Design, Synthesis and Evaluation of New Azoles as Antifungal Agents: a Molecular Hybridization Approach

Article abstract of DOI:10.1007/s11094-016-1354-9

Two benzimidazole derivatives and one nitroimidazole derivative were designed using molecular hybridization approach. The designed compounds were synthesized and their in vitro antifungal activities were tested against Candida albicans and Saccharomyces cerevisiae strains. Based on the antifungal activity data, compound 9 containing 2-methyl-5-nitroimidazole moiety proved to be the most potent compound. It was more active than the reference drugs fluconazole and ketoconazole against S. cerevisiae.

Full text of DOI:10.1007/s11094-016-1354-9

DOI 10.1007/s11094-016-1354-9
Pharmaceutical Chemistry Journal, Vol. 49, No. 10, January, 2016 (Russian Original Vol. 49, No. 10, November, 2015)
DESIGN, SYNTHESIS AND EVALUATION
OF NEW AZOLES AS ANTIFUNGAL AGENTS:
A MOLECULAR HYBRIDIZATION APPROACH
Maryam Iman,1 Talin Peroomian,2 Asghar Davood,2* Mohsen Amini,3
Soroush Sardari,4 and Parisa Azerang4
Original article submitted April 20, 2015.
Two benzimidazole derivatives and one nitroimidazole derivative were designed using molecular hybridiza-
tion approach. The designed compounds were synthesized and their in vitro antifungal activities were tested
against Candida albicans and Saccharomyces cerevisiae strains. Based on the antifungal activity data, com-
pound 9 containing 2-methyl-5-nitroimidazole moiety proved to be the most potent compound. It was more
active than the reference drugs fluconazole and ketoconazole against S. cerevisiae.
Keywords: benzimidazole, nitroimidazole, azole, antifungal activity.
INTRODUCTION
Azole antifungal agents inhibit the cytochrome P450 sterol
14a-demethylase (14DM, CYP51) by a mechanism in which
the heterocyclic nitrogen atom (N-3 of imidazole and N-4 of
triazole) binds to the heme iron atom in the binding site of
fungal enzyme [7, 8]. Oxyconazole (Fig. 1) is one of the fa-
mous azole antifungal agents containing the imidazole ring
with oxyimino moiety that has been widely used in the treat-
ment of fungal infections [9].
Research and development of potent and effective
antifungal agents represents one of the most important ad-
vances in therapeutics, not only in the control of serious in-
fections, but also in the prevention and treatment of some in-
fectious complications of other therapeutic modalities such
as cancer chemotherapy and surgery. Over the past decade,
fungal infection became an important complication and a
major cause of morbidity and mortality in immunocompro-
mised individuals such as those suffering from tuberculosis,
cancer or AIDS and in organ transplant cases [1]. In clinical
practice, antifungal agents that can be used for treating
life-threatening fungal infections are limited. These drugs
fall under five major classes: azoles, allylamines, polyenes,
fluropyrimidines and thiocarbamates [2]. Among these, az-
oles are the most widely used antifungal agents because of
their high therapeutic index.
In addition, some nitroimidazole- and benzimidazole-
containing drugs such as metronidazole, thiabenazole, par-
bendazole, benomyl and carbendazim (Fig. 2) were shown to
have very potent antifungal activity [10]. Recently, a number
of new benzimidazoles have been synthesized and screened
for their antifungal activities (Fig. 3) [11 – 14]. Some evi-
dence suggests that the benzimidazole moiety present in
some compounds (Fig. 2) exhibit a pharmacophore character
for the inhibition of fungal activity [15]. Metronidazole is
one of the nitroimidazole-containing compounds with anti-
bacterial and antifungal activity.
Azoles (Fig. 1) are a large and relatively new group of
synthetic compounds, of which imidazoles and triazoles are
two clinically beneficial families employed in the treatment
of systemic fungal infections as well as in agriculture [3 – 6].
Here we report the design and synthesis of novel
imidazole and benzimidazole derivatives (compounds 7 – 9)
and their screening for antifungal activity. As shown in
Fig. 4, the proposed design is based on the molecular hybrid-
ization approach, with hybridization of two imidazole
(oxyconazole and benzimidazole) pharmacophores capable
of acting as antifungal agents. Therefore, we explored this
idea further based on design, synthesis and pharmacological
evaluation of the new series of compounds containing
benzimidazole and nitroimidazole with oxyimino moiety. To
1
Chemical Injuries Research Center, Baqiyatallah University of Medical
Sciences, Tehran, Iran.
2
Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Is-
lamic Azad University, Tehran, Iran.
3
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Uni-
versity of Medical Sciences, Tehran, Iran.
4
Department of Bioinformatics and Drug Design, Institute Pasteur, Tehran,
Iran.
687
0091-150X/15/4910-0687 © 2015 Springer Science+Business Media New York

688
Maryam Iman et al.
Cl
Cl
Cl
Cl
O
O
N
Cl
Cl
Cl
O
N
H3C
N
N
N
Oxyconazole
Omoconazole
Cl
Cl
Cl
Cl
Cl
O
N
N
N
N
Miconazole
Fig. 1. Structures of azole antifungal agents.
Clotrimazole
achieve a good structure – activity relationship (SAR) in this
series of compounds, the oxyimino part was kept like
oxyconazole and the azole part was changed with
nitroimidazole and various benzimidazoles.
2-chloro-1-(2,4-dichlorophenyl)ethanone (2 g, 8.8 mmol) in
methanol (30 mL) and the reaction mixture was stirred for
72 h at room temperature. The reaction product was precipi-
tated by addition of water (50 mL), filtered, and dried to ob-
tain the target compound as white crystals; yield, 91%; MP,
75 – 78°C; IR (KBr; n, cm–1): 3200 (OH), 1590 (C=N); H
1
EXPERIMENTAL
NMR (CDCl ; d, ppm): 9.07 (bs, 1H, OH), 7.40 – 7.50 (m,
3
1H, phenyl), 7.25 – 7.30 (m, 2H, phenyl), 4.61 (s, 2H, CH );
Chemistry
2
C H Cl NO.
8
6
3
1H-Benzimidazole (2). This compound was prepared
Nitroimidazole and benzimidazole derivatives (com-
pounds 7 – 9) were synthesized according to scheme in
Fig. 5. These compounds were prepared by reaction of
nitroimidazole and benzimidazoles (compounds 2 and 3)
[16] with 2-chloro-1-(2, 4-dichlorophenyl)-N-hydroxyetha-
nimine and 2, 4-dichlorobenzylchloride in two steps
[17 – 19].
according to the literature [16]; MP, 171 – 172°C; IR (KBr;
1
n, cm–1): 3110 (NH); H NMR (CDCl ; d, ppm): 8.05 (bs,
3
1H, NH), 7.58 – 7.70 (m, 3H, H-2, H-4 and H-7
benzimidazole), 7.28 – 7.39 (m, 2H, H-5 and H-6
benzimidazole); C H N
7
6
2
2-Methyl-1H-benzimidazole (3). This compound was
prepared according to the literature [16]; MP, 176°C; IR
All compounds were characterized by TLC, followed by
IR, elemental analysis and, proton NMR. Melting points
were determined using a Thomas-Hoover capillary apparatus
1
(KBr; n, cm–1): 3120; (NH); H NMR (CDCl ; d, ppm):
3
7.35 – 7.55 (m, 2H, H-4 and H-7 benzimidazole), 7.05 – 7.30
(m, 2H, H-5 and H-6 benzimidazole), 6.30 (bs, 1H, NH),
2.59 (s, 3H, CH ); C H N .
1
and were uncorrected. The H NMR spectra were recorded
on a Bruker FT-500 spectrometer, using TMS as an internal
standard. The IR spectra were measured on a Nicolet 550
FT-IR spectrometer. Elemental analysis was carried out with
a Perkin-Elmer model 240-C apparatus. The results of ele-
mental analysis (C, H, N) were within 0.4% of the calcu-
lated values.
3
8
8
2
2-(1H-Benzimidazol-1-yl)-1-(2,4-dichlorophenyl)-N-h
ydroxyethanimine (4). Compound 1 (1 g, 4.19 mmol) was
gradually added to a solution of compound 2 (1.5 g,
12.7 mmol) in DMF (10 mL) and the resulting mixture was
stirred for 10 h at room temperature. The reaction product
was precipitated by addition of water (20 mL), filtered,
washed, and dried to obtain the target compound; yield, 79%;
MP, 200 – 201°C; IR (KBr; n, cm–1): 3205 (OH), 1592
2-Chloro-1-(2,4-dichlorophenyl)-N-hydroxyethanimi
ne (1). An aqueous solution of hydroxylamine hydrochloride
(1.86 g, 26.7 mmol) was added to
a
solution of

Design, Synthesis and Evaluation of New Azoles
689
H
N
O
H
+
N
N
S
N
NH
O
-
O
N
N
N
N
O
H3C
OH
CH3
Thiabendazole
Carbendazim
Metronidazole
H
N
O
NH
NH
O
CH3
H3C
N
N
N
O
NH
O
CH3
O
CH3
Benomyl
Parbendazole
Fig. 2. Structures of some nitroimidazole and benzimidazole based antifungal agents.
(C=N).; 1H NMR (CDCl ; d, ppm): 7.55 – 7.80 (m, 2H, H-4
OH), 7.04 – 7.60 (m, 7H, aromatic), 5.21 (s, 2H, CH ), 2.40
2
3
(s, 3H, CH ); C H Cl N O.
and H-7 benzimidazole), 7.00 – 7.50 (m, 4H, H-5, H-6
benzimidazole and H-3, H-6 phenyl), 6.73 (d, J= 8.1 Hz, 1H,
H-5 phenyl), 5.25 (s, 2H, CH ); C H Cl N O.
3
16 13
2
3
1-(2,4-Dichlorophenyl)-N-hydroxy-2-(2-methyl-5-ni-
tro-1H-imidazol-1-yl)ethanimine (6). Compound 1 (0.5g,
2
15 11
2
3
2.09 mmol) was gradually added to
a solution of
1-(2,4-Dichlorophenyl)-N-hydroxy-2-(2-methyl-1H-b
enzimidazol-1-yl)ethanimine (5). Compound 1 (0.97g,
4.06 mmol) was gradually added to a solution of compound
3 (1.6 g, 12.20 mmol) in DMF (10 mL) and the resulting
mixtrue was stirred for 10 h at room temperature. The reac-
tion product was precipitated by addition of water (20 mL),
filtered, washed, and dried to obtain the target compound;
yield 71%; MP, 240 – 241°C; IR (KBr; n, cm–1): 3480 (OH),
2-methyl-5-nitroimidazole (0.8 g, 6.3 mmol) in DMF (7 mL)
and the resulting mixture was stirred for 48 h at room tem-
perature. The reaction product was precipitated by addition
of water (15 mL), filtered, washed, and dried to obtain the
target compound; yield, 74%; MP, 220 – 221°C; IR (KBr; n,
cm–1): 1602 (C=N), 1535 and 1369 (NO ); 1H NMR
2
(DMSO-d ; d, ppm): 7.59 (s, 1H, imidazole), 7.50 (d,
6
1
J = 2.4 Hz, 1H, H-3 phenyl), 7.31 (dd, J = 8.4 Hz, J = 2.4 Hz,
1610 (C=N); H NMR (DMSO-d ; d, ppm): 11.43 (s, 1H,
6
CH3
N
N
N
F
CH3
N
H2N
O
N
N
NH
O
S
N
H
N
O
CH3
Fig. 3. Some recently synthetized benzimidazole-containing antifungal agents.

690
Maryam Iman et al.
H-5 phenyl), 6.90 (d, J = 8.4 Hz, 1H, H-6 phenyl), 5.18 (s,
2H, CH ), 2.45 (s, 3H, CH ); C H Cl N O .
N-((2,4-Dichlorobenzyl)oxy)-1-(2,4-dichlorophenyl)-2
-(2-methyl-1H-benzimidazol-1-yl)ethanimine (8). To a
suspension of compound 5 (1 g, 2.99 mmol) and potassium
carbonate (0.41 g, 2.99 mmol) in 15 mL dry DMF was grad-
2
3
12 10
2
4
3
2-(1H-Benzimidazol-1-yl)-N-((2,4-dichlorobenzyl)oxy
)-1-(2,4-dichlorophenyl)ethanimine (7). To a suspension of
compound 4 (1 g, 3.125 mmol) and potassium carbonate
(0.43 g, 3.125 mmol) in 15 mF of dry DMF was gradually
added 0.5 mL (0.6 g, 3.15 mmol) of 2,4-dichlorobenzyl chlo-
ride and the reaction mixture was stirred for 72 h at room
temperature. Then, 40 mL water was added to the mixture
and it was extracted with ethylacetate (3 ´ 20 mL). The sol-
vent was removed under reduced pressure and the oily resi-
due was purified by TLC (silica gel; ethyl acetate – chloro-
form, 5:1) to give the title compound as a white solid; yield,
70%; MP, 132 – 134.5°C; IR (KBr; n, cm–1): 1601 (C=N);
ually
added
0.4 mL
(0.58 g,
2.99 mmol)
of
2,4-dichlorobenzyl chloride and the reaction mixture was
stirred for 72 h at room temperature. Then, 40 mL water was
added and the mixture was extracted with ethylacetate
(3 ´ 20 mL). The solvent was removed under reduced pres-
sure and the oily residue was purified by column chromatog-
raphy (silica gel, chloroform) to obtain the title compound as
a white solid; yield, 63%; MP 124 – 125.5°C; IR (KBr; n,
1
cm–1): 1590 (C=N); H NMR (CDCl ; d, ppm): 7.68 (d,
3
J = 8 Hz, 1H, aromatic), 7.13 – 7.44 (m, 7H, aromatic)7.07
(dd, J = 8.4 Hz, J = 1.6 Hz, 1H, aromatic), 6.40 (d,
1H NMR (CDCl ; d, ppm): 7.85 (d, J = 8 Hz, 1H, aromatic),
3
J = 8.4 Hz, 1H, aromatic), 5.15 (s, 2H, CH O), 5.05 (s, 2H,
2
7.37 (d, J = 2.4 Hz, 1H, aromatic), 7.32 (t, J = 7.6 Hz, 2H, ar-
omatic), 7.08 (m, 5H, aromatic), 6.90 (dd, J = 8.4 Hz,
J = 2.0 Hz, 1H, aromatic), 6.10 (d, J = 8.8 Hz, 1H, aro-
matic), 5.27 (s, 2H, OCH ), 4.28 (s, 2H, CH );
CH ), 2.35 (s, 3H, CH ); C H Cl N O.
2
3
23 17
4
3
N-((2,4-Dichlorobenzyl)oxy)-1-(2,4-dichlorophenyl)-2
-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanimine (9). To a
suspension of compound 6 (0.7 g, 2.208 mmol) and potas-
sium carbonate (0.3 g, 2.208 mmol) in 8 mL dry DMF was
2
2
C H Cl N O.
22 15
4
3
Cl
Cl
Cl
H
NO
N
S
Cl
N
N
N
N
Thiabendazole
Oxyconazole
Design
Cl
Cl
Cl
O
N
Cl
N
R
N
Fig. 4. Using molecular hybridization approach to design new antifungal agents.

Design, Synthesis and Evaluation of New Azoles
691
NH2
NH2
O
Cl
Cl
Cl
RCOOH
NH2OH.HCl
N
O
N
OH
Cl
+
R
N
Cl
N
-
N
H
O
N
H3C
H
(2,3)
Cl
(1)
HO
H3C
HO
N
N
Cl
N
Cl
N
N
+
N
R
Cl
O
-
N
Cl
O
(4,5)
(6)
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O
H3C
N
Cl
N
Cl
N
N
N
R
Cl
N
+
N
-
O
(9)
O
(7,8)
R=-H,-CH
3
Fig. 5. Synthesis of nitroimidazole and benzimidazole derivatives.
as a white solid; yield 67%; IR (KBr; n, cm–1): 1615 (C=N),
gradually added 0.3 mL (0.43 g, 2.208 mmol) of
2,4-dichlorobenzyl chloride and the reaction mixture was
stirred for 96 h at room temperature. Then, 30 mL water was
added and the mixture was extracted with ethylacetate
(3 ´ 20 mL). The solvent was removed under reduced pres-
sure and the oily residue was purified by TLC (silica gel;
ethyl acetate – chloroform, 3:1) to obtain the title compound
1
1367 and 1530 (NO ); H NMR (CDCl ; d, ppm): 7.59 (s,
2
3
1H, imidazole), 7.56 (s, 1H, aromatic), 7.45 (s, 1H, aro-
matic), 7.36 (d, J = 6.8 Hz, 1H, aromatic), 7.30 (d,
J = 8.4 Hz, 1H, aromatic), 7.24 (d, J = 8 Hz, 1H, aromatic),
6.94 (d, J = 8 Hz, 1H, aromatic), 5.25 (s, 2H, CH O), 4.95 (s,
2
2H, CH ), 2.35 (s, 3H, CH ); C H Cl N O .
2
3
19 14
4
4
3

692
Maryam Iman et al.
TABLE 1. Antifungal Activity of Compounds 7 – 9 against S.
cerevisiae PTCC 5052
TABLE 2. Antifungal Activity of Compounds 7 – 9 against C.
albicans ATCC 10231
MIC, mM
MIC, mM
Compound
R
Compound
R
24 h
48 h
24 h
48 h
7
8
benzimidazole
>2086.89
>2027.57
>2086.89
>2027.57
7
8
benzimidazole
>2086
>2027
>2086
>2027
2-methylbenzimid-
azole
2-methylbenz-
imidazole
9
2-methyl-5-nitro-
imidazole
128.02
128.02
9
2-methyl-5-nitro-
imidazole
64.01*
64.01*
Fluconazole
Ketoconazole
Amphotericin B
DMSO
2.28
<1.3
4.89
1.3
Fluconazole
Ketoconazole
Amphotericin B
DMSO
326.5
94.08
326.5
188.16
<4.2
4.2
Not tested
10% v/v
Not tested
10% v/v
5% v/v
5% v/v
* p < 0.05.
RESULTS AND DISCUSSION
Antifungal Activity Evaluation
Chemistry
The synthesized compounds were tested against Candida
albicans (ATCC10231) and Saccharomyces cervisiae (PTCC
5052) fungal strains using broth microdilution assay. The
broth microdilution method was implemented according to
NCCLS guidelines [20, 21]. Both strains were sub-cultured
on Sabouraud Maltose Agar (DIFCO, Becton, Dickinson,
USA) growth media. C. albicans and S. cervisiae were sus-
pended in sterile 0.9% NaCl solution. The turbidity of fungal
suspensions was adjusted at 75 – 77% transmittance (T) us-
ing a spectrophotometer at 530 nm. The suspensions were di-
luted 1:1000 in Sabouraud maltose broth for testing. Serial
dilutions of the test compounds with growth medium were
prepared in microdilution wells, and 100 mL of diluted sus-
pension was added to 100 mL of each test compounds solu-
tion. Microdilution trays were incubated at 35°C and exam-
ined after 24 and 48 h to determine MIC (minimum inhibi-
tory concentration) values. Amphotericin B (AppliChem,
Germany), fluconazole, and ketoconazole solutions and
DMSO (Merck) 2.5% were used, respectively, as medium
positive and negative controls [22].
Three new derivatives of imidazole and benzimidazole,
compounds 7 – 9 (Fig. 5), were synthesized using dry DMF
at room temperature and were purified by chromatography in
good yield (63 – 70%). Chemical structures of synthesized
compounds were confirmed using TLC followed by IR, ele-
mental analysis, and proton NMR.
Antifungal Activity
The in vitro antifungal activities of the synthesized com-
pounds 7 – 9 were tested against two representative patho-
genic yeast fungi (C. albicans and S. cerevisiae) using broth
microdilution assay (Tables 1 and 2). The MIC values were
determined by comparison to amphotericin B, fluconazole,
and ketoconazole as reference drugs.
Antifungal activity evaluation against S. cerevisiae (Ta-
ble 1) showed that compounds 7 and 8 did not possess signif-
icant antimicrobial properties against tested pathogenic
fungi, while compound 9 exhibited significant antifungal ef-
fect. MIC values of the synthesized compounds indicate that
compounds 7 and 8, which contain benzimidazole ring, are
not active against S. cerevisiae. Compound 9, which contains
2-methyl-5-nitroimidazolemoiety, is most active against S.
cerevisiae (with a MIC value of 64.01 mM). In addition, the
activity of this compound against S. cerevisiae after 24 h is
higher than that of reference drugs fluconazole and
ketoconazole (with MIC values 326.5 and 94.08 respec-
tively). Our antifungal evaluation results showed that com-
pound 9 was active against S. cerevisiae after 24 and 48 h,
being about 5 and 1.5 times more active than fluconazole and
ketoconazole after 24 h, respectively, and about 3 times more
active than ketoconazole after 48 h.
Statistical Analysis
The one-way ANOVA statistical test was used to assess
the significance of differences between various groups. In
the case of significant F values, multiple comparison Tukey
test was used to compare the means of different treatment
groups. Results with P < 0.05 were considered to be statisti-
cally significant.

Design, Synthesis and Evaluation of New Azoles
693
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