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Antifungal Azole Derivatives and their Pharmacological Potential: Prospects &

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Article · October 2014

DOI: 10.2174/221031550402141009100632

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The Natural Products Journal, 2014, 4, 000-000 1

Antifungal Azole Derivatives and their Pharmacological Potential:

Prospects & Retrospects

Sardul Singh Sandhu1,*, Harshita Shukla1, Ravindra Prasad Aharwal1, Suneel Kumar1 and
Shyamji Shukla2

1
Fungal Biotechnology and Invertebrate Pathology Laboratory, Department of Biological Sciences, Rani Durgawati
University Jabalpur- 482001, M.P. India; 2Department of Biotechnology, Mata Gujri College (Autonomous), Jabalpur-
482001, M.P. India

Abstract: Despite numerous efforts by researchers the increasing fungal infections are still a major threat to the society.
To combat this dilemma several antifungal drugs have come up through extensive research. Azoles are one of the most
promising antifungal agents of them. They are heterocyclic five membered organic compounds which show activity
against hazardous fungal pathogens. But the growing resistance against azoles in fungal pathogens and side effects
accompanied with the use of synthetic azoles has generated an urgent need to search for natural and eco-friendly azoles.
The present review provides a detailed account about the structure and function of clinically important antifungal azole
derivatives and some patents related to them. This article also gives a brief overview about some naturally derived
antifungal azoles.
Keywords: Azole, antifungal, cytochrome P450, ergosterol, fluconazole, imidazole, ketoconazole, triazole.

INTRODUCTION
There has been a dramatic increase in the prevalence
of serious invasive fungal infections over the past decade
[1]. Up to 5% of the total infections in the world are
caused by fungi. Some of the major factors behind the
increasing incidences of fungal infections include greater
use of broad spectrum antibiotics; indwelling catheters;
immunosuppressive drugs and increase in the number of
individuals suffering from acquired immunodeficiency
syndrome (AIDS) [2]. These infections are mainly caused
by fungi like Candida spp., Cryptococcus neoformans,
Aspergillus spp., Pneumocystis carinii and Histoplasma
capsulatum [3, 4]. Candida species are the fourth most
common cause of nosocomial bloodstream infections in the
United States [5]. For the treatment of such fungal infections
several antifungal drugs have been produced as a result of
advances in medicinal chemistry. Azoles are one of the most
promising antifungal agents out of all [6]. They are the
largest class of synthetic antimycotics used to treat both
superficial dermatophytic as well as systemic fungal
infections [7]. It is approved by FDA for treating candidiasis,
chronic mucocutaneous candidiasis oral thrush, candiduria,
coccidioidomycosis, histoplasmosis, chromomycosis and
paracoccidioidomycosis [8]. The antifungal azoles belong to
two main classes, namely the Imidazoles and the Triazoles
[9]. Although the earliest azole, Chlormidazole was not very
efficient but with gradual improvements over last 50 years,
*Address correspondence to this author at the Fungal Biotechnology and
Invertebrate Pathology Laboratory, Department of Biological Sciences, Rani
Durgawati University Jabalpur- 482001, (M.P.) India; Tel: +91 9424395270;
Fax: +917612608704; E-mail: ssandhu@rediffmail.com
many new and more potent antifungal azole derivatives have
been developed [10]. The azole antifungal agents developed
so far for clinical uses mainly include ketonazole, fluconazole,
voriconazole and itraconazole [11].
History of Antifungal Azoles
The first report of antifungal activity of an azole
compound was described in the 1940s. But the development
of more potent azole antifungal derivatives accelerated in the
late 1950s [12]. Some key events in the development of
azole antifungal agents [13-26] are described in the Table 1.
Chemistry of Azoles
Azoles are heterocyclic five-membered nitrogen
containing organic compounds. In these compounds usually
one non-carbon like nitrogen, sulphur and oxygen is also
present. Numbering of the ring atoms in azoles start with the
heteroatom that is not part of a double bond and then
proceeds towards the other heteroatom. Depending upon the
heteroatom’s present in the ring, azoles are classified into
following compound classes [27] as given in Table 2.
Mechanism of Action of Azoles
Several targets for the antifungal activity of azole
compounds have been revealed by extensive research but its
primary mode of action is inhibition of the ergosterol
biosynthesis in fungal cell [28]. Ergosterol is an essential
sterol component of fungal cell membrane but absent in
animals, hence serves as a major target for treatment of
fungal infections [29]. The azoles kill fungal cells by
inhibiting the enzyme called lanosterol 14α-demethylase.

2210-3155/14 $58.00+.00 © 2014 Bentham Science Publishers

2 The Natural Products Journal, 2014, Vol. 4, No. 2 Sandhu et al.

Table 1. Milestones in the development of azole antifungal agents [13-26].

Year Major Developments References

1944 First antifungal azole “Benzimidazole” reported by Woolley. [13]

1952 Jerchel reported antifungal activity of certain substituted Benzimidazoles. [14]

1958 First azole derivative Chlorimidazole developed and marketed as antifungal drug for topical use. [15,16]

1961 Introduction of Thiabendazole effective against dermatophytes and Aspergillus species. [17]

1969 Introduction of three major azole derivatives as antifungal agents for topical use: Clotrimazole, developed by Bayer [18]
AG (Wuppertal, Federal Republic of Germany), Miconazole and Econazole, developed by Janssen Pharmaceutica.

1973 Mebendazole, a benzoyl-benzimidazole developed by Janssen Pharmaceutica (Beerse, Belgium) was shown to have [19]
antifungal activity.

1979 Miconazole parental formulation introduced in UK for the treatment of systemic candida infections. [20]

1981 Approval of oral formulations of ketoconazole for systemic use developed by Janssen Pharmaceutica. [21]

1990 A broad spectrum triazole Fluconazole developed by Pfizer and approved for systemic use. [22]

1992 Another triazole Itraconazole introduced for systemic mycoses developed by Janssen Pharmaceutica. [23]

1993-1995 Second generation triazoles introduced having potent activity. Voriconazole developed by Pfizer Pharmaceuticals [24, 25]
and Posaconazoles developed by Schering- Plough Research Institute.

1997 Itraconazole oral solution approved. [26]

This enzyme is needed for the production of ergosterol from
a precursor compound called lanosterol [30]. The enzyme
lanosterol 14α-demethylase is dependent on activation of
cytochrome P450. During its action the azole drugs binds to
the heme iron of the cytochrome P450 via one of its nitrogen
atom and forms a stoichiometric complex thereby inhibiting
cytochrome activation and enzyme action [31]. The nitrogen
atoms N-3 in imidazoles and N-4 in triazoles participate in
the complex formation [31]. The formation of this complex
can be measured spectrophotometrically, by the red shift of
the Soret band of the heme from 417 to 447nm [32]. As a
consequence of this inhibition there is a depletion of
ergosterol and accumulation of lanosterol and other 14-
methylated sterols in the plasma membrane of the fungi.
Azole also acts by inhibiting a similar functioning enzyme
24-methylene dihydrolanosterol demethylase in the fungal
cell. These changes results in interference with the functions
of fungal plasma membrane, disruption of its structure and
alteration of the activity of several membrane bound
enzymes for example enzymes associated with nutrient
transport and chitin synthesis [33], thus making it more
vulnerable to further damage [34]. The final result of activity
of azoles is inhibition of growth and proliferation of fungal
cells [35]. Azoles at higher concentrations exhibit fungicidal
activity while at lower concentrations exhibit fungistatic
activity [8, 36]. Fig. (1) clearly depicts the mechanism of
action of azole compounds inside the fungal cell.
Antifungal Azole Derivatives
Two classes of azoles are used for treatment of invasive
fungal infections. These are the Imidazoles and the Triazoles
as shown in Table 3 [26, 27]. These classes of azoles
produce different degree and type of inhibition depending
upon their physiochemical characteristics and pharma-
cokinetics [37, 38].
Some Clinically Important Imidazole Derivatives
Clotrimazole
It is a derivative of 1-methylimidazole with lipophilic
substituents at methyl group. It was the first compound to be
developed as a broad spectrum imidazole based antifungal
agent for topical use [39, 40]. The antifungal activity of
clotrimazole is seen against dermatophytes particularly,
Candida species, Candida immitis, Candida neoformans and
Aspergillus spp. [41]. It is available in cream form and is
used to treat fungal infections like vaginal yeast infections,
ringworm, and athlete’s foot [2]. The oral intake of this
compound as antimycotic is not suitable because it has
inductive effect on microsomal liver enzymes leading to
rapid metabolism and inactivation of active substances [42].
Miconazole
It is an ether group containing phenethyl imidazole class of
antifungal agent [43, 44]. The antifungal activity of miconazole
is narrow spectrum and is effective against dermatophytes,
Candida species, dimorphic fungi, and Pseudallescheria
boydii [45]. It has been used successfully in the treatment of
systemic Candida infections, pseudallescheriasis and some
refractory cases of cryptococcal meningitis [46]. It was the
first azole introduced for parenteral administration but
toxicity associated with the vehicle used for intravenous
administration has limited its parenteral use. As a
Antifungal Azole Derivatives and their Pharmacological Potential The Natural Products Journal, 2014, Vol. 4, No. 2 3

Table 2. Compound classes of Azoles [27].

S. No. Classes Types Structure

4 3
1. One nitrogen containing Pyrrole
5 2
N
H

4 3
2. Two or more nitrogen containing Pyrazole
5 N 2
N
H

4 3
Imidazole N

5
2
N
H
1

H 1
Triazole N

5 N 2

4 N 3

H 1
Tetrazole N
5 N 2

N N 3
4

H 1
Pentazole N
5 N N 2

N N 3
4

3
3. One nitrogen atom and one oxygen atom Oxazole 4
N
containing
5 2
O
1

3
Isoxazole 4

5 N2
O
1

3
4. One nitrogen atom and one sulphur atom Thiazole 4
N
containing
5 2
S
1

3
Isothiazole 4

5 N2
S
1

consequence of the toxic effects produced by miconazole it use has been limited. It is now considered as second line
has recently been withdrawn from the market [47]. drug and has been replaced by more potent antimycotics
called the triazoles [2]. Before the introduction of traizoles,
Ketoconazole ketoconazoles were used for the treatment of chronic
It is a ketal group containing and highly lipophilic mucocutaneous candidiasis [51], less severe blastomycosis
compound [41], possessing fungistatic activity [12]. It was [49], histoplasmosis [49], paracoccidioidomycosis [52] and
developed by Jansen pharmaceutica and approved for coccidioidomycosis [53].
systemic use by Food and drug administration (FDA)
in 1981 [21]. Ketonazole is active against dimorphic Some Clinically Important Triazoles Derivatives
moulds, Histoplasma capsulatum, Blastomyces dermatitidis,
Fluconazole
Coccidioides immitis, Sporothrix schenckii, Paracoccidioides
brasiliensis and Penicillium marneffei [48]. But because of It is a 1, 2, 4-triazole derivative, also known as bis-
the side effects accompanied with its use like incomplete triazole propanol derivative [54]. It was developed by Pfizer
penetration to cerebrospinal fluid, toxicity in the and approved for use in early 1990. As compared to
gastrointestinal tract [49] and drug induced hepatitis [50], its ketoconazoles it is soluble in water and hence, gets easily
4 The Natural Products Journal, 2014, Vol. 4, No. 2
Fig. (1). (a) Ergosterol biosynthesis pathway in normal fungal cell (b) Ergosterol biosynthesis pathway inhibited in azole treated fungal cell.
Table 3. Classes of antifungal azoles [26, 27].
IMIDAZOLES
These contain two nitrogen atoms in the azole ring [27]. Their
use is limited to topical administrations and has been replaced
by triazoles for systemic applications [26]. Their derivatives
commonly used as antifungal agents are:
Clotrimazole, Econazole, Miconazole, Ketoconazole,
Butconazole
absorbed (90% bioavailability) after oral administration [55].
After entering in the body fuconazole distributes throughout
without being influenced by the gastric pH [56] and
penetrates completely into the cerebrospinal fluid [57]. This
favourable pharmacokinetic profile of fluconazole makes it
suitable for oral as well as intravenous administrations [58].
It shows activity against several pathogenic fungi [59]. The
major ones are Candida albicans, Candida tropicalis,
Candida neoformans, Trichosporon beigelii, Epidermophyton
floccosum, Trichophyton mentagrophytes, Pseudallescheria
Boydii and Blastomyces dermatitidis. Fluconazole is approved
for the treatment of oropharyngeal, oesophageal, vaginal,
peritoneal and genito-urinary candida infections, disseminated
candidiasis (including chronic disseminated candidiasis) and
cryptococcal meningitis and coccidioidomycosis. It is a good
alternative to ketoconazole in chronic mucocutaneous
candidiasis [58].
Itraconazole
It is also a 1, 2, 4 triazole derivative which is highly
lipophilic and hence has very less solubility in water [60].
After oral administration its absorption in the body is
influenced by the acidity of the gastric fluid [61]. The
solution form of the itraconazoles shows better bioavailability
Sandhu et al.
TRIAZOLES
These contain three nitrogen atoms in the azole ring [27]. They are advantageous over
imidazoles in terms of having broad spectrum activity against both superficial and
systemic fungal infections and having greater affinity for fungal rather than
mammalian cytochrome P450 enzymes thus reducing the risk factors [26]. Their
derivatives commonly used as antifungal agents are: Fluconazole, itraconazole,
Rosaconazole, Voriconazole, Ravuconazole
as compared to the capsule form. The absorption of
intravenous formulations on the other hand is invariable
[62]. Itraconazoles display excellent activity against various
types of fungi like yeasts, moulds and dimorphic fungi.
Among these are, Candida spp., Cryptococcus neoformans,
Aspergillus spp., Pseudallescheria boydii, Sporothrix
schenckii, Histoplasma capsulatum, Blastomyces dermatitidis,
Coccidioides immitis, Paracoccidioides brasiliensis,
Penicillium marneffei, Trichosporon beigelii, Epidermophyton
floccosum, Microsporum canis, Microsporum gypseum,
Trichphyton mentagrophytes, Trichophyton rubrum,
Trichophyton simii and Trichophyton verrucosum [63-66].
Voriconazole
It is a new triazole derivative which is structurally similar
to fluconazole. It is discovered by Pfizer and is being
developed for oral as well as intravenous administration [67].
As compared to fluconazole it exhibits greater inhibition of
enzyme involved in ergosterol biosynthesis [68], for e.g. 1.6
and 160 fold greater inhibition is seen in case of Candida
albicans and Aspergillus fumigatus respectively [69]. The
pharmacokinetic studies revealed its bioavailability to be
about 60% or greater [70]. It displays antifungal activity against
several pathogenic fungi like Cryptococcus neoformans
Antifungal Azole Derivatives and their Pharmacological Potential The Natural Products Journal, 2014, Vol. 4, No. 2 5

Table 4. Some of the commonly used synthetic azole containing anti-fungal drugs [79].

Generic Name Trade Name(s) Chemical Structure Clinical Uses

Ketoconazole Nizoral COCH3 Systemic fungal infections,

Fungarol N including blastomycosis,
Orifungal N certain forms of
coccidioidomycosis and
histoplasmosis, chronic
mucocutaneous candidiasis,
chromoblastomycosis and
O para-coccidioidomycosis
OCl

Cl N

Bifonazole Mycosporan Superficial fungal infections,

Mycospor including dermatomycoses,
tinea versicolor and cutaneous
CH candidiasis.
N

Econazole Spectazole Cl Superficial fungal infections,

Pevaryl Cl including dermatomycoses,
OCH2 tinea versicolor, cutaneous and
vaginal candidiasis.
Cl HNO3
N

Miconazole Monistat Monistat- Cl Cl Systemic fungal infections,

Derm Cl CH2 including coccidioidomycosis,
Monistat IV O candidiasis, cryptococcosis
and chronic mucocutaneous
Cl candidiasis.

N
Clotrimazole Canesten Mycelex Superficial fungal infections,
Lotrimin including dermatomycoses,
Cl
tinea versicolor, cutaneous and
C vaginal candidiasis.
N

Cl
Butoconazole Femstat Vaginal candidiasis.

Cl
Cl CH2CHCH2CH2 HNO3

Cl

Croconazole Pilzcin Cl Superficial fungal infections,

including dermatomycoses,
O C tinea versicolor and cutaneous
H2 candidiasis.
CH2

N HCl
N
6 The Natural Products Journal, 2014, Vol. 4, No. 2 Sandhu et al.

Table 4. contd….

Generic Name Trade Name(s) Chemical Structure Clinical Uses

Isoconazole Travogen Cl Cl Superficial fungal infections,

Gyne H including dermatomycoses,
Travogen Cl C O tinea versicolor, cutaneous and
CH vaginal candidiasis.
CH2 2
N Cl

N
Fenticonazole Lomexin HCH2 Superficial fungal infections,
Cl C N including dermatomycoses,
O N tinea versicolor and cutaneous
Cl
CH2
and vaginal candidiasis.
HNO3

Oxiconazole Oceral N Superficial fungal infections,

Myfungar including dermatomycoses,
Gyno- Myfungar N tinea versicolor, cutaneous and
Okinazole vaginal candidiasis.
CH2 Cl
Derimine
Cl C CH2
O Cl
N
Cl
HNO3
Tioconazole Trosyd Cl Cl Superficial fungal infections,
Gyne- including dermatomycoses,
Trosyd H tinea versicolor, cutaneous and
Cl C O S
CH2 vaginal candidiasis.
CH2
N

Sulconazole Sulcosyn Superficial fungal infections,

H
Exelderm Cl C C N including dermatomycoses,
H2 tinea versicolor and cutaneous
S CH2 N candidiasis.
Cl

Cl

Itraconazole Sporanox N Systematic and superficial

mycoses.
N

Cl
N
CH3

H 2CH 2CH 2C O O CH3

N Cl

N N N OCH 2 O

N H

Fluconazole Diflucan OH Systematic and superficial

N N
N C C C N mycoses.
H2 H2
N F N

F
Antifungal Azole Derivatives and their Pharmacological Potential
[71, 72]; dimorphic fungi such as Blastomyces dermatitidis,
Coccidioides immitis and Histoplasma capsulatum [73];
Candida spp. [74, 75]; Aspergillus spp. [76, 77]. The most
important advantage of voriconazole is that it shows
excellent activity against such pathogenic fungi which have
developed resistance against fluconazole and itraconazole
like Candida krusei and Candida glabrata [76]. Data from
clinical trials indicates that voriconazole is a promising agent
for the treatment of invasive fungal infections [78]. The
imidazole and triazole derivatives therefore, possess
significant activity against a variety of pathogenic fungi and
are being used in several antifungal drug formulations [79]
as shown in Table 4.
Emerging Resistance to Azoles
Development of resistance against azole containing drugs
has been one of the major causes for the increasing
incidences of fungal infections in recent years. The repeated
use of azole containing drugs for treatment of fungal
infections has resulted in the development of resistance
towards them in infectious fungal strains [80]. Mostly the
azole resistant fungal strains have been witnessed in the
immunocompromised patients such as those infected with
HIV [35, 81-83]. About one third of the AIDS patients are
found to harbor fluconazole resistant C. albicans in their oral
cavities [84]. On the other hand such resistant strains are
uncommon in patients suffering from other diseases like
vaginal candidiasis [80] and candidema [83]. This implies
that the immune system of the host is related to the action of
azoles [85]. However the rate of resistance varies from
species to species, for e.g. in Candida albicans it is 1.0%-
2.1% whereas in Candida parapsilosis and Candida
tropicalis it is 1.4%–6.6% and 0.4%–4.2% respectively [86,
87]. Beside various species of Candida the incidence of
azole resistance have been observed in Aspergillus isolates
particularly Aspergillus fumigatus which have developed
resistance to fluconazole and itraconazole intrinsically [88-
90].
Mechanism of Development of Azole Resistance
There are several mechanisms through which fungal
pathogens develop resistance against azole antifungal agents
[35, 81, 82, 85, 91-93]. The major mechanisms involved are
as follows:
Alteration in the Drug Target Interaction
In this type of mechanism there occurs a change in the
interaction between the target enzyme and the antifungal
azole compound. This change is due to the mutations in the
gene coding for the enzyme 14α-demethylase or cytochrome
P450. One such mutation is seen in an azole-resistant
Candida albicans strain (NCPF 3363) isolated from a patient
with chronic mucocutaneous candidosis [94]. The
cytochrome P450 of this strain showed low affinity for azole
antifungal compounds because it contained a Y132H
mutation (replacement of tyrosine with histidine at amino
acid 132) on both of its CYP51 alleles [95]. Such alterations
in fluconazole resistant Candida albicans isolates have also
been demonstrated by several researchers [96-98]. Another
example of such mutation is that which occurs in the
The Natural Products Journal, 2014, Vol. 4, No. 2 7
gene ERG 11 coding for the target enzyme lanosterol C14α-
demethylase, and prevents it from binding to the azoles
[99].
Changes in the Ergosterol Biosynthesis Pathway
Through this mechanism the fungi achieve resistance by
preventing the formation of toxic products which are usually
formed after the azole inhibition of ergosterol synthesis. This
toxic product, 14α-methyl-3,6-diol is formed from precursor
sterol, 14α-methylfecosterol and arrests the growth of non
resistant fungi. In resistant fungi there occurs a mutation in
the ERG3 gene which inhibits the formation of this
toxic product and leads to accumulation of its precursor
sterol 14α-methylfecosterol [100]. This sterol replaces the
ergosterol in fungal cell membrane and converts it into
functional membrane thus nullifying the effect of azole drug
and protecting the fungi [101]. Such resistance is witnessed
in Candida albicans isolates [100].
Inhibition of Drug Accumulation
This is one of the most important resistance mechanisms
found in several fungal isolates like Candida glabrata [92,
93, 102], C. neoformans [103], Aspergillus flavus and
Aspergillus fumigatus [104], Candida albicans [105-107]
and Candida krusei [108]. In this mechanism the resistant
fungal isolates fail to accumulate azole antifungal agents due
to the enhanced drug efflux. There are many efflux pumps in
fungi which are made up of membrane transporter proteins.
It has been identified that when the genes encoding for these
transporter proteins are over expressed it results in the
enhanced activity of efflux pumps, leading to the low level
accumulation of drug inside the fungal cell, thus making
them resistant to the action of drugs. For example the over
expression of CDR1 and CDR2 genes encoding for the
ABC-type transporters confers resistance to Sachromyces
cerevisiae against antifungal azoles like fluconazole,
ketoconazole, itraconazole, terbinafine and amorolfine [82,
96, 107, 109, 110]. Such mechanism is also demonstrated in
fluconazole-resistant Candida albicans isolates where low
level of accumulation of fluconazole occurs due to
overexpression of CaMDR1 gene, encoding for MFS-type
transporters leading to low level of accumulation of
fluconazole inside the fungal cell [107].
Although there is an increasing resistance among
fungal pathogens against the azole antifungals but still the
new generation azoles possess promising activity against
these resistant strains and act as broad spectrum antifungal
drugs.
Side Effects of Antifungal Azoles
Azoles are definitely efficient antifungal therapy but like
every coin has two sides it has some harmful effects too.
Ketoconazole are more toxic as compared to other azoles
[111]. The most common adverse effects encountered with
azoles are:
• Nausea and vomiting.
• Headache and abdominal pain.
• Skin infections.
8 The Natural Products Journal, 2014, Vol. 4, No. 2 Sandhu et al.

• Transient elevations in serum liver enzymes, noted
occasionally.
• Gastrointestinal disturbances and pruiritus.
• Liver toxicity (rarely hepatitis).
• Inhibition of adrenocortical steroid and testosterone
synthesis, thus resulting in gynecomastia in some male
patients.
Antifungal Azoles from Natural Sources
The emerging fungal pathogens with azole resistance and
the side effects accompanied with the synthetic azoles have
stressed upon the need to search for new azole compounds
having antifungal activity. Natural products have always
played a remarkable role in drug discovery [112]. Over past
75 years natural product derived compounds are being used
for treating numerous diseases [113]. As a result of
technological advancements in the field of medicine about 1
million natural biologically active compounds have been
discovered out of which 22,500 are obtained from microbes
[114]. A large number of natural products, in particular from
the marine environment contain triazoles, imidazoles,
thiazole, oxazole, thiazolines or oxazolines heterocycles
which shows promising bioactivities. Table 5 contains some
naturally derived antifungal azole [115-121] containing
compounds.

Table 5. Antifungal azoles derived from natural sources [115-121].

S. No. Natural Sources Compound References

1. Indonesian marine sponge Leucetta chagosensis. Imidazole alkaloid Naamine G [115]

2. Okinawan marine sponge Pseudoceratina spp. N-imidazolyl-qunolinonemoiety Ceratinadin A (1) [116]

3. Penicillium sp. FKI-1938 Phenylfuropyridinones, citridones A, B, B´ and C [117]

4. Marine sponge associated fungi Aspergillus clavatus MFD15 1H-1,2,4 Triazole 3- carboxaldehyde 5- methyl [118]

5. Marine sponge Pachastrissa spp. Bengazole derivatives [119]

6. Marine sponge Phorbas spp. Phorboxazole A and B [120]

7. Egg masses of muricid molluscs 2,4,5-Tribromo-1H-imidazole [121]

Table 6. List of some patented antifungal azole compounds [124].

Patents No. Country Inventor Issue Date Title Assignee

US 5149707 A United State Bartroli et al. 22 Sep. 1992 1-{(2-fluorophenyl) J. Uriach& Cia, S.A.,
(4-fluorophenyl) phenylmethyl)}-1h- Barcelona, Spain
imidazole useful as antifungal agent

US 20020119984 A1 United State Salman et al. 29 Aug. 2002 Azole compounds as anti-fungal agents Ranbaxy Laboratories Limited,
Suite 2100, 600 College Road
East Princeton, NJ 08540 (US)

US 6486159 B2 United State Hudyma et al. 26 Nov. 2002 Water soluble prodrugs of Bristol-Myers Squite Company,
azole compounds Princeton, NJ (US)

US 6710049 B2 United State Salman et al. 23 mar. 2004 Azole compounds as anti-fungal agents Ranbaxy Laboratories Limited,
New Delhi (India)

EP 1646284 A4 European Nam et al. 24 Sep. 2008 Azole derivatives and methods for
making the same

EP 2095816 A1 European Rainer et al. 2 Sep. 2009 Nanosuspension with antifungal

medication to be administered via
inhalation with improved impurity
profile and safety

US 8207352 B2 United State Soukup et al. 26 Jun. 2012 Process for the manufacture of Drug Process Licensing
enantiomerically pure antifungal azoles Associates LLC, Dallas, TX
as ravuconazole and isavuconazole (US)

US 8394815 B2 United State Al-Qawasmeh 12 Mar. 2013 2,4,5-trisubstituted imidazoles and Lorus Therapeutics Inc.,
et al. their use as anti-microbial agents Toronto (CA)
Antifungal Azole Derivatives and their Pharmacological Potential
Patents on Antifungal Azole Compounds
Patent system has become an important part of research
because it promotes scientific and technological progress by
granting exclusive rights to the inventors. It encourages all
kinds of research including basic, applied and translational
[122, 123]. Some of the newly discovered antifungal azole
derivatives have been patented [124] which are presented in
the Table 6.
Antifungal Azoles for Plant Protection
Along with the field of medicine antifungal azoles have
also set new standards in the field of agriculture with respect
to efficacy and spectrum of disease control. These so called
azole fungicides have been commercially developed and
successfully used for the control of plant diseases [125].
Plant pathogenic fungi not only cause considerable loss of
crop yield but also produce several mycotoxins which cause
serious harm to the consumers. The use of azoles for
protection of plants from such fungal infections is
advantageous over other antimycotics because they are
inexpensive, long lasting and have broad spectrum activity.
The azole antifungals in agriculture are effective against
powdery mildew in cereals, berry fruits, vines and tomatoes;
leaf spots and flower blights in flowers, shrubs and trees;
mildews and rusts of grains, fruits, vegetables and
ornamentals; and several other plant pathogenic fungi. They
are not only used for preventing fungal infections in plants
but also are used for the treatment of the same [126]. Some
of the commonly used azole derivatives as systemic
fungicides in agriculture [127] include:
• Triadimefon (Bayleton) having high activity against
powdery mildew and rust fungi. It is used in different
crops but mainly in cereals and fruits.
• Triadimenol has excellent systemic properties. It is used
for control of seed-borne, soil-borne and wind-borne
fungal pathogens.
• Bitertanol penetrates plant tissue and thus possess
curative and eradicative properties along with protective
activity. It is used for the control of foliar diseases of
various crops tree fruit, peanuts and bananas.
Recent Developments
Antifungal triazole agents with piperidine side chains
were synthesized and tested against eight human pathogenic
fungi in vitro. All the compounds showed moderate to
excellent activities. Molecular docking was also done
between 8d and the active site of the Candida albicans
CYP51 strain which showed that the triazole compounds
interacts with the iron of the heme group [128]. Besides
using simple azoles for antifungal activity their
organometallic complexes were prepared by using ruthenium
metal. Nine organoruthenium complexes were synthesized
and characterized by NMR, HRMS, IR, UV-Vis, and X-ray
crystallography. All the complexes exhibited activity against
the fungus Curvularia lunata at low millimolar concentrations
[129]. Similarly, new ruthenium-ketoconazole (KTZ)
complexes have been synthesized and characterized. These
compounds were found to be highly active against Leishmania
The Natural Products Journal, 2014, Vol. 4, No. 2 9
major and Trypanosoma cruzi [130]. In an another study
synthesis of a series of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-
arylethanones 4a-k was achieved and their antibacterial,
DNA photocleavage and anticancer activities were
evaluated. Some compounds displayed good inhibitory
profile against Escherichia coli and Staphylococcus aureus.
On the other hand few compounds were found to be highly
active and completely degraded both forms of DNA (SC and
OC), even at a very low concentration of 1 µg (4c) under
irradiation of UV light during DNA photocleavage study.
These compounds also exhibited cytotoxic activity on colon
(HCT116 and HT29), prostate (DU145), ovarian (SKOV3)
and lung (A549) cancer cell lines [131].
CONCLUSION
The development of azole antifungal agents represents a
major advancement in the field of medical mycology. They
have been steadily refined and improved more than any other
antifungal class over recent years [9]. They are not
only active against human pathogenic fungi but are equally
active against the plant pathogenic fungi. Its imidazole
derivatives including ketoconazole, miconazole, tioconazole,
clotrimazole and sulconazole are recognized as potent
ligands of the heme iron atom of cytochrome P450s [132],
thereby inhibiting synthesis of normal membrane sterols in
fungi. On the other hand the triazole such as fluconazole and
itraconazole derivatives of azoles, exhibits better specificity
for the cytochrome P450 and are less toxic than the
imidazole derivatives. Therefore triazoles are more potent
than imidazoles [133]. But the problem of emerging
resistance to azole antifungal derivatives among the fungal
pathogens has urged upon the need for newer potent
antifungals to combat resistance developed against widely
used azoles [134, 135]. High rate of fluconazole resistance
has been reported in patients suffering from esophageal
candidiasis thus raising the question that whether treatment
of this disease with fluconazole is appropriate or not [136].
The new generation triazoles however provide an alternative
to the older azoles because they show activity even
against the azole resistant fungal pathogens. These include
voriconazole, posaconazole, ravuconazole which are being
developed both in oral and intravenous formulations and
have shown promising results during the clinical trials. Many
of the clinical trials are still under way [137-139]. All these
synthetic derivatives of azoles have many side effects
accompanied with their use which pose another serious
problem in front of the users as well as the researchers.
This problem has drawn the attention of the researchers
towards the natural sources of azole containing compounds.
Many antifungal azole compounds have been extracted
from several natural sources particularly from marine
environment. These compounds have shown better efficacy
than the synthetic ones and are not bound by any toxic
effects [114]. Thus, much effort is devoted to develop novel
antifungal azole agents, from natural sources which are more
safe and efficacious.
CONFLICT OF INTEREST
The authors have no potential conflict of interest
regarding publication of the said manuscript.
10 The Natural Products Journal, 2014, Vol. 4, No. 2
ACKNOWLEDGEMENTS
The authors of this review would like to thank Dr. K. N.
Singh Yadav, Vice-Chancellor, R.D. University, Jabalpur for
his kind support and help. We would also like to thank Prof.
Y. K. Bansal, Head, Dept. of Biological Sciences, R. D.
University, Jabalpur, India for technical and linguistic
assistance.
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Received: June 08, 2013 Revised: December 25, 2013
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Accepted: December 25, 2013