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Imidazoles as Potential Antifungal Agents: A Review Nidhi Rani*1, Ajay Sharma1, Girish Kumar Gupta2 and Randhir Singh3 1
Himalayan Institute of Pharmacy, Kala-Amb, Distt. Sirmour-173030, Himachal Pradesh, India; 2Department of Pharmaceutical Chemistry, Maharishi Markandeshwar College of Pharmacy, Maharishi Markandeshwar University, Mullana-133203, Haryana, India; 3Department of Pharmacology, Maharishi Markandeshwar College of Pharmacy, Maharishi Markandeshwar University, Mullana -133203, Haryana, India Abstract: Imidazoles are one of the most promising and vigorously pursued areas of contemporary antifungal chemotherapy depicting broad spectrum and potent activity. They have relatively simple molecular nucleus, which is amenable to many structural modifications. These agents have several favorable properties such as excellent bioavailability, good tissue penetrability and permeability and a relatively low incidence of adverse and toxic effects. They have been found effective in the treatment of various infectious diseases. This paper is an attempt to review the therapeutic potential of imidazoles as antifungal with an updated account on their development.
Keywords: Antifungal agent, Antimycotic agent, Imidazole, Structure-Activity Relationship study. 1. INTRODUCTION Over the past two decades, fungal infections have been increased significantly. It results into high rate of morbidity and mortality. Both bacteria and fungi are responsible for large number of human and other animal diseases. Part of them are life threatening. Fungi are heterophilic organisms which dependon dead or living organisms for their growth. They can quickly develop colonies on all kinds of dead organic matter and play a major role in causing decomposition of organic matter enabling the recycling of nutrients throughout the ecosystem. Fungi are ubiquitous and have been estimated to comprise approximately 25% of the global biomass [1]. Fungal infection is a critically significant problem. Although its magnitude is difficult to determine, but efforts have been made in this article to highlight the role of imidazole in fungal infection. At present, much of what is known about fungal infections is limited to what happens in human beings [2]. Despite the remarkable progress in diagnostic modalities and antifungal drug research during the past 10 years, difficulty in prompt diagnosis and the complexity of the clinical characteristics of at-risk patients continue to make the management of invasive fungal infections (IFIs) a great challenge. Different fungi produce characteristic patterns of tissue injury, which are modified by the special structures of the tissues in which they invade [4]. At present, the two main focus of attention in the study of fungal diseases are as follows:(1) The mechanism of pathogen city that causes usually saprophytic fungal species to transform into an aggress or in disease or even death of the host animal. (2) Mechanisms of the host’s resistance to infections and diseases [5]. There are three main groups of *Address correspondence to this author at the Himalayan Institute of Pharmacy, Kala-Amb, Distt. Sirmour, Himachal Pradesh, India; Tel: +919034114133; E-mail:
[email protected] 1875-5607/13 $58.00+.00
fungal infection: Superficial, Subcutaneous, Systemic mycoses (inflammatory condition caused by fungus) [3]. The most commonly recognized causes of opportunistic IFIs traditionally are Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus [2]. Representatives of all fungal infections are endemic in some tropical areas. Some may present in the patients who have made a short visit to a tropical environment or in immigrants whose incubation period is very long although they have left the endemic area. Some of the subcutaneous fungal infections such as mycetoma (subcutaneous infection caused by fungus) may remain dormant for many yearseven after the patient has left the endemic area. These infections may be congenital or acquired but congenital infections are very uncommon [6]. H 3 N 4
2 N 1
5 1
Fig. (1). The structure of imidazole.
Imidazole (1) is a five membered heterocyclic compound having two nitrogen atoms at position 1 and 3. Imidazoles are common scaffolds in highly significant biomolecules including the essential amino acid histidine, histamine, pilocarpine alkaloids [7,8], and other alkaloids, which have been shown to exhibit interesting biological activities such as antimicrobial, anti-inflammatory [9,10], histamine H 3 antagonist [9,11], antioxidant [9,12], farnesyltransferase and geranylgeranyltransferase-I inhibitor [9,13], antitumoral [14], antiparasitic [15], antiprotozoal [16,17], and antidiabetic activities [18]. Imidazole derivatives have also been found to possess many pharmacological properties and are widely © 2013 Bentham Science Publishers
Imidazoles as Potential Antifungal Agents: A Review
Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 11
implicated in biochemical processes. Members of this class are also known to possess nitric oxide (NO) synthase inhibition [8,19], antibiotic [8,20], antifungal [8,21], antimalarial [22], antiulcerative activities [8,23] and analgesic [24] and include compounds, which are inhibitors of 5-lipoxygenase [8,25] and substances with CB1 and CB2 (Canabinoid) receptors [8,26,27], vascular endothelial growth factor (VEGF) receptor I and II [8,28], and neuropeptide Y antagonistic activities [8,29]. In addition to this heterocycle include several inhibitors of p38 MAP kinases [30-33], a subgroup of mitogen-activated protein kinases, which are assumed to be involved in a variety of inflammatory and immunological disorders, and some derivatives such as Cimetidine (2), Etomidate (3), Ketoconazole (4), Metronidazole (5), Ornidazole (6), Azomycin (7), Oxiconazole (8), and Clonidine (9) have found application in drug therapy [12,34,35].
reactive peroxide compounds within the microbial cell [42,43]. It was also found that Ketoconazole induces conformational changes in the active site of cytochrome P450eryF [44]. 2. MARKETED IMIDAZOLE ANTIFUNGAL DRUGS [34,45,46]
The compound 10 is available for topical therapy and intravenous formulation while compounds 11 and 13 are available only for topical therapy. Compound 4, a water soluble imidazole can be administered orally for the treatment of both superficial and deep seated fungal infections [37]. The presence of free fatty acids in liposome model membranes sensitizes these membranes to the action of the imidazole antifungals, 11 and 21 [47]. Previous studies suggested that compound 12 may be useful for treating onychomycosis (in a special nail formulation), napkin-rash due to C. albicans, impetigo, and Vaginal trichomoniasis [48]. Enilconazole/Imazalil (15) and Parconazole have been developed for veterinary applications [49,50]. However compound 15 is also employed as plant protectant [50]. On the other hand compound 18 as a cream is effective in eradicating the fungi from the infected feet [51]. It is a racemic compound and only the R-enantiomer is active [52]. Drug 19 is used in the topical treatment of vaginal discharge and in mycotic skin infections that are superinfected with bacteria [53]. H
NH NC
N
N
HN
O
O
N
O
NH
O
N
N
3 NO2
H N
OH O2N
N
N
7
6 Cl Cl O
N N
Cl
N
H N
H N N
Cl 8
Fig. (2). Compounds found application in drug therapy.
N
NO2 N
N
5
O
4
Cl
HO N
N
N
2
CONTAINING
Several imidazole derivatives have been introduced for the chemotherapy of fungal infection which are well known marketed antifungal imidazole drugs such as Ketoconazole (4), Miconazole (10), Clotrimazole (11), Tioconazole (12), Econazole (13), Tinidazole (14), Enilconazole/Imazalil (15), Parconazole (16), Eberconazole (17), Lanoconazole (18), Fenticonazole (19), Bifonazole (20), Sulconazole (21), Lombazole (22), and Sertaconazole (23).
Imidazole rings are widely employed as spin trapping species, a fact that makes them effective is their interesting feature of the designing of drugs with neuroprotective activity [9,36]. Imidazoles have also been reported to possess broad spectrum of in vitro antifungal activity against a variety of pathogenic fungi including species of Microsporum, Trichophyton, Epidermophyton, C. neoformans, Candida spp., Torulopsis glabrata and dimorphic fungi: Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis. At low concentrations, imidazoles are fungistatic and at higher concentrations fungicidal [37-39]. Imidazoles inhibit the cytochrome P450 dependent 14-demethylation step in the formation of ergosterol. Ergosterol synthesis is inhibited and precursor sterols accumulate in the membranes of fungi exposed to imidazoles. The consequent depletion of ergosterol and accumulation of methylated sterol lead to alteration in a number of membrane associated functions [37,40,41]. According to a recent study, Miconazole (10) and Ketoconazole (4) may result in the accumulation of toxic
S
1627
Cl 9
Cl
O
Cl
Cl
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Rani et al.
Cl Cl Cl
Cl
Cl Cl
O N
Cl
S
N
N
N 12
O N
Cl
NO2
O S O
N
13
N N 14
N
N
N
N
N
O
O
Cl
O
O
Cl
N
Cl
Cl
Cl
O
N 11
10
N
Cl
Cl
Cl
Cl
15
17
16 N N
S
N
S
N
O
Cl
Cl N
S N
N H
Cl
20
19
18 N
N
Cl
N
Cl Cl
N
Cl
N Cl
21
22
Cl
N
S
S O
Cl
23
Fig. (3). Marketed Imidazole Drugs.
Compound 20 is found to be effective for the treatment of dermatophytes infection of the skin, candidiasis, pityriasis versicolor and erythrasma and thus is recommended for the treatment of Tinea unguium [54,55]. Other preliminary in vitro study has showed Eberconazole (17) to be an excellent antifungal compound against yeasts of the genus Candida and dermatophytes. Therefore it has been developed as a topical antimycotic for the treatment of superficial fungal infections. Recently it is in phase III clinical trials [61]. Lombazole (22) another antimicrobial agent is used for the treatment of acne and is active against several budding and filamentous fungi [63]. Similarly compound 23 is indicated for the treatment of superficial skin mycoses such as dermatophytosis (including T. corporis, T. cruris, T. manus, T. barbae and T. pedis), cutaneous candidiasis, pityriasis versicolor and seborrhoeic dermatitis of the scalp, and in the US for T. pedis only [38].
3. REPORTED IMIDAZOLES HAVING ANTIFUNGAL ACTIVITY The present review aims tohighlighting the imidazoles possessing antifungal activity which has been analyzed here on the basis of substitution on ring i.e., monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted. 3.1. Mono Substituted A new series of 3-phenyl-1-(1,1-biphenyl-4-yl)-2-(1Himidazol-1-yl)propane derivatives (24 and 25) was evaluated for in vitro antifungal activity against yeasts (C. albicans, C. parapsilosis, and C. neoformans), dermatophytes (T. verrucosum, T. rubrum, M. gypseum) and moulds (A. fumigatus) via Microtiter plate method. All the carbaanalogs displayed fairly good antimycotic activity against yeasts and dermatophytes. Its antimycotic activity is more than Bifonazole (20). Interestingly, it was observed that
Imidazoles as Potential Antifungal Agents: A Review
Table 1.
Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 11
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Antifungal Drugs and their Sensitive Fungal Strains.
Drugs
Sensitive Fungal Strains
Route of Administration
Miconazole (10)
H. capsulatum and B. dermatitidis [37], C. dubliniensis [49], C. albicans, C. tropicalis, C. parapsilosis, C. glabrata, Trichophyton spp., Aspergillus spp. (A. fumigatus, A. flavus), S. apiospermum, S. prolificans, Fusarium oxysporum and F. solani, Scedosporium apiospermum, M. furfur, T. beigelii, M. canis [50] and Cryptococcus [42,56,57].
Topical, vaginal, i/v, intrathecal, oral
Ketoconazole (4)
E. floccosum, M. canis, M. gypseum, T. mentagrophytes, T. verrucosum. Cladosporium spp., Exophiala dermatitidis, Cladophialophora spp., Scopulariopsis chartarum, Paecilomyces spp., F. solani, Candida spp., B. dermatitidis, H. capsulatum, some isolates of C. immitis and Aspergillus spp. [50,58].
Oral, Topical
Clotrimazole (11)
Candida spp., Aspergillus spp., C. immitis, C. neoformans, B. oralis group, Gardnerell vaginalis, Mobiluncus spp., Coryneforms, Allescheria boydii and Phialophora spp. are less sensitive [50, 53, 59].
Topical, vaginal, Oral
Econazole (13)
B. dermatitidis, H. capsulatum, A. fumigatus, A. flavus, S. schenckii, Absidia corymbifera and Allescheria boydii [50, 60].
Topical, Vaginal
Parconazole (16)
Candida spp. and B. dermatitidis [50].
Oral
Enilconazole (15)
M. canis, M. gypseum, T. mentagrophytes, T. verrucosum, M. pachydermatis and Aspergillus spp.[50].
Topical
Eberconazole (17)
Absidia ramos, Mucor spp., Rhizopus spp., Aspergillus spp. (except A. nidulans), Fusarium spp., S. schenckii, Alternaria spp. and S. brevicaulis are less sensitive [49]. C. krusei, C. glabrata and dermatophytes are sensitive [61,62].
Topical
Lombazole (22)
C. albicans [63].
Sertaconazole (23)
Trichophyton, Epidermophyton and Microsporum genera, and yeasts of the genera Candida and Cryptococcus [38].
Topical, Vaginal
Tioconazole (12)
C. albicans [48].
Topical
Lanoconazole (18)
C. neoformans [64].
Topical
Fenticonazole (19)
Microsporum, Epidermophyton, Trichophyton spp. and C. albicans [53].
Topical, Vaginal
Bifonazole (20)
Candida spp., Aspergillus spp. and Trichophyton spp. [55].
Topical
Sulconazole (21)
C. albicans [47].
Topical
Tinidazole (14)
Candida spp. [47].
Oral
unsubstituted compound 24 with minimum inhibitory concentration (MIC) ranging from 0.4-33 M proved to be the most effective in this series followed by 2,4-difluoro derivative 25 with MIC 3.2-33 M. The para substitution with a bulky group leads to decrease in activity. Introduction of two methylene bridges between the aromatic rings and the chiral carbon directly linked to imidazole N-1 is profitable for antimicrobial properties [65]. Representative compounds of 1H-imidazol-1-amine derivative series depicted N-[(1,1-biphenyl)-4-ylmethyl]-N[(2,4-dichlorophenyl)methyl]-1H-imidazol-1-amine (26) to exhibit promising activity against C. parapsilosis (6.2 M), C. neoformans (2.5 M), C. albicans (6.2 M), T. verrucsum (2.4 M), T. rubrum (7.4 M) and M. gypseum (0.8 M) when determined by Microtiter plate method. The presence of substituted phenyl group was found to be necessary for antifungal property while on substitution at position 2 and 4 with chloro or fluoro group lead to dramatic decrease in activity. 2-substituted phenyl compounds displayed better
results than 4-substituted phenyl ones, especially against C. neoformans [66]. Imidazole derivatives having hydrophobic substituents derived from an isoprenoid unit were evaluated with respect to direct cell-membrane damaging activity, ergosterol biosynthesis inhibition, MIC and therapeutic effect for experimental dermatophytosis in guinea pigs. Among all compounds the geranyl derivative AFK-108 (27) showed the highest in vivo fungicidal activity with dual inhibition. Outcome of the study showed that substitution of the geranyl moiety with other isoprenoid group or partial modifications of the geranyl moiety decreased either one or both of the inhibitory effects on above mentioned evaluating parameters [67]. Characterization of azoles as anti-fungal agents lead to the development of new derivatives which exhibited significant in vitro activity when determined by agar dilution method. Out of them imidazole analogues such as 1(4methoxy-2-hydroxyphenyl)-2-(1H-imidazol-1-yl)ethanone (28) may be considered as promising for the development of
1630 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 11
Rani et al. N
N
N
N
N Cl
N N
F
Cl F
24
26
25
Fig. (4). The structure of 3-phenyl-1-(1,1-biphenyl-4-yl)-2-(1H-imidazol-1-yl)propane derivatives (24 and 25); N-[(1,1-biphenyl)-4ylmethyl]-N-[(2,4-dichlorophenyl)methyl]-1H-imidazol-1-amine (26). N
C3H7 N
N O
N
O
Cl
OH Cl
N Cl
O
N N
28
27
29
Fig. (5). The Structure of geranyl derivative AFK-108 (27); 1(4-methoxy-2-hydroxyphenyl)-2-(1H-imidazol-1-yl)ethanone (28); 1-[(Aryl)(4aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole (29).
new antifungal agent with low MIC values in the range of 0.25-32g/ml [68].
produce an intermediate which on further treatment with imidazole produced the imidazole derivative (31). On evaluation of antifungal spectrum by disk diffusion technique, it was found to be a potent anti-Candidal agent with 70 % inhibition [71].
1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole (29) has been described to possess anti-Candida activity with MIC90 = 0.032 g/ml when evaluated by serial microdilution test, which was 4 to 250 fold more potent than reference drugs [69].
In the hope of identifying a potent antifungal agent 1-[4(4-chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]-1Himidazole nitrate (32) was designed and screened. Compound demonstrated good activity against the representative dermatophyte T. mentagrophytes in an in vivo guinea pig model and C. albicans infections in mice [72].
In view of molecular modeling study of 2phenylazoimidazoles, it was found that (Z)-2-(diethylamino) ethyl-4-((1H-imidazol-2-yl)diazenyl)benzoate (30) might form a tight-binding that leads to inhibiton of the cytochrome P450 target for the validation of antifungal activity [70].
It is also worth mentioning here that pseudoreceptor molecular modeling study predicted that enantiomers R and S of drug Bifonazole (20) and related imidazole compounds (33-35) were active against C. albicans [73].
In recent study another imidazole derivative methyl-4oxo-4-(imidazole phenylamino)butanoate (31) was synthesized by treating N-Phenylacetamide with methylchloroacetate to
N
C2H5 N C2H5
N
O N
NH N
O
N
O
O
S Cl
Cl
O
NH
N
.HNO
3
Cl
N 30
32
31
Fig. (6). The structure of imidazole derivatives 30-32. N Cl
N
O N
N
N 33
N N
34
O
N
F 35
Fig. (7). The structure of imidazole compounds related to Bifonazole (33-35); compound 36.
36
Imidazoles as Potential Antifungal Agents: A Review
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In 1996, Tafti et al. investigated series of fifty six azoles as antifungal agents using comparative molecular field analysis and identified 36 and 37 to be the only biologically active ones [74].
between 0.2 and 7.0 g/ml) but when tested in vivo in the rat vaginal candidiasis model, derivative 41 although showed significant antifungal activity when compared to controls but less effective than compound 4 [77].
It is worth noted that halogen-substituted isobenzofuran analogues containing imidazoles (38, 39) exhibited potent activity against dermatophytes, topical Trichophyton infection in guinea pigs and hamster vaginal C. albicans infection [75].
In 1983, Ogata et al. described the synthesis and antifungal properties (determined by agar dilution method) of 1-[1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole hydrochloride (43). Compound 43 wasfound to inhibit typical dermatophytespp. with MIC 0.16-1.25 g/ml and Aspergillus spp. and Penicillium spp. (MIC 0.63-5 g/ml). It also possessed inhibitory property against Candida spp. and other yeasts at 10-80 g/ml [78]. Compoundsuch as (E)-l-(5Chlorothien-2-yl)-2-(1H-imidazol-l-yl)ethanone-2,6dichlorophenyl hydrazone hydrochloride (44) was prepared and screened for in vitro antifungal property by Dyeret al.. Compound 44 showed antifungal activity against C. albicans equipotent to 5. At low concentrations, they block the demethylation of lanosterol resulting into inhibiting the formation of ergosterol [79,80]. This mechanism was essentially fungistatic. Both compounds 44 and 5 were found fungicidal at 10-3M and fungistatic at 210-5M while compound 4 was ineffective. Toxicological studies have shown 1420 mg/kg and 1250 mg/kg to be the LD50 value in male and female rats respectively. From all of the above mentioned biological activities, the compound 44 has been selected for clinical trial [81,82].
The antifungal activity of a series of bis-imidazole derivatives has been described by Zampieri et al. via microdilution method. Almost all compounds were found to exhibit moderate to high activity against two clinical isolates of C. albicans and C. glabrata. Binding mode of all the compounds in binding pocket of cytchrome P450 14-sterol demethylase (14DM) of C. albicans were also predicted by using docking procedures combined with molecular dynamic simulations. The results obtained from in silicostudy depicted that the active compounds may interact at the active site of protein, and their binding free energy values are compatible with the corresponding experimental activity values. The derivative 1-(4-biphenylyl)-3-[(1H-imidazol-1yl)methyl]-1-propan-1-one (40),in which the biphenyl moiety is present, exhibited a good inhibitory activity against the clinical strain of C. albicans with MIC values of 2 and 4 g/ml, after 24 h and 48 h, respectively [76].
Ogata et al. reported the synthesis and evaluation of antifungal potency of new 1-vinylimidazoles against C. albicans, A. fumigates and T. asteroids (using microtiter dilution method). Trifluoroacetamide derivative of imidazole 45 possessed antifungal activity at MIC of 1.6 and 50 g/ml against the fungal strains [83].
In particular 3,5-diphenyl-3-(1H-imidazol-l-ylmethyl)-2alkylisoxazolidine derivatives were synthesized via 1,3dipolarcycloaddition reaction of -substituted ketonitrones with appropriate styrene precursors and screened for antifungal activity via solid agar test method. The two bis(4chlorophenyl) analogues 41 and 42 were found to be the most potent compoundsin vitro (MIC values ranging O
N
N
O
N N
O N
N
N
N
O
N Cl
N
Cl 38
37
Cl
39
Ph
N
40
Fig. (8). Chemical structure of Compound 37; halogen-substituted iso-benzofuran analogues containing imidazoles (38, 39) and of 1-(4biphenylyl)-3-[(1H-imidazol-1-yl)methyl]-1-propan-1-one (40). Cl
N
Cl
N
N
N
N
N O
N O
H
H
Cl
N Cl
N O
S
.HCl Cl
Cl 41
42
Cl
43
Cl
NH
.HCl
N N 44
Fig. (9). Chemical Structure of 3,5-diphenyl-3-(1H-imidazol-l-ylmethyl)-2-alkylisoxazolidine derivatives (41,42); 1-[1-[2-[(3chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole hydrochloride (43) and (E)-l-(5-Chlorothien-2-yl)-2-(1H-imidazol-l-yl)ethanone-2,6dichlorophenyl hydrazone hydrochloride (44).
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Rani et al.
Cl
N
N N
N N
O
N
N
Cl
R O
O
CF3
Cl
Cl 46
45
47
Fig. (10). Structure of Trifluoroacetamide derivative of imidazole 45 and imidazole analogues of fluoxetine (46, 47). Cl Cl
N
N
Cl
HN
NH N
N N H
N
O
N SO2
O
NH N
Cl 48
N
O
HN
HN
49
50
51
Fig. (11). The structure of3-aryl-4-[-(1H-imidazol-l-yl)arylmethyl]pyrrole derivatives (48, 49); 4-substituted imidazoles (50, 51).
Silvestri et al. reported that imidazole analogues of Fluoxetine were also active against C. albicans with MIC = 0.125-128 g/ml when measured by microdilution tray method. Outcome of SAR study depictedthat imidazole group is essential for the antifungal property. The study also revealed that replacement of trifluoromethyl group with different substituents such as NO2, CH3, Cl and F leads to substantial increase in the activity. The maximum activity was found with chloro group. However, monosubstituted derivative(s) (46) wasless active. Furthermore, trichloro derivative (47) was most active with less cytotoxic profile [84]. Artico and coworkers tested 3-aryl-4-[-(1H-imidazol-lyl)arylmethyl]pyrroles against C. albicans using serial dilution techniqueand found that only the compound 49 was the most active derivative with MIC90 of 8 g/ml while the rest were equipotent to compound 20. Derivatives 48 and 49 were shown to be highly effective in rabbit skin candidosis. Further, SAR study anticipated that the presence of the imidazole pharmacophoric group leads to potent antifungal activity [85]. Compound Roquefortine (50), a cyclopeptide had been derived from the diketopiperazinecyclo (Trp-dehydroHis). It is a secondary metabolite produced by several Penicillium species reported to cause neurotoxic effect. In this study Aninat et al. investigated the interaction of 50 with mammalian cytochromes P450. It was found that compound 50 exhibited high affinity for microsomes in rats treated with various inducers. The Ks (spectrally estimated dissociation constant) valuewas in the range of 0.2-8 M. Similar results were observed with human P450 enzymes 1A1, 1A2, 2D6, and 3A4 and found no effect on NADPH cytochrome c reductase. Outcome ofthese studies indicated that the presence of nitrogen in imidazole moiety, dehydroHis moiety anda fused teracycle in compound 50 play an important role in inhibitory power [86].
In order to achieve a potent antifungal agent a series of 4substituted imidazole sulfonamides were prepared by solidphase chemistry. These compounds constitute the first example of C-linked azoles with such activity. It was found that the compound 51 was the most potent inhibitor of Candida strains at concentration of
