Professional Documents
Culture Documents
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
There has been a dramatic increase in the prevalence of been developed [10]. The azole antifungal agents developed
serious invasive fungal infections over the past decade [1]. so far for clinical uses mainly include ketonazole,
Up to 5% of the total infections in the world are caused by fluconazole, voriconazole and itraconazole [11].
fungi. Some of the major factors behind the increasing
incidences of fungal infections include greater use of broad- History of Antifungal Azoles
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 by
late 1950s [12]. Some key events in the development of azole
fungi like Candida spp., Cryptococcus neoformans,
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
United States [5]. For the treatment of such fungal infections Azoles are heterocyclic five-membered nitrogen
several antifungal drugs have been produced as a result of containing organic compounds. In these compounds usually
advances in medicinal chemistry. Azoles are one of the most one non-carbon like nitrogen, Sulphur and oxygen is also
promising antifungal agents out of all [6]. They are the present. Numbering of the ring atoms in azoles start with the
largest class of synthetic antimycotics used to treat both heteroatom that is not part of a double bond and then
superficial dermatophytic as well as systemic fungal proceeds towards the other heteroatom. Depending upon the
infections [7]. It is approved by FDA for treating candidiasis, heteroatom’s present in the ring, azoles are classified into
chronic mucocutaneous candidiasis oral thrush, candiduria, following compound classes [27] as given in Table 2.
coccidioidomycosis, histoplasmosis, chromomycosis and
paracoccidioidomycosis [8]. The antifungal azoles belong to Mechanism of Action of Azoles
two main classes, namely the Imidazoles and the Triazoles
[9]. Although the earliest azole, Chlormidazole was not very Several targets for the antifungal activity of azole
efficient but with gradual improvements over last 50 years, 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
*Address correspondence to this author at the Fungal Biotechnology and sterol component of fungal cell membrane but absent in
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: ssandhu@rediffmail.com
inhibiting the enzyme called lanosterol 14α-demethylase.
Table 1. Milestones in the development of azole antifungal agents.
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.
5 2
N
H
1
4 3
2. Two or more nitrogen containing Pyrazole
5 N 2
N
H
4 3
Imidazole N
5 2
N
H
1
Triazole H
N
1
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
Isoxazole 4
5 N 2
O
1
3
4. One nitrogen atom and one sulphur atom Thiazole 4
N
containing
5 2
S
1
3
Isothiazole 4
5 N 2
S
1
IMIDAZOLES TRIAZOLES
These contain two nitrogen atoms in the azole ring [27]. These contain three nitrogen atoms in the azole ring [27]. They are advantageous over
Their use is limited to topical administrations and has been imidazoles in terms of having broad spectrum activity against both superficial and
replaced by triazoles for systemic applications [26]. Their systemic fungal infections and having greater affinity for fungal rather than
derivatives 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
Table 4. Some of the commonly used synthetic azole containing anti-fungal drugs [79].
Econazole Spectazole Cl
Superficial fungal infections,
Pevaryl Cl including dermatomycoses,
OCH2 tinea versicolor, cutaneous and
vaginal candidiasis.
Cl HNO3
N
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
N HCl
N
Table 4. contd….
N
Fenticonazole Lomexin HCH2 Superficial fungal infections,
Cl C N including dermatomycoses,
O N tinea versicolor and cutaneous
Cl and vaginal candidiasis.
CH2
HNO3
Sulconazole Sulcosyn H
Superficial fungal infections,
Exelderm Cl C C N including dermatomycoses,
H2 tinea versicolor and cutaneous
S CH2 N candidiasis.
Cl
Cl
Cl
N
CH3
O CH3
H2CH2CH2C O
N Cl
N N OCH2 O
N
N H
F
Antifungal Azole Derivatives and their Pharmacological Potential The Natural Products Journal, 2014, Vol. 4, No. 2 7
4. Marine sponge associated fungi Aspergillus clavatus MFD15 1H-1,2,4 Triazole 3- carboxaldehyde 5- methyl [118]
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
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,
as ravuconazole and isavuconazole TX (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