Design, synthesis and antifungal activity of some new imidazole and triazole derivatives

Article abstract of DOI:10.1002/ardp.201000357

Triazole and imidazole are incorporated into the structures of many antifungal compounds. In this study a novel series of 1,2,4-triazole, imidazole, benzoimidazole, and benzotriazole derivatives was designed as inhibitors of cytochrome P450 14α-demethylase (14DM). These structures were docked into the active site of MT-CYP51, using Autodock program. Sixteen compounds with the best binding energy were synthesized. The chemical structures of the new compounds were confirmed by elemental and spectral (¹H-NMR and Mass) analyses. All compounds were investigated for antifungal activity against Candida albicans, Candida tropicalis, Candida glabrata, Candida parapeilosis, Candida kruzei, Candida dubliniensis, Aspergillus fomigatus, Aspergillus flavus, Microsporum canis, Microsporum gypseum, Trichophyton mentagrophyte, Epidermophyton floccosum. Some compounds showed excellent in-vitro antifungal activity against most of the tested fungi. Compounds 2, 9, and 10 had antifungal activity against several resistant fungi against fluconazole and itraconazole. A novel series of azole derivatives was designed and synthesized as inhibitors of cytochrome P450 14α-demethylase and the compounds were investigated for antifungal activity. Copyright

Full text of DOI:10.1002/ardp.201000357

658
Arch. Pharm. Chem. Life Sci. 2011, 344, 658–665
Full Paper
Design, Synthesis and Antifungal Activity of Some New
Imidazole and Triazole Derivatives
Zahra Rezaei1, Soghra Khabnadideh1, Kamiar Zomorodian2, Kyvan Pakshir2, Giti Kashi1,
Narges Sanagoei1, and Sanaz Gholami1
1 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Parasitology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
Triazole and imidazole are incorporated into the structures of many antifungal compounds. In this
study a novel series of 1,2,4-triazole, imidazole, benzoimidazole, and benzotriazole derivatives was
designed as inhibitors of cytochrome P450 14a-demethylase (14DM). These structures were docked
into the active site of MT-CYP51, using Autodock program. Sixteen compounds with the best binding
energy were synthesized. The chemical structures of the new compounds were confirmed by
elemental and spectral (1H-NMR and Mass) analyses. All compounds were investigated for
antifungal activity against Candida albicans, Candida tropicalis, Candida glabrata, Candida parapeilosis,
Candida kruzei, Candida dubliniensis, Aspergillus fomigatus, Aspergillus flavus, Microsporum canis, Microsporum
gypseum, Trichophyton mentagrophyte, Epidermophyton floccosum. Some compounds showed excellent in-
vitro antifungal activity against most of the tested fungi. Compounds 2, 9, and 10 had antifungal
activity against several resistant fungi against fluconazole and itraconazole.
Keywords: Antifungal activity / Docking / Imidazole / Triazole
Received: November 20, 2010; Revised: February 14, 2011; Accepted: February 16, 2011
DOI 10.1002/ardp.201000357
Introduction
their clinical use by their spectrum of activity, potency,
solubility, or side effects, but the imidazole group has con-
tributed significantly to the therapy of both superficial and
systemic mycotic infections. Newer antifungal imidazole
derivatives are being developed and this chemical group is
well represented with numerous clinically useful drugs [6].
Antifungal triazole derivatives presently under develop-
ment represent a much needed advance in the field of anti-
fungal chemotherapy. They are the second major chemical
group of antifungal azole derivatives. In general, the triazole
group appears to have a broader spectrum of antifungal
activity and reduced toxicity when compared with the imi-
dazole antifungal drugs [6]. There are many reports on the
structure activity relationships of imidazole and triazole
derivatives that show not only azole rings but also other
moieties in the structure and streoisomerism of the molecule
are effective on antifungal activity [7–9].
In recent years, systemic fungal infections have become
increasingly common, especially in the immunocompro-
mised hosts with cancer or AIDS and in organ transplant
cases [1, 2]. Among the antifungal agents, azoles were used
widely in treatment of fungal infections. Recent epidemio-
logical trends have confirmed the increasing importance of
the infections caused by resistant fungal species to azoles [3].
Azole antifungals act by inhibiting lanosterol cytochrom
P450 14-a-demethylase (CYP51) [4]. CYP51 is an essential
enzyme in the sterol biosynthetic pathway in eukaryotes,
where inhibition by azole drugs in fungi leads to a depletion
of ergosterol [5].
The imidazoles are one of the two major classes of anti-
fungal azole derivatives. Many of these drugs are limited in
In this line, we have recently reported synthesis and also
antifungal activity of several imidazole and triazole deriva-
tives [10–12]. Here a series of azole compounds were designed
by a generating virtual library of compounds. We investi-
gated the active site of the MT-CYP51 (PDB code, 1E9X) using
Correspondence: Zahra Rezaei, Department of Medicinal Chemistry,
Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Shiraz University of Medical Sciences, Shiraz, Iran.
E-mail: rezaeiza@sums.ac.ir
Fax: þ98 711 2424126
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Arch. Pharm. Chem. Life Sci. 2011, 344, 658–665
Design, Synthesis and Antifungal Activity
659
Autodock program and the structures were docked into the
active site of this enzyme. In addition, we synthesized, and
investigated antifungal activity of some new 1,2,4-triazole,
benzotriazole, imidazole and benzimidazole analogues.
mum negative FDE and compound 13 had the lowest negative
FDE (Table 2). Although most of compounds had FDE more
than fluconazole, compounds 1, 2, 6, 7 showed antifungal
activities more than fluconazole. Therefore, there is no cor-
relation between antifungal activity and FDE.
Chemistry
Antifungal Assay
All compounds were prepared according to the method pre-
viously described with minor modification [10]. Imidazole or
triazole, alkyl halide, potassium bicarbonate, tetraethylam-
monium iodide (TEAI) and NaOH in acetonitrile (30–40 mL)
were refluxed for 24–48 h. Then, the reaction mixture was
filtered and the solid was washed with acetonitrile. The
solvent was evaporated in vacuo and the residue was washed
with water and dichloromethane. The organic layer was
dried over Na2SO4, filtered and evaporated in vacuo. The crude
product was purified by column chromatography using
chloroform/ethanol for triazole and imidazole derivatives
and dichloromethane/ethyl acetate for benzotriazole and
benzimidazole derivatives to get the final compounds. The
yield of reactions was 30–66.6% (Table 1). The synthetic route
to these compounds is shown in Scheme 1.
The stock solution of compounds was prepared in DMSO at a
concentration of 200 mg/mL. Agar dilution assay and micro-
dilution method were used to establish the minimum inhibi-
tory concentration (MIC) as well as minimum fungicidal
concentration (MFC) of synthetic derivatives [13, 14]. The
compounds were diluted in solid and broth media to obtain
final concentration from 0.0312 to 256 mg/mL, using PDA
and RPMI 1640 media. The inocula of the molds and yeasts
were prepared from 2-7 days mature colonies grown.
Fluconazole and itraconazole or griseofulvin, depending
on the kind of fungus was used as positive and the solvents
of the compounds as negative blanks. The results are pre-
sented in Tables 3, 4, and 5. As shown in Table 4, compounds
1, 2, 3, 9, 10, and 16 had good antifungal effects against tested
clinical species of Candida. Some compounds like com-
pounds 9 and 10 showed the most antifungal activity against
Candida tropicalis and Candida albicans, which were resistant to
fluconazole as well as itraconazole. Compounds 3, 5, 9, 10,
and 16 had the most antifungal activity against standard
species of Candida (Table 3). The result of antifungal assay
against Aspergillus species showed that compounds 1, 2, 3, 9,
and 10 had good activities (Table 5). All of the compounds also
were tested against several Dermatophytes such as Trichophyton
mentagrophyte, Epidermophyton floccosum and the compounds 1,
2, 3, 5, 8, 9, 10, 11, 15, 16 had the most antifungal activities
(Table 5). As shown in Tables 3, 4, and 5, compounds 3, 9, and
10 had antifungal activity against all the tested fungi and
compounds 12, 13, and 14 did not show any antifungal effect
against investigated fungi in range 0.0312 to 256 mg/mL.
As all alkyl halide used for these reactions were not com-
mercially available, some of them were prepared from appro-
priate alcohols using SOCl2 (Scheme 1).
Results and discussion
Modeling
All the compounds as well as fluconazole were docked into
the active site of 14a-demethylase, which was obtained from
Protein Data Bank (1E9X) using Autodock 3.0.5. All new azole
compounds were characterized by a docking mode in the
active site of the cytochrome P450 14-a-sterol demethylase.
According to the data of FDEs, compound 11 had the maxi-
ROH
SAR
a
The structural activity study shows that antifungal activity is
dependent on the heterocyclic moiety as well as on the
nature of the substituents. The best MFC was 0.5 mg/mL that
was observed for compounds 9 against clinical Candida albi-
cans and 10 against standard Candida albicans and Candida
kruzei. Compounds 9 and 10 were also effective against all
the tested fungi; these compounds have imidazole ring and
smaller size than the other compounds. Also, these com-
pounds are very close to clotrimazole and may be attributed
to the better penetration into fungi cell. In series benzimi-
dazoles, compound 14 did not have any antifungal activity
but compounds 15 and 16 showed moderate to low antifun-
gal activities. The benzotriazoles derivatives also showed very
low antifungal effect against investigated fungi exception
H
N
X
b
X
N
R
RCl
+
N
N
ROH
R
N
a
H
N
b
X
+
RCl
X
N
N
–
Scheme 1. X N or C, (a) SOCl , pyridine, (b) NaOH, K CO ,
–
2
TEAI, acetonitrile.
2
3
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Arch. Pharm. Chem. Life Sci. 2011, 344, 658–665
Table 1. Synthesis of compounds 1–16.
Entry
Azole ring
Alkyl or aryl halide
Product
Time
[h]
Yield
[%]
Cl
N
N
N
NH
1
N
24
55
N
N
Cl
N
N
N
NH
2
3
24
36
N
N
Cl
Cl
O
Cl
N
O
NH
N
24
24
40
30
N
N
N
OCH
3
Cl
N
N
NH
4
5
H CO
3
OCH
N
3
N
(4a)
OCH
3
Cl
N
N
N
N
N
N
N
NH
N
24
30
N
Cl
Cl
(5b)
H
N
N
N
Cl
6
7
48
48
49
48
N
N
N
Cl
H
N
N
N
N
N
N
Cl
Cl
O
Cl
H
N
N
N
O
8
9
48
24
49
N
N
N
Cl
N
N
N
NH
66.6
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Design, Synthesis and Antifungal Activity
661
Cl
Cl
N
10
11
24
30
50
N
N
NH
NH
N
Cl
O
Cl
O
N
46.6
N
OCH
3
Cl
N
N
N
N
N
NH
NH
12
24
38
40
40
H
CO
OCH
3
3
(4a)
OCH
3
Cl
N
N
N
N
N
13
14
Cl
Cl
(5b)
H
N
Cl
N
36
36
53
N
N
Cl
H
N
15
16
56.6
N
N
N
Cl
Cl
O
Cl
H
N
O
36
66.6
N
N
N
(4a) and (5b) were prepared from appropriate alcohols using SOCl2 (Scheme 1).
Microsporum canis. Although it has been reported that a series
of 2-(4-methoxy-phenyl)-1,2,4-triazole [15] and some methox-
yquinoline triazole derivatives [16] showed good antifungal
activity, here the activity decreased by introduction of
methoxy group on triazoles as well as imidazole derivatives.
Furthermore, the compounds with two methoxy groups in
imidazole series like compound 12 did not show any anti-
fungal activity. We have previously reported that the anti-
fungal activity was decreased by the presence of methoxy
group on benzotriazoles derivatives, too [10]. Introducing of
ethyl piperazine moiety in compound 13 resulted in reduced
antifungal activity, compared to compound 10. However,
there is no correlation between FDE and antifungal activity
for all cases, and compounds with low antifungal effect like
compound 12 and 13 have the lowest negative FDE value
(Table 2).
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Arch. Pharm. Chem. Life Sci. 2011, 344, 658–665
Table 2. Docking results of synthesized compounds into the active
site of MT-CytP51 (1E9X).
antifungal effect against the investigated fungi in range
0.0312 to 256 mg/mL. Some compounds like 9 and 10 had
antifungal activity against tested clinical species of Candida
which were resistant to fluconazole as well as itraconazole.
Furthermore, there is no correlation found between FDE and
logp with antifungal activity.
Entry
logp
Final docking energy
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1.9
1.67
2.25
ꢀ0.09
1.45
2.34
2.11
2.69
1.37
1.15
1.72
ꢀ0.61
0.93
1.63
1.41
1.98
0.84
ꢀ10.53
ꢀ11.02
ꢀ11.07
ꢀ9.28
ꢀ9.04
Experimental
ꢀ11.42
ꢀ12.47
ꢀ9.68
All solvents and reagents were purchased from Sigma or Merck
Chemical Companies. The products were purified by column
chromatography techniques. NMR spectra were recorded on a
Brucker Avance DPX 250 MHZ instrument. Mass spectra were
recorded on a Hewlett-Packard GC-MS.
ꢀ10.51
ꢀ10.65
ꢀ13.84
ꢀ8.42
ꢀ8.32
ꢀ8.88
Molecular Docking
ꢀ11.39
ꢀ10.66
ꢀ9.88
The ligands were drawn in the Hyperchem 7.5. The geometry was
optimized through the molecular dynamic method AMBER and
semi-empirical method AM1. The protein was obtained from
Protein Data Bank (1E9X) and then water molecules were
removed from the protein for docking.
Fluconazole
The Autodock software version 3.0.5 was used for the molecu-
lar docking process. The grids were constructed around the
proteins. The Lamarckian Genetic Algorithm method was used
for the global optimum binding position search. A number of
100 cycles of calculation were used in order to get a final binding
position as accurate as possible. All the compounds as well as
fluconazole were docked into the active site of 14a-demethylase.
The complex of ligand-receptor was viewed by Accelry’s
Discovery Studio Visualizer. The docking procedure was run
and the maximum negative final docking energy (FDE) was
calculated (Table 2).
Conclusion
In conclusion, we have synthesized a series of 1,2,4-triazole,
benzotriazole, imidazole, and benzimidazole derivatives.
These compounds were evaluated against some yeasts and
molds. Among the synthesized compounds, compounds 3, 9,
and 10 showed antifungal activity against all tested micro-
organism and compounds 12, 13, and 14 did not show any
Table 3. In-vitro antifungal activities of compounds 1–16 against standard species of Candida.
Compound
Tested fungi (MIC 90% and MFC mg/mL)
C. glabrata C. parapeilosis
MIC MFC
C. albicans
MIC MFC
C. tropicalis
C. kruzei
C. dubliniensis
MIC
MFC
MIC
MFC
MIC
MFC
MIC
MFC
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
32
32
64
>256
32
>256
>256
>256
1
>256
64
128
>256
32
>256
>256
>256
64
1
0.5
16
>256
>256
>256
>256
>256
1
256
64
256
>256
>256
>256
>256
>256
32
0.5
0.5
16
>256
32
>256
>256
>256
0.5
256
128
128
>256
256
>256
>256
>256
0.5
64
256
64
>256
64
>256
>256
>256
0.5
128
>256
>256
>256
256
>256
>256
>256
16
>256
256
>256
256
8
4
4
256
64
256
>256
NT
>256
>256
>256
1
16
256
>256
>256
>256
>256
256
>256
>256
>256
>256
>256
>256
0.5
>256
>256
>256
>256
>256
>256
2
>256
NT
>256
>256
>256
0.5
0.5
0.5
2
256
32
128
0.5
128
2
256
8
32
0.5
0.5
0.5
>256
>256
>256
>256
16
64
>256
>256
>256
>256
>256
>256
>256
–
>256
>256
>256
>256
>256
128
>256
>256
>256
>256
>256
128
>256
>256
>256
>256
>256
128
>256
>256
>256
>256
>256
128
128
>256
>256
>256
128
32
>256
>256
>256
>256
64
>256
>256
>256
>256
64
>256
>256
>256
>256
64
>256
>256
>256
>256
256
Fluconazole
Itraconazole
>256
>256
32
>256
>256
>256
4
0.06
>256
>256
2
0.03
16
0.25
16
0.03
>256
0.06
1
>256
>256
>256
NT ¼ not tested
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Design, Synthesis and Antifungal Activity
663
Table 4. In-vitro antifungal activities of compounds 1–16 against clinical species of Candida.
Compound
Tested fungi (MIC 90% and MFC mg/mL)
C. albicans
C. tropicalis
C. parapeilosis
C. albicans
C. tropicalis
(resistant to fluconazole
and itraconazole)
(resistant to fluconazole
and itraconazole)
MIC
MFC
MIC
MFC
MIC
MFC
MIC
MFC
MIC
MFC
1
2
3
4
8
0.5
4
>256
32
256
128
256
>256
64
16
8
8
>256
64
>256
256
256
>256
256
64
256
256
>256
NT
>256
256
256
>256
NT
8
0.5
>256
>256
NT
>256
256
>256
>256
NT
>256
256
>256
>256
NT
>256
256
>256
>256
NT
5
6
7
8
9
10
11
12
13
14
15
16
>256
>256
>256
0.5
>256
>256
>256
0.5
>256
>256
>256
1
>256
>256
>256
64
>256
>256
>256
0.5
2
256
>256
>256
>256
>256
128
>256
>256
>256
128
32
256
>256
>256
>256
>256
>256
0.5
>256
>256
>256
0.5
>256
>256
>256
32
>256
>256
>256
64
>256
>256
>256
256
0.5
16
4
32
8
64
4
4
>256
>256
>256
>256
64
64
2
0.03
>256
>256
>256
>256
256
128
>256
>256
>256
>256
>256
>256
64
64
4
1
>256
>256
>256
>256
>256
256
>256
>256
>256
>256
256
32
>256
>256
>256
>256
>256
>256
R
>256
>256
>256
>256
>256
128
>256
>256
>256
>256
>256
128
Fluconazole
Itraconazole
>256
>256
0.25
0.125
R
R
R
R
R
R
0.25
R
NT ¼ not tested
R ¼ resistant
General procedures for the synthesis of compounds
(0.065 g, 0.25 mmol), anhydrous potassium carbonate (0.55 g,
4 mmol), and sodium hydroxide (0.16 g, 4 mmol) in acetonitrile
and then stirred for 24–48 h at reflux temperature. Then, the
reaction mixture was filtered and the solid washed with aceto-
Four millimoles of azole compound (1, 2, 4-triazole, 1,2,3-benzo-
triazole, imidazole or benzimidazole) and 3 mmol of aryl or alkyl
halide were added to a solution of tetraethyl ammonium iodide
Table 5. In-vitro antifungal activities of compounds 1–16 against Aspergillus and Dermatophytes.
Compound
Tested fungi (MIC mg/mL)
A. fumigatus
A. flavus
T. mentagrophytes
T. mentagrophytes
M. canis
M. gypseum
MIC
MIC
MIC
MIC
MIC
MIC
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
32
32
128
>256
256
>256
>256
>256
0.5
64
256
256
>256
>256
>256
>256
256
0.5
0.5
128
>256
>256
>256
>256
128
16
32
32
>256
>256
>256
>256
>256
1
4
16
64
>256
64
>256
>256
256
0.5
0.5
64
>256
>256
>256
64
128
NT
1
0.5
8
8
2
8
2
16
1
1
32
>256
>256
>256
8
64
NT
0.6
64
64
64
>256
>256
>256
>256
>256
0.5
4
0.5
8
>256
>256
>256
>256
>256
64
128
>256
>256
>256
32
128
NT
5
>256
>256
>256
>256
>256
128
Fluconazole
Griseofulvin
4
NT
NT
NT
NT
8
1
NT ¼ not tested
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Arch. Pharm. Chem. Life Sci. 2011, 344, 658–665
nitrile. The solvent was evaporated in vacuo and the residue was
washed with water and dichloromethane. The organic layer was
dried over Na2SO4 and then evaporated in vacuo.
reflux condition. The time of reaction was 16 h and the yield was
30%. 1H NMR (CDCl3) d (ppm): 7.2–7.36 (m, 9H, phenyl), 4.27 (s,
1H, CH), 3.58–3.59 (t, 2H, CH2Cl), 2.54 (t, 2H, CH2N), 2.18–2.42 (m,
8H, piperazine). MS (m/z %) 353 (M þ 4, 1.7), 351(M þ 2, 10) 349
(Mþ, 16), 312 (74), 285 (14), 256 (13), 202(100), 179 (16), 125 (21),
165 (100), 147 (100), 84 (42), 70 (16) 42 (28). Anal. calcd. for C19H22
Cl2N2: C, 65.33; H, 6.35; N, 8.02; Found: C, 64.81; H, 5.83; N, 7.97.
1-(Diphenylmethyl)-1H-1,2,4-triazole (1)
The reaction time was 24 h (55%, mp: 528C). 1H-NMR (CDCl3) d
(ppm): 8.00 (s, 1H, triazole), 7.89 (s, 1H, triazole), 7.08–7.39 (m,
10H, phenyl), 6.74 (s, 1H CH). MS (m/z %) 235 (Mþ, 100), 165 (100),
89 (51), 77 (100), 51 (74). Anal. calcd. for C15H13N3: C, 76.57; H,
5.57; N, 17.86; Found: C, 76.41; H, 5.21; N, 17.1.
1-[(4-Chlorophenyl)(phenyl)methyl]-4-[2-1H-1,2,4-triazole-
1-yl)ethyl]piperazine (5)
This product obtained from the reaction of 1 mmol (349 mg) 5b
and 2 mmol (139 mg) 1,2,4-triazole according to the general
procedure. The reaction time was 24 h and the yield was 30%
(mp: 678C). 1H-NMR (CDCl3) d (ppm): 8.17 (s, 1H, triazole), 7.91 (s,
1H, triazole), 7.20–7.71 (m, 9H, phenyl), 4.19 (s, 1H, CH), 4.24–4.30
(t, 2H, CH2N-triazole), 2.78–2.81 (t, 2H, CH2N-piperazine), 2.50 (m,
8H, piperazine). MS (m/z %) 383 (M þ 2, 19), 381 (Mþ, 67), 201
(100), 179 (100), 166 (100), 150 (19), 111 (42), 97 (44) 83 (46), 68
(29), 42 (44). Anal. calcd. for C21H24ClN5: C, 66.04; H, 6.33; N,
18.34; Found: C, 66.28; H, 6.17; N, 18.03.
1-[(4-Chlorophenyl)(phenyl)methyl]-1H-1,2,4-triazole (2)
This compound was synthesized after 24 h (40%, mp: 558C).
1H-NMR (CDCl3) d (ppm): 8.00 (s, 1H, triazole), 7.9 (s, 1H, triazole),
7.02–7.45 (m, 9H, phenyl), 6.7 (s, 1H, CH). MS (m/z %) 271 (M þ 2,
31), 269 (Mþ, 100), 201 (100), 165 (100), 152 (16), 89 (5), 77 (31),
51(9). Anal. calcd. for C15H12ClN3: C, 66.79; H, 4.48; N, 15.58;
Found: C, 67.31; H, 4.58; N, 15.29.
1,2-Diphenyl-2-(1H-1,2,4-triazol-1-yl)ethanone (3)
The reaction time was 24 h (40%, mp: 558C). 1H-NMR (CDCl3)
d (ppm): 8.06 (s, 1H, triazole), 7.69 (s, 1H, triazole), 7.23–7.54
(m, 10H, phenyl), 7.17 (s, 1H CH). MS (m/z %) 263 (Mþ, 12.5), 174
(12), 105 (100), 77 (100), 51 (24). Anal. calcd. for C16H13N3O: C,
72.99; H, 4.98; N, 15.96; Found: C, 73.21; H, 5.15; N, 14.1.
1-(Diphenylmethyl)-1H-1,2,3-benzotriazole (6)
This compound was synthesized after 48 h (49%, mp: 678C). H-
1
NMR (CDCl3) d (ppm): 7.22–7.40 (m, 14H, H-Ar), 7.10 (s, 1H, CH).
MS (m/z %) 285 (Mþ, 42), 167 (100), 139 (13), 89 (10), 77 (59), 64 (20),
51 (26), 39 (14). Anal. calcd. for C19H15N3: C, 79.98; H, 5.30; N,
14.75; Found: C, 80.15; H, 5.84; N, 15.00.
1,10-(Chloromethylene)bis(4-methoxybenzene) (4a)
This product obtained from the reaction of 500 mg 4,40-dimeth-
oxy benzhydrol and 10 mL thionyl chloride in the presence of
pyridine under reflux condition. The time of reaction was 16 h
1-[(4-Chlorophenyl)(phenyl)methyl]-1H-1,2,3-
benzotriazole (7)
This compound was synthesized after 48 h (48%, mp: 668C). H-
1
1
and the yield was 50% with mp: 588C. H-NMR (CDCl3) d (ppm):
6.82–7.26 (m, 8H, phenyl), 6.26 (s, 1H, CH), 3.78 and 3.89 (2s, 6H,
OCH3). MS (m/z %) 264 (M þ 2, 4), 262 (Mþ, 12), 227 (100), 197 (14),
153 (12), 77 (16). Anal. calcd. for C15H15ClO2: C, 68.57; H, 5.75;
Found: C, 69.01; H, 6.15.
NMR (CDCl3) d (ppm): 7.15–8.11 (m, 13H, H-Ar), 7.11 (s, 1H, CH).
MS (m/z %) 321 (M þ 2, 30), 319 (Mþ, 100), 201 (100), 165 (80), 152
(41), 127 (18), 115 (12), 89 (10), 77 (42), 63 (16), 51 (14). Anal. calcd.
for C19H14ClN3: C, 71.36; H, 4.41; N, 13.14; Found: C, 71.21; H,
4.13; N, 13.01.
1-[bis(4-Methoxyphenyl)methyl]-1H-1,2,4-triazole (4)
This compound was synthesized from 2 mmol (523 mg) 4a and
3 mmol (207.21 mg) triazole according the general procedure.
The reaction time was 24 h (30%, mp: 578C). 1H-NMR (CDCl3) d
(ppm): 7.78 (s, 1H, triazole), 7.77 (s, 1H, triazole), 6.8–7.23 (m, 8H,
phenyl), 5.26 (s, 1H, CH), 3.76–3.86 (s, 6H, OCH3). MS (m/z %) 295
(Mþ, 100), 265 (100), 233 (100), 228 (14), 197 (15), 167 (9), 31 (11).
Anal. calcd. for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23; Found: C,
69.81; H, 5.10; N, 14.09.
2-(1H-1,2,3-Benzotriazol-1-yl)-1,2-diphenylethanone (8)
This compound was synthesized after 48 h (48%, mp: 668C).
1H-NMR (CDCl3) d (ppm): 7.15–8.11 (m, 13H, H-Ar), 7.11 (s, 1H,
CH). MS (m/z %) 319 (Mþ, 100), 201 (100), 165 (80), 152 (41), 127
(18), 115 (12), 89 (10), 77 (42), 63 (16), 51 (14). Anal. calcd.
for C20H15N3O: C, 76.66; H, 4.82; N, 13.41; Found: C, 76.14; H,
4.22; N, 12.99.
1-(Diphenylmethyl)-1H-imidazole (9)
This compound was synthesized after 24 h (66.6%, mp: 558C). 1H-
NMR (CDCl3) d (ppm): 7.37 (s, 1H, N–CH–N-imidazole), 7.35–7.06
(m, 10H, phenyl), 6.82 (s, 1H, imidazole), 6.49 (s, 1H, imidazole),
5.42 (s, 1H, CH). MS (m/z %) 234 (Mþ, 100), 168 (80), 77 (80), 51 (20).
Anal. calcd. for C16H14N2: C, 82.02; H, 6.02; N, 11.96; Found: C,
82.65; H, 5.83; N, 11.73.
2-{4-[(4-Chlorophenyl)(phenyl)methyl]piperazino}-1-
ethanol (5a)
This product obtained after 20 h (60%, mp: 618C). 1H-NMR (CDCl3)
d (ppm): 7.2–7.36 (m, 9H, phenyl), 4.21 (s, 1H, CH), 3.58–3.6 (t, 3H,
OH and CH2), 2.54 (t, 2H, N–CH2), 2.18–2.42 (m, 8H, piperazine).
MS (m/z %) 332 (M þ 2, 31), 330 (Mþ, 100), 312 (17), 271 (20), 256
(19), 203 (100). 179 (12), 165 (100), 129 (100), 86 (43), 74 (36), 42
(40). Anal. calcd. for C19H23ClN2O: C, 68.97; H, 7.01; N, 8.47;
Found: C, 68.91; H, 5.71; N, 8.12.
1-[(4-Chlorophenyl)(phenyl)methyl]-1H-imidazole (10)
This compound was synthesized after 24 h (50%, mp: 568C). H-
1
NMR (CDCl3) d (ppm): 7.37 (s, 1H, N–CH–N-imidazole), 7.34–7.01
(m, 9H, phenyl), 6.98 (s, 1H, imidazole), 6.76 (s, 1H, imidazole),
6.46 (s, 1H, CH). MS (m/z %) 270 (M þ 2, 13), 268 (Mþ, 43), 201
(100), 166 (80), 77 (29), Anal. calcd. for C16H13ClN2: C, 71.51; H,
4.88; N, 10.42; Found: C, 71.55; H, 4.71; N, 10.17.
1-(2-Chloroethyl)-4-[(4-chlorophenyl)(phenyl)methyl]-
piperrazine (5b)
This product obtained from reaction between 2 mmole (661 mg)
5a and 15 mL thionyl chloride in the presence of pyridine under
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 344, 658–665
Design, Synthesis and Antifungal Activity
665
Sciences, southern Iran. Sabouraud dextrose agar (SDA), potato
dextrose agar (PDA), oat meal, and RPMI 1640 were used for agar
dilution and macrodilution methods. The clinical isolates of
fungi including Candida albicans, Candida tropicalis, and Candida
parapeilosis were purified and subcultured on SC, SCC, and PDA
media before testing. The stock solution of compounds was
prepared in DMSO at a concentration of 200 mg/ml. The com-
pounds were diluted in solid and broth media to obtain final
concentration from 0.0312 to 256 mg/mL, using PDA and RPMI
1640 media. The inocula of the molds and yeasts were prepared
from 1-10 days mature colonies grown. Fluconazole and itraco-
nazole or griseofulvin were used as positive and the solvents of
the compounds as negative blanks.
2-(1H-imidazol-1-yl)-1,2-diphenylethanone (11)
The time of reaction was 24 h (46.6%, mp ¼ 628C). 1H NMR
(CDCl3) d (ppm): 7.97 (s, 1H, N–CH–N–imidazole), 7.94–2354
(m, 10H, phenyl), 7.07 (s, 1H, imidazole), 5.94 (s, 1H, imidazole),
5.88 (s, 1H, CH). MS (m/z %) 262 (Mþ, 13), 194 (2), 105 (100), 77 (42),
51 (4). Anal. calcd. for C17H14N2O: C, 77.84; H, 5.38; N, 10.68;
Found: C, 77.12; H, 5.18; N, 10.11.
1-[bis(4-Methoxyphenyl)methyl]-1H-imidazole(12)
This compound was synthesized from 3 mmol (787.5 mg) 4a and
4 mmol (272.3 mg) imidazole according the general procedure.
The reaction time was 24 h (40%, mp: 578C). 1H-NMR (CDCl3) d
(ppm): 7.78 (s, 1H, N–CH–N–imidazole), 7.77–6.92 (m, 8H, phe-
nyl), 6.83 (s, 1H, imidazole), 6.8 (s, 1H, imidazole), 5.26 (s, 1H, CH),
3.86–3.76 (s, 6H, OCH3). MS (m/z %) 294 (Mþ, 15), 232 (100), 227
(100), 196 (41), 165 (16), 67 (31), Anal. calcd. for C18H18N2O2: C,
73.45; H, 6.16; N, 9.52; Found: C, 73.06; H, 6.81; N, 9.09.
This work was supported by Shiraz University of Medical Sciences. We are
also thankful to Shiraz University, Dr. Habib Firouzabadi and Dr. S.
Mohammad Reza Jafari. Our thanks are also due to H. Khajehei for his
linguistic copy editing.
1-[(4-Chlorophenyl)phenylmethyl]4-(ethylimidazole)-
piperazine (13)
The authors have declared no conflict of interest.
This product obtained from the reaction of 1 mmol (349 mg) 5b
and 2 mmol (136 mg) imidazole according to the general pro-
cedure. The reaction time was 24 h and the yield was 40% (mp:
658C). 1H-NMR (CDCl3) d (ppm): 7.77 (1H, N–CH–N-imidazole), 7.70
(s, 1H, imidazole), 7.03–7.51 (m, 9H, phenyl), 6.98 (s, 1H, imida-
zole), 4.19 (s, 1H, CH-diphenyl), 4.00–4.03 (t, 2H, CH2N-triazole),
2.68–2.70 (t, 2H, CH2N-piperazine), 1.00–2.50 (m, 8H, piperazine).
MS (m/z %) 382 (M þ 2, 14), 380 (Mþ, 47), 345 (10), 313 (13), 201
(100), 181 (100), 167 (42), 111 (100), 97 (38). Anal. calcd.
for C22H25ClN4: C, 69.37; H, 6.62; N, 14.71; Found: C, 69.10; H,
5.81; N, 14.00.
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201 (100), 168 (50), 90 (31), 77 (16). Anal. calcd. for C20H15ClN2: C,
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HAr), 7.26 (s, 1H, CH). MS (m/z %) 312 (Mþ, 100), 207 (100), 194 (30),
105 (100), 77 (86), 51 (36). Anal. calcd. for C21H16N2O: C, 80.75; H,
5.16; N, 8.97; Found: C, 80.16; H, 4.95; N, 8.65.
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Antifungal Assay
Microorganisms were obtained from the Mycology and
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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com