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Antifungal Azole Derivatives and their Pharmacological Potential: Prospects &


Article · October 2014

DOI: 10.2174/221031550402141009100632

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Ravindra Prasad Aharwal Suneel Kumar

Rani Durgavati Vishwavidyalaya Motilal Nehru National Institute of Technology


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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

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 many new and more potent antifungal azole derivatives have
been developed [10]. The azole antifungal agents developed
There has been a dramatic increase in the prevalence
so far for clinical uses mainly include ketonazole, fluconazole,
of serious invasive fungal infections over the past decade
voriconazole and itraconazole [11].
[1]. Up to 5% of the total infections in the world are
caused by fungi. Some of the major factors behind the
History of Antifungal Azoles
increasing incidences of fungal infections include greater
use of broad spectrum antibiotics; indwelling catheters; The first report of antifungal activity of an azole
immunosuppressive drugs and increase in the number of compound was described in the 1940s. But the development
individuals suffering from acquired immunodeficiency of more potent azole antifungal derivatives accelerated in the
syndrome (AIDS) [2]. These infections are mainly caused late 1950s [12]. Some key events in the development of
by fungi like Candida spp., Cryptococcus neoformans, azole antifungal agents [13-26] are described in the Table 1.
Aspergillus spp., Pneumocystis carinii and Histoplasma
capsulatum [3, 4]. Candida species are the fourth most Chemistry of Azoles
common cause of nosocomial bloodstream infections in the
Azoles are heterocyclic five-membered nitrogen
United States [5]. For the treatment of such fungal infections
containing organic compounds. In these compounds usually
several antifungal drugs have been produced as a result of
one non-carbon like nitrogen, sulphur and oxygen is also
advances in medicinal chemistry. Azoles are one of the most
present. Numbering of the ring atoms in azoles start with the
promising antifungal agents out of all [6]. They are the
heteroatom that is not part of a double bond and then
largest class of synthetic antimycotics used to treat both
superficial dermatophytic as well as systemic fungal proceeds towards the other heteroatom. Depending upon the
heteroatom’s present in the ring, azoles are classified into
infections [7]. It is approved by FDA for treating candidiasis,
following compound classes [27] as given in Table 2.
chronic mucocutaneous candidiasis oral thrush, candiduria,
coccidioidomycosis, histoplasmosis, chromomycosis and
Mechanism of Action of Azoles
paracoccidioidomycosis [8]. The antifungal azoles belong to
two main classes, namely the Imidazoles and the Triazoles Several targets for the antifungal activity of azole
[9]. Although the earliest azole, Chlormidazole was not very compounds have been revealed by extensive research but its
efficient but with gradual improvements over last 50 years, 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
*Address correspondence to this author at the Fungal Biotechnology and
Invertebrate Pathology Laboratory, Department of Biological Sciences, Rani
animals, hence serves as a major target for treatment of
Durgawati University Jabalpur- 482001, (M.P.) India; Tel: +91 9424395270; fungal infections [29]. The azoles kill fungal cells by
Fax: +917612608704; E-mail: 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 produce different degree and type of inhibition depending
a precursor compound called lanosterol [30]. The enzyme upon their physiochemical characteristics and pharma-
lanosterol 14α-demethylase is dependent on activation of cokinetics [37, 38].
cytochrome P450. During its action the azole drugs binds to
the heme iron of the cytochrome P450 via one of its nitrogen Some Clinically Important Imidazole Derivatives
atom and forms a stoichiometric complex thereby inhibiting
cytochrome activation and enzyme action [31]. The nitrogen Clotrimazole
atoms N-3 in imidazoles and N-4 in triazoles participate in It is a derivative of 1-methylimidazole with lipophilic
the complex formation [31]. The formation of this complex substituents at methyl group. It was the first compound to be
can be measured spectrophotometrically, by the red shift of developed as a broad spectrum imidazole based antifungal
the Soret band of the heme from 417 to 447nm [32]. As a agent for topical use [39, 40]. The antifungal activity of
consequence of this inhibition there is a depletion of clotrimazole is seen against dermatophytes particularly,
ergosterol and accumulation of lanosterol and other 14- Candida species, Candida immitis, Candida neoformans and
methylated sterols in the plasma membrane of the fungi. Aspergillus spp. [41]. It is available in cream form and is
Azole also acts by inhibiting a similar functioning enzyme used to treat fungal infections like vaginal yeast infections,
24-methylene dihydrolanosterol demethylase in the fungal ringworm, and athlete’s foot [2]. The oral intake of this
cell. These changes results in interference with the functions compound as antimycotic is not suitable because it has
of fungal plasma membrane, disruption of its structure and inductive effect on microsomal liver enzymes leading to
alteration of the activity of several membrane bound rapid metabolism and inactivation of active substances [42].
enzymes for example enzymes associated with nutrient
transport and chitin synthesis [33], thus making it more Miconazole
vulnerable to further damage [34]. The final result of activity
of azoles is inhibition of growth and proliferation of fungal It is an ether group containing phenethyl imidazole class of
cells [35]. Azoles at higher concentrations exhibit fungicidal antifungal agent [43, 44]. The antifungal activity of miconazole
activity while at lower concentrations exhibit fungistatic is narrow spectrum and is effective against dermatophytes,
activity [8, 36]. Fig. (1) clearly depicts the mechanism of Candida species, dimorphic fungi, and Pseudallescheria
action of azole compounds inside the fungal cell. boydii [45]. It has been used successfully in the treatment of
systemic Candida infections, pseudallescheriasis and some
Antifungal Azole Derivatives refractory cases of cryptococcal meningitis [46]. It was the
first azole introduced for parenteral administration but
Two classes of azoles are used for treatment of invasive toxicity associated with the vehicle used for intravenous
fungal infections. These are the Imidazoles and the Triazoles administration has limited its parenteral use. As a
as shown in Table 3 [26, 27]. These classes of azoles
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

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

4 3
Imidazole N


H 1
Triazole N

5 N 2

4 N 3

H 1
Tetrazole N
5 N 2

N N 3

H 1
Pentazole N
5 N N 2

N N 3

3. One nitrogen atom and one oxygen atom Oxazole 4
5 2

Isoxazole 4

5 N2

4. One nitrogen atom and one sulphur atom Thiazole 4
5 2

Isothiazole 4

5 N2

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,
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 Sandhu et al.

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].


These contain two nitrogen atoms in the azole ring [27]. Their These contain three nitrogen atoms in the azole ring [27]. They are advantageous over
use is limited to topical administrations and has been replaced imidazoles in terms of having broad spectrum activity against both superficial and
by triazoles for systemic applications [26]. Their derivatives systemic fungal infections and having greater affinity for fungal rather than
commonly used as antifungal agents are: mammalian cytochrome P450 enzymes thus reducing the risk factors [26]. Their
Clotrimazole, Econazole, Miconazole, Ketoconazole, derivatives commonly used as antifungal agents are: Fluconazole, itraconazole,
Butconazole Rosaconazole, Voriconazole, Ravuconazole

absorbed (90% bioavailability) after oral administration [55]. as compared to the capsule form. The absorption of
After entering in the body fuconazole distributes throughout intravenous formulations on the other hand is invariable
without being influenced by the gastric pH [56] and [62]. Itraconazoles display excellent activity against various
penetrates completely into the cerebrospinal fluid [57]. This types of fungi like yeasts, moulds and dimorphic fungi.
favourable pharmacokinetic profile of fluconazole makes it Among these are, Candida spp., Cryptococcus neoformans,
suitable for oral as well as intravenous administrations [58]. Aspergillus spp., Pseudallescheria boydii, Sporothrix
It shows activity against several pathogenic fungi [59]. The schenckii, Histoplasma capsulatum, Blastomyces dermatitidis,
major ones are Candida albicans, Candida tropicalis, Coccidioides immitis, Paracoccidioides brasiliensis,
Candida neoformans, Trichosporon beigelii, Epidermophyton Penicillium marneffei, Trichosporon beigelii, Epidermophyton
floccosum, Trichophyton mentagrophytes, Pseudallescheria floccosum, Microsporum canis, Microsporum gypseum,
Boydii and Blastomyces dermatitidis. Fluconazole is approved Trichphyton mentagrophytes, Trichophyton rubrum,
for the treatment of oropharyngeal, oesophageal, vaginal, Trichophyton simii and Trichophyton verrucosum [63-66].
peritoneal and genito-urinary candida infections, disseminated
candidiasis (including chronic disseminated candidiasis) and Voriconazole
cryptococcal meningitis and coccidioidomycosis. It is a good It is a new triazole derivative which is structurally similar
alternative to ketoconazole in chronic mucocutaneous to fluconazole. It is discovered by Pfizer and is being
candidiasis [58]. 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
It is also a 1, 2, 4 triazole derivative which is highly and 160 fold greater inhibition is seen in case of Candida
lipophilic and hence has very less solubility in water [60]. albicans and Aspergillus fumigatus respectively [69]. The
After oral administration its absorption in the body is pharmacokinetic studies revealed its bioavailability to be
influenced by the acidity of the gastric fluid [61]. The about 60% or greater [70]. It displays antifungal activity against
solution form of the itraconazoles shows better bioavailability 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

Cl N

Bifonazole Mycosporan Superficial fungal infections,

Mycospor including dermatomycoses,
tinea versicolor and cutaneous
CH candidiasis.

Econazole Spectazole Cl Superficial fungal infections,

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

Miconazole Monistat Monistat- Cl Cl Systemic fungal infections,

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

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

Butoconazole Femstat Vaginal candidiasis.



Croconazole Pilzcin Cl Superficial fungal infections,

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

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

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

Oxiconazole Oceral N Superficial fungal infections,

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

Sulconazole Sulcosyn Superficial fungal infections,

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


Itraconazole Sporanox N Systematic and superficial



H 2CH 2CH 2C O O CH3

N Cl



Fluconazole Diflucan OH Systematic and superficial

N C C C N mycoses.
H2 H2

Antifungal Azole Derivatives and their Pharmacological Potential The Natural Products Journal, 2014, Vol. 4, No. 2 7

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

• Transient elevations in serum liver enzymes, noted having antifungal activity. Natural products have always
occasionally. played a remarkable role in drug discovery [112]. Over past
75 years natural product derived compounds are being used
• Gastrointestinal disturbances and pruiritus.
for treating numerous diseases [113]. As a result of
• Liver toxicity (rarely hepatitis). technological advancements in the field of medicine about 1
• Inhibition of adrenocortical steroid and testosterone million natural biologically active compounds have been
synthesis, thus resulting in gynecomastia in some male discovered out of which 22,500 are obtained from microbes
patients. [114]. A large number of natural products, in particular from
the marine environment contain triazoles, imidazoles,
Antifungal Azoles from Natural Sources thiazole, oxazole, thiazolines or oxazolines heterocycles
which shows promising bioactivities. Table 5 contains some
The emerging fungal pathogens with azole resistance and naturally derived antifungal azole [115-121] containing
the side effects accompanied with the synthetic azoles have compounds.
stressed upon the need to search for new azole 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 The Natural Products Journal, 2014, Vol. 4, No. 2 9

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

ACKNOWLEDGEMENTS of new azole derivatives containing a Nacylmorpholine ring. J.

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Received: June 08, 2013 Revised: December 25, 2013 Accepted: December 25, 2013

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