J. J. Med. Food 2004,
7, 327.
Amin, M.; Kapadnis, B. P. Indian J. Exp. Biol. 2005, 43, 751.
Mihara, R.; Barry, K. M.; Mohammed, C. L.; Mitsunaga, T. J. Chem. Ecol. 2005, 31, 789.
Deepa, M. A.; Narmatha, V.; Basker, S. Fitoterapia 2004, 75, 581.
Cvetnic, Z.; Vladimir, S. Acta Pharm. 2004, 54, 243.
Bafi, N. F.; Arnason, J. T.; Baker, J.; Smith, M. L. Phytomedicine 2005, 12, 370.
Taguchi, Y.; Ishibashi, H.; Takizawa, T.; Inoue, S.; Yamaguchi, H.; Abe, S. Nippon Ishiukin
Gakkai Zasshi 2005, 46, 27.
Takahashi, T.; Kokubo, R.; Sakaino, M. Lett. Appl. Microbiol. 2004, 39, 60.
Silva, M. R.; Oliveira, J. G., Jr.; Fernández, O. F.; Passos, X. S.; Costa, C. R.; Souza, L. K.;
Lemos, J. A.; Paula, J. R. Mycoses 2005, 48, 172.
Lemos, J. A.; Passos, X. S.; Fernandes, O. F.; Paula, J. R.; Ferri, P. H.; Souza, L. K.; Lemos,
A. A.; Silva, M. R. Mem. Inst. Oswaldo Cruz 2005, 100, 55.
Amanlov, M.; Fazeli, M. R.; Arvin, A.; Amin, H. G.; Farsam, H. Fitoterapia 2004, 75, 768.
Masoko, P.; Picard, J.; Eloff, J. N. J. Ethnopharmacol. 2005, 99, 301.
ISSN 1424-6376
Page 139
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
36. Batawila, K.; Kokov, K.; Koumaglo, K.; Gbeassor, M.; De Foucalt, B.; Bouchet, P.;
Akpagana, K. Fitoterapia 2005, 76, 264.
37. Khattak, S.; Saeed, P.; Ullah, H.; Ahmad, W.; Ahmad, M. Fitoterapia 2005, 76, 254.
38. Wilson, B.; Abraham, G.; Manju, V. S.; Mathew, M.; Vimala, B.; Sundaresan, S.;
Nambisan, B. J. Ethnopharmacol. 2005, 99, 147.
39. Nidiri, E. S.; Babu, C.S. Phytother. Res. 2005, 19, 447.
40. Unver, N.; Irem, G.; Tansel, H. Fitoterapia 2005, 76, 226.
41. Gurgel, L. A.; Sidrim, J. J.; Martins, D. T.; Cechinel, V.; Rao, V. S. J. Ethnopharmacol.
2005, 97, 409.
42. Agrawal, A.; Srivastava, S.; Srivastava, J. N.; Srivasava, M. M. Biomed. Environ Sci. 2004,
17, 359.
43. Torras, M. A.; Faura, C. A.; Schonlau, F.; Rohdewald, P. Phytother. Res. 2005, 19, 647.
44. Lahlou, M.; El Mahi, M.; Hamamouchi, J. Ann. Pharm. Fr. 2002, 60, 410.
45. De Campos, M. P.; Cechinel, V.; Da Silva, R. Z.; Yunes, R. A.; Zacchino, S.; Juarez, S.;
Bella, R. C.; Bella, A. Biol. Pharm. Bull. 2005, 28, 1527.
46. Aljabre, S. H.; Randhawa, M. A.; Akhtar, N.; Alakloby, O. M.; Alqurashi, A. M.; Aldossary,
A. J. Ethnopharmacol. 2005, 101, 116.
47. Favel, A.; Kemertelidze, F.; Benidze, M.; Fallague, K.; Regli, P. Phytother. Res. 2005, 19,
158.
48. Agrawal, A.; Srivastava, S.; Srivastava, M. N. Hindustan Antibiot. Bull. 2003, 45, 1.
49. Agrawal, A.; Srivastava, S.; Srivastava, J. N.; Srivastava, M. M. J. Environ. Biol. 2004, 25,
307.
50. Fenner, R.; Sortino, M.; Rates, S. M.; Dall’Agnol, R.; Ferraz, A.; Bernardi, A. P.; Albring,
D.; Nor, C.; Van Poser, G.; Schapoval, E.; Zacchino, S. Phytomedicine 2005, 12, 236.
51. Rojas, R.; Doroteo, V.; Bustamante, B.; Baver, J.; Lock, O. Fitoterapia 2004, 75, 754.
52. Ahmadu, A.; Haruno, A. K.; Garba, M.; Ehinmida, J. Q.; Sarker, S. D. Fitoterapia 2004, 75,
729.
53. Wordeamauvel, Y.; Abate, G.; Chryssanthon, E. Ethip. Med. J. 2005, 43, 31.
54. Meepagala, K. M.; Sturtz, G.; Wedge, D. E.; Schroder, K. K.; Duke, S. Q. J. Chem. Ecol.
2005, 31, 1567.
55. Kumar, R. S.; Sivakumar, T.; Sunderam, R. S.; Gupta, M.; Mazumdar, N. K.; Gomathi, P.;
Rajeshwar, Y.; Saravanan, S.; Kumar, M. S.; Murugesh, K.; Kumar, K. A. Braz. J. Med.
Biol. Res. 2005, 38, 1015.
56. Taira, T.; Ohdomari, A.; Nakama, N.; Shimoji, M.; Ishihara, M. Biosci. Biotechnol.
Biochem. 2005, 69, 811.
57. Quiroga, E. N.; Samprieto, A. R.; Vattuone, M. A. Lett. Appl. Microbiol. 2004, 39, 7.
58. Tarfa, F. D.; Obodozic, O. O.; Mshelin, E.; Ibrahim, K.; Temple, V. J. Indian J. Exp. Biol.
2004, 42, 326.
59. Giordani, R.; Regli, P.; Kaloustian, J.; Mikail, C.; Abou, L.; Portugal, H. Phytother. Res.
2004, 18, 990.
ISSN 1424-6376
Page 140
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
60. D’Auria, F. D.; Tecca, M.; Strippoli, V.; Salvatore, G.; Battinelli, L.; Mazzanti, G. Med.
Mycol. 2005, 43, 391.
61. Angioni, A.; Barra, A.; Coronco, V.; Dessi, S.; Cabras, P. J. Agric. Food Chem. 2006, 54,
4364.
62. Angioni, A.; Barra, A.; Cereti, E.; Barile, D.; Coisson, J. D.; Arlorio, M.; Dessi, S. ;
Coroneo, V.; Cabras, P. J. Agric. Food Chem. 2004, 52, 3530.
63. Nakamura, C. V.; Ishida, K.; Faccin, L. C.; Filho, B. P.; Cortez, D. A.; Rozental, S.; De
Souza, W.; Ueda, T. Res. Microbiol. 2004, 155, 579.
64. Sachetti, G.; Medici, A.; Maietti, S.; Radice, M.; Muzzoli, M.; Manfredini, S.; Braccioli, E.;
Bruni, R. J. Agric. Food Chem. 2004, 52, 3486.
65. Sonboli, A.; Salehi, P.; Yousefzadi, M. Z. Naturforsch. 2004, 59, 653.
66. Salgueiro, L. R.; Piato, E.; Goncalves, M. J.; Pina, C.; Cavaleiro, C.; Rodrigues, A. G.;
Palmeira, A.; Tavares, C.; Costa, S.; Martinez, J. Planta Med. 2004, 70, 572.
67. Alvarez, P. P.; Bishop, C. D.; Pascual, M. J. Phytochemistry 2001, 57, 99.
68. Kordali, S.; Cakir, A.; Mavi, A.; Kilic, H.; Yildirim, A. J. Agric. Food Chem. 2005, 53,
1408.
69. Govinden, J.; Magan, N.; Gurib, A.; Gauvin, A.; Smadja, J.; Kodja, H. Biol. Pharm. Bull.
2004, 27, 1814.
70. Romagnoli, C.; Bruni, R.; Andreotti, E.; Rai, M. K.; Vicentini, C. B.; Mares, D.
Protoplasma 2005, 225, 57.
71. Cardenas, N. C.; Zavala, M. A.; Aguirre, J. R.; Perez, C.; Perez, S. J. Agric. Food Chem.
2005, 53, 4347.
72. Tundis, R.; Statti, G. A.; Conforti, F.; Bianchi, A.; Agrimonti, C.; Sachetti, G.; Muzzoli, M.;
Ballero, M.; Menichini, F.; Poli, F. Nat. Prod. Res. 2005, 19, 379.
73. Portillo, M. C.; Viramontes, S.; Muñoz, L. N.; Gastelum, M. G.; Nevarez, G. V. J. Food
Prot. 2005, 68, 2713.
74. Viljoen, A. M.; Subramoney, S.; Van Vuuren, S. F.; Baser, K. H.; Demirci, B. J.
Ethnopharmacol. 2005, 96, 271.
75. Lopez, A. G.; Theumer, M. G.; Zygadlo, J. A.; Rubinstein, H. R. Mycopathologica 2004, 58,
343.
76. Sharma, N.; Tripathi, A. World J. Microbiol. Biotechnol. 2006, 22, 587.
77. Al Burtamani, S. K.; Fatope, M. O.; Marwah, R. G.; Onifade, A.K.; Al Saidi, S.H. J.
Ethnopharmacol. 2005, 96, 107.
78. Simic, A.; Sokovic, M.D.; Ristic, M.; Grujic, S.; Vukojevic, J.; Marin, P.D. Phytother. Res.
2004, 18, 713.
79. Wang, S. Y.; Chen, P. F.; Chang, S. T. Bioresour. Technol. 2005, 96, 813.
80. Cheng, S. S.; Wu, C. L.; Chang, H. T.; Kao, Y. T.; Chang, S. T. J. Chem. Ecol. 2004, 30,
1957.
81. Hong, E. J.; Na, K. J.; Choi, I. G.; Choi, K. C.; Jeung, E. B. Biol. Pharm. Bull. 2004, 27,
863.
ISSN 1424-6376
Page 141
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
82. Cavaleiro, C.; Pinto, E.; Goncalves, M. J.; Salgueiro, L. J. Appl. Microbiol. 2006, 100, 1333.
83. Pyun, M. S.; Shin, S. Phytomedicine 2006, 13, 394.
84. Singh, G.; Maurva, S.; Catalan, C.; De Lampasona, M. P. J. Agric. Food Chem. 2004, 52,
3292.
85. Cheng, S. S.; Lin, H. Y.; Chang, S. T. J. Agric. Food Chem. 2005, 53, 614.
86. Maksimovic, Z. A.; Dordevic, S.; Mraovic, M. Fitoterapia 2005, 76, 112.
87. Zhang, Z. Z.; Li, Y. B.; Qi, L.; Wan, X. C. J. Agric. Food Chem. 2006, 54, 3936.
88. Alviano, W. S.; Mendinca, R. R.; Alviano, D. S.; Bizzo, H. R.; Souto, T.; Rodrigues, M. L.;
Bolognese, A. M.; Alviano, C. S.; Souza, M. M. Oral Microbiol. Immunol. 2005, 20, 101.
89. Shin, S.; Lim, S. J. Appl. Microbiol. 2004, 97, 1289.
90. Fernandez, A. M.; Gomez, M. V.; Velasco, A.; Camacho, A. M.; Fernandez, C.; Altarejos, J.
J. Agric. Food Chem. 2004, 52, 6414.
91. Ahmed, A. A.; Bishr, M. M.; El Shanawany, M. A.; Attia, E. Z.; Ross, S. A.; Pare, P. W.
Phytochemistry 2005, 66, 1680.
92. Jasicka, I.; Lipok, J.; Nowakowska, E. M.; Wieczorek, P. P.; Mylnarz, P.; Kafarsli, P. Z.
Naturforsch. 2004, 59, 791.
93. Portillo, A.; Vila, R.; Freixa, B.; Ferro, E.; Parello, T.; Casanova, J.; Cañigeral, S. J.
Ethnopharmacol. 2005, 97, 49.
94. Scher, J. M.; Speakman, J. B.; Zapp, J.; Becker, H. Phytochemistry 2004, 65, 2583.
95. Fujita, K.; Kubo, I. J. Agric. Food Chem. 2005, 53, 5187.
96. Barrero, A. F.; Quilez, J. F.; Lara, A.; Herrador, M. M. Planta Med. 2005, 71, 67.
97. Yokose, T.; Katamoto, K.; Park, S.; Matsuura, H.; Yoshihara, T. Biosci. Biotechnol.
Biochem. 2004, 68, 2640.
98. Barrero, A. F.; Oltra, J. E.; Alvarez, M.; Raslan, D. S.; Saude, D. A.; Akssira, M.
Fitoterapia 2000, 71, 60.
99. Skaltsa, H.; Lazari, D.; Panagouleas, C.; Georgiadov, E.; Garcia, B.; Sokovic, M.
Phytochemistry 2000, 55, 903.
100. Meng, J. C.; Hu, Y. F.; Chen, J. H.; Tan, R. X. Phytochemistry 2001, 58, 1141.
101. Lavault, M.; Landreau, A.; Larcher, G.; Bouchara, J. P.; Pagniez, F.; Le Pape, P.;
Richomme, P. Fitoterapia 2005, 76, 363.
102. Cavin, A. L.; Hay, A. E.; Marston, A.; Stoeckli, H.; Scopelliti, R.; Diallo, D.; Hostettmann,
K. J. Nat. Prod. 2006, 69, 768.
103. Marthanda, M.; Subramanyan, M.; Hima, M.; Annapurna, J. Fitoterapia 2005, 76, 336.
104. Adou, E.; Williams, R. B.; Schilling, J. K.; Malone, S.; Meyer, J.; Wisse, J. H.; Frederik, D.;
Koere, D.; Werkhoven, M. C.; Snipes, C. E.; Werk, T. L.; Kingston, D. G. Bioorg. Med.
Chem. 2005, 13, 6009.
105. Thongnest, S.; Mahidol, C.; Sutthivaivakit, S.; Ruchirawat, S. J. Nat. Prod. 2005, 68, 1632.
106. Abdelgaleil, S. A.; Hashinaga, F.; Nakatani, M. Pest Manag. Sci. 2005, 61, 186.
107. Becker, H.; Scher, J. M.; Speakman, J. B.; Zapp, J. Fitoterapia 2005, 76, 580.
108. Luo, D. Q.; Wang, H.; Tian, X.; Shao, N. J.; Liu, J. K. Pest Manag. Sci. 2005, 61, 85.
ISSN 1424-6376
Page 142
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
109. Tostao, Z.; Nonoha, J. P.; Cabrita, E. J.; Medeiros, J.; Justino, J.; Bermejo, J.; Rauter, A. P.
Fitoterapia 2005, 76, 173.
110. Renault, S.; De Lucca, A. J.; Bove, S.; Bland, J. M.; Vigo, C. B.; Selitremikoff, C. P. Med.
Mycol. 2003, 4, 75.
111. Gonzalez, M.; Zamilpa, A.; Marquina, S.; Navarro, V.; Alvarez, L. J. Nat. Prod. 2004, 67,
938.
112. Zamilpa, A.; Tortoriello, J.; Navarro, V.; Delgado, G.; Alvarez, L. J. Nat. Prod. 2002, 65,
1815.
113. Du, Z.; Zhu, N.; Ze, N.; Shen, Y. Planta Med. 2003, 69, 547.
114. Plaza, A.; Cinco, M.; Tubaro, A.; Pizza, C.; Piacente, S. J. Nat. Prod. 2003, 66, 1606.
115. Sauton, M.; Mitaine, A. C.; Miyamoto, T.; Dongmo, A.; Lacaille, M. A. Planta Med. 2004,
70, 90.
116. Sauton, M.; Mitaine, A. C.; Miyamoto, T.; Dongmo, A.; Lacaille, M. A. Chem. Pharm. Bull.
2004, 52, 1353.
117. Sauton, M.; Miyamoto, T.; Lacaille, M. A. J. Nat. Prod. 2005, 68, 1489.
118. Pistelli, L.; Bertoli, A.; Lepori, E.; Morelli, I.; Panizzi, L. Fitoterapia 2002, 73, 336.
119. Mandal, P.; Sinha, S. P.; Mandal, N. C. Fitoterapia 2005, 76, 462.
120. Mel’nichenko, E. G.; Kirsanova, M. A.; Grishkovets, V. I.; Tysh, L. V.; Krivorutchenko, I.
L. Mikrobiol. Z. 2003, 65, 8.
121. Javasinghe, V. L.; Puvanendran, S.; Hara, N.; Fujimoto, Y. Nat. Prod. Res. 2004, 18, 571.
122. Lago, J. H.; Ramos, C. S.; Casanova, D. C.; Morandim, A. A.; Bergamo, D. C.; Cavalheiro,
A. J.; Bolzani, V. S.; Furlan, M.; Guimaraes, E. F.; Young, M. C.; Kato, M. J. J. Nat. Prod.
2004, 67, 783.
123. De Leo, M.; Braca, A.; De Tomasi, N.; Norscia, I.; Morelli, I.; Battinelli, L.; Mazzanti, G.
Planta Med. 2004, 70, 841.
124. Lee, D. G.; Park, Y.; Kim, M. R.; Jung, H. J.; Seu, Y. B.; Hahm, K. S.; Woo, E. R.
Biotechnol. Lett. 2004, 26, 1125.
125. Ezoubeiri, A.; Gadhi, C. A.; Edil, N.; Benharref, A.; Jana, M.; Vanhaelen, M. J.
Ethnopharmacol. 2005, 99, 287.
126. Athikomkulchal, S.; Prawat, H.; Thasana, N.; Ruangrungsi, N.; Ruchirawat, S. Chem.
Pharm. Bull. 2006, 54, 262.
127. Lee, S. K.; Lee, H. J.; Min, H. Y.; Park, E. J.; Lee, K. M.; Ahn, Y. H.; Cho, Y. J.; Pyee, J. H.
Fitoterapia 2005, 76, 258.
128. Svetaz, L.; Tapia, A.; Lopez, S. N.; Furlan, R. L.; Petenatti, E.; Pioli, R.; Schmeda, G.;
Zacchino, S. A. J. Agric. Food Chem. 2004, 52, 3297.
129. Rojas, R.; Bustamante, B.; Ventosilla, P.; Fernandez, I.; Caviedes, L.; Gilman, R. M.; Lock,
O.; Hammond, G. B. Chem. Pharm. Bull. 2006, 54, 278.
130. Yadava, R. N.; Jain, S. Nat. Prod. Res. 2004, 18, 537.
131. Sohn, H. Y.; Son, K. H.; Kwon, C. S.; Kwon, G. S.; Kang, S. S. Phytomedicine 2004, 11,
666.
ISSN 1424-6376
Page 143
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
132. Jayasinghe, L.; Balasooriva, B. A.; Padmini, W. C.; Hara, N.; Fujimoto, Y. Phytochemistry
2004, 65, 1287.
133. Wang, Y. H.; Hou, A. J.; Zhu, G. F.; Chen, D. F.; Sun, H. D. Planta Med. 2005, 71, 273.
134. Ragasa, C. Y.; Co, A. L.; Rideout, J. A. Nat. Prod. Res. 2005, 19, 231.
135. Li, S.; Zhang, Z.; Cain, A.; Wang, B.; Long, M.; Taylor, J. J. Agric. Food Chem. 2005, 53,
32.
136. Yenesew, A.; Derese, S.; Midiwo, J. O.; Bii, C. C.; Heydenreich, M.; Peter, M. G.
Fitoterapia 2005, 76, 469.
137. Bylka, W.; Szaufer, M.; Matlawska, J.; Goslinska, O. Lett. Appl. Microbiol. 2004, 39, 93.
138. Carpinella, M. C.; Ferravoli, C. G.; Palacios, S. M. J. Agric. Food Chem. 2005, 53, 2922.
139. Viturro, C. F.; De la Fuente, J. R.; Maier, M. S. J. Nat. Prod. 2004, 67, 778.
140. Yemele, M.; Krohn, K.; Hussain, H.; Dongo, E.; Schulz, B.; Hu, Q. Nat. Prod. Res. 2006,
20, 842.
141. Deng, Y.; Nicholson, R. A. Planta Med. 2005, 71, 364.
142. Manojlovic, N. T.; Solujic, S.; Sukdolak, S.; Milosev, M. Fitoterapia 2005, 76, 244.
143. Kim, Y. M.; Lee, C. H.; Kim, H. G.; Lee, H. S. J. Agric. Food. Chem. 2004, 52, 6096.
144. Kanokmedhakul, K.; Kanokmedhakul, S.; Phatchana, R. J. Ethnopharmacol. 2005, 100,
284.
145. Cantrell, C. L.; Schrader, K. K.; Mamonov, L. K.; Sitpaeva, G. T.; Kustova, T. S.; Dunbar,
C.; Wedge, D. E. J. Agric. Food Chem. 2005, 53, 7741.
146. Slobodnikova, L.; Kost’alova, D.; Labudova, D.; Kotulova, D.; Kettmann, V. Phytother.
Res. 2004, 18, 674.
147. Dabur, R.; Chhillar, A. K.; Yadav, V.; Kamal, P. K.; Gupta, J.; Sharma, G. L. J. Med.
Microbiol. 2005, 54, 549.
148. Klausmeyer, P.; Chmurny, G. N.; McCloud, T. G.; Tucker, K. D.; Schoemaker, R. H. J. Nat.
Prod. 2004, 67, 1732.
149. Bahceeuli, A. K.; Kurnan, S.; Kolak, U.; Topcu, G.; Adou, E.; Kingston, D. G. J. Nat. Prod.
2005, 68, 956.
150. Ferheen, S.; Ahmed, E.; Afza, N.; Malik, A.; Shah, M. R.; Nawaz, S. A.; Choudhary, M. I.
Chem. Pharm. Bull. 2005, 53, 570.
151. Wong, J. H.; Ng, T. B. Int. J. Biochem. Cell Biol. 2005, 37, 1626.
152. Wang, S.; Wu, J.; Rao, P.; Ng, T. B.; Ye, X. Protein Expr. Purif. 2005, 40, 230.
153. Wang, S.; Ng, T. B.; Chen, T.; Lin, D.; Wu, J.; Rao, P.; Ye, X. Biochem. Biophys. Res.
Commun. 2005, 327, 820.
154. Olli, S.; Kirti, P. B. J. Biochem. Mol. Biol. 2006, 39, 278.
155. Park, Y.; Choi, B. H.; Kwak, J. S.; Kang, C. W.; Lim, H. T.; Cheong, H. S.; Hahm, K. S. J.
Agric. Food Chem. 2005, 53, 6491.
156. Taira, T.; Toma, N.; Ishihara, M. Biosci. Biotechnol. Biochem. 2005, 69, 189.
157. Shenoy, S. R.; Kameshwari, M. N.; Swaminathan, S.; Gupta, M. N. Biotechnol. Prog. 2006,
22, 631.
ISSN 1424-6376
Page 144
©
ARKAT
Issue in Honor of Prof. Atta-ur-Rahman
ARKIVOC 2007 (vii) 116-145
158. Yan, Q.; Jiang, Z.; Yang, S.; Deng, W.; Han, L. Arch. Biochem. Biophys. 2005, 442, 72.
159. Vanden Bergh, K. P.; Rouge, P.; Proast, P.; Coosemans, J.; Krouglova, T.; Engelborghs, Y.;
Peumans, W. J.; Van Damme, E. J. Planta 2004, 219, 221.
160. Leone, P.; Menu, L.; Peumans, W. J.; Pavan, F.; Barre, A.; Roussel, A.; Van Damme, E. J.;
Rouge, P. Biochimie 2006, 88, 45.
161. Wang, H.; Ng, T. B. Biochem. Biophys. Res. Commun. 2005, 336, 100.
ISSN 1424-6376
Page 145
©
ARKAT