Synthesis and?antifungal activities of?some?aryl [3-(imidazol-1-yl/triazol-1-ylmethyl) benzofuran-2-yl] ketoximes

Article abstract of DOI:10.1016/j.ejmech.2005.12.013

In this study, some aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketones, aryl (3-methyl-benzofuran-2-yl) ketoximes and aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketoximes were synthesised starting from 2-aryloyl-3-methyl-be

Full text of DOI:10.1016/j.ejmech.2005.12.013

European Journal of Medicinal Chemistry 41 (2006) 651–656
http://france.elsevier.com/direct/ejmech
Short communication
Synthesis and antifungal activities of some aryl
[3-(imidazol-1-yl/triazol-1-ylmethyl) benzofuran-2-yl] ketoximes
Nalan Gündoğdu-Karaburun a,*, Kadriye Benkli a, Yağmur Tunali b, Ümit Uçucu a,
Şeref Demirayak a
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey
b Department of Microbiology, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey
Received 10 January 2005; received in revised form 12 September 2005; accepted 18 December 2005
Available online 22 March 2006
Abstract
In this study, some aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketones, aryl (3-methyl-benzofuran-2-yl) ketoximes and aryl [3-
(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketoximes were synthesised starting from 2-aryloyl-3-methyl-benzofuranes. The structure elu-
1
cidation of the compounds was performed by IR, H-NMR, MASS spectroscopy and elemental analyses. Antifungal activities of the compounds
were examined and moderate activity was obtained.
© 2006 Elsevier SAS. All rights reserved.
Keywords: Aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketoximes; Antifungal activity
1. Introduction
stitute a large group in antifungal drugs, in our literature re-
searches we could find only so few efforts [10,11,17,18] on
combining this group with oximes. Furthermore, we consider
it of high importance to obtain novel azoles as their widespread
and prolonged use has led to the development of the multidrug
resistance, possessing a major hurdle in antifungal therapy [19,
20]. In this study, in continuation of our works on aryl benzo-
furyl ketoxime series, we aimed to combine our potent antifun-
gal aryl (3-methyl-benzofuran-2-yl) ketoximes with an azole
residue, i.e. a well known inhibitor of fungal growth by inhibit-
ing ergosterol synthesis binding to the heme cofactor of the
cytochrome CYP51 [21,22], with the above mentioned ratio-
nale and test the newly synthesised (3-methyl-benzofuran-2-
yl) ketoxime’s, 2-aryloyl-3-(1-imidazolyl or triazolylmethyl)
benzofurane’s and their ketoxime’s antifungal activities.
It is an irrefutable fact that, not only the increase in fungal
infections but also the resistance gained to the currently used
drugs in recent years directed the studies on obtaining new anti-
fungal drugs. Present drugs’ renal toxicity and drug–drug inter-
actions they caused are also major features appealing the search
for novel potent compounds [1]. Concerning this issue, after it
was discovered that oxiconazole I, i.e. carrying both azole and
oxime residue, is a very effective antifungal agent, oximes be-
came of interest. Since then, a number of oximes [2–14] were
synthesised and found to be active against fungi. Encouraged
by the successful results obtained from these works, we
planned to prepare series of diaryl ketoximes, in which one of
the aryl residues was replaced with benzofuran in a bioisosteric
approach and obtained significant antifungal activity, against
Candida albicans, from our works on aryl benzofuryl ketoxime
series [15,16]. Highly effective compounds of these works
should be characterised as; aryl benzofuryl ketoximes, non-sub-
stituted or substituted with a small alkyl group on the oxime
residue. On the other hand, even though azole antifungals con-
* Corresponding author. Tel.: +90 222 335 0581/3781;
fax: +90 222 335 0750.
E-mail address: ngundogd@anadolu.edu.tr (N. Gündoğdu-Karaburun).
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.12.013

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N. Gündoğdu-Karaburun et al. / European Journal of Medicinal Chemistry 41 (2006) 651–656
2. Chemistry
results might seldom be encountered [24]; it was surprising us
to find out that combination of our aryl benzofuryl ketoxime
moiety with azole residue—both with proven antimycotic ac-
tivity and gave satisfactory increases in activity introduced
alone—in a single molecule did not give the desired successful
activity values. Nonetheless, it may be attributed to an unsoli-
cited interaction of the mechanisms involved in these residue’s
activities or the molecule’s changed physicochemical properties
with the introduction of the other moiety.
Aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl]
ketoxime derivatives were synthesised as outlined in the
scheme. The ketones (1) were obtained in modified Rap-Stör-
mer reaction condition [23]. Consequently, they were reacted
with N-bromosuccinimide (NBS) for obtaining aryl [3-(bromo-
methyl)benzofuran-2-yl] ketone derivatives (2) and the latter
with imidazole or triazole for obtaining aryl [3-(imidazol-1-yl/
triazol-1-ylmethyl)benzofuran-2-yl] ketone derivatives (3). The
aimed oxime derivatives, 4 and 5, were obtained by reacting
hydroxylamine hydrochloride with aryl (3-methyl-benzofuran-
2-yl) ketones (1) and aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)
benzofuran-2-yl] ketones (3), respectively. As expected the pre-
sence of E and Z isomers of the oxime derivatives was con-
firmed by a thin layer chromatography and NMR spectral data.
Beside the OH group of the oxime residue, methyl, methoxy
and methylene groups belonging to the E and Z isomers of
the oxime derivatives resonated as two peaks with the corre-
sponding integral values. In the IR spectra C=C and C=N
stretching bands, characteristic for all the compounds were ob-
tained at 1510–1616 cm−1 region. Ketone’s C=O and oxime’s
O–H bands were observed at 1638–1647 and at
3115–3272 cm−1 regions, respectively. All the protons reso-
nated as expected in the NMR spectra. In the NMR spectra
aliphatic protons resonated in two groups for methyl 2.12 and
2.15, methoxy 3.77 and 3.80 and methylene 5.28 and 5.42 ppm
regions, respectively, confirming the presence of the E and Z
isomers. Also, characteristic oxime OH peaks were obtained at
11.80 and 12.87 ppm in two groups.
4. Experimental protocols
4.1. Chemistry
Melting points were determined by using an Electrothermal
9100 digital melting point apparatus and were uncorrected.
Spectroscopic data were recorded on the following instrument,
1
FTIR: Schimadzu 8400S spectrophotometer. H-NMR: Bruker
DPX 400 NMR spectrometer in DMSO-d6 using TMS as inter-
nal standard. MS: VG Platform Mass spectrometer. Analyses
for C, H, N was within 0.4% of the theoretical values, Leco
CHNS Analyser.
The reaction sequences depicted in Scheme 1 were followed
to obtain the new derivatives. Some characteristics of the com-
pounds were given in Table 1.
4.1.1. Aryl (3-methyl-benzofuran-2-yl) ketones (1)
The suitable 2′-hydroxyacetophenone (5 mmol), 2-bromoa-
cetophenone (5 mmol) and potassium carbonate (6 mmol) were
refluxed in acetonitrile for 4 hours. The solvent was evapo-
rated, the residue was washed with water and crystallised from
ethanol.
3. Results and discussion
1b IR (KBr) υmax (cm−1): 1645 (C=O), 1647–1564 (C=N,
1
Antifungal activity tests were performed by macrobroth di-
lution method using C. albicans (NRRL Y-27077 and clinical
isolate, Osmangazi University, Faculty of Medicine, Eskişehir,
Turkey) and Candida glabrata (ATCC 36583) strains. Antifun-
gal agent ketoconazole was used as control. The MIC value
obtained for the control compound is 12.5 μg ml–1 for all Can-
dida strains. The activities of the aimed oxime and azole resi-
due bearing compounds range between 5–12.5 and
5–25 μg ml–1 against C. glabrata and C. albicans, respectively.
In consideration of the results; in regard to the activities of the
benzofuryl ketones 1 to benzofuryl ketoximes 4 and (azol-1-yl)
methylbenzofuryl ketones 3 to (azol-1-yl)methylbenzofuryl ke-
toximes 5, it is seen that furnishing the oxime residue to the
ketones increases the activity almost up to two or four folds
in most of the compounds. However, addition of the azole re-
sidue; in regard to the activities of the benzofuryl ketones 1 to
(azol-1-yl)methylbenzofuryl ketones 3, slightly increased some
of the compound’s activity. Uncooperatively, oxime azole com-
bination; in regard to the activities of the benzofuryl ketoximes
4 to (azol-1-yl)methylbenzofuryl ketoximes 5, was not worked
and the most active compounds appeared to be ketoximes 4.
Although, it is known that failure rate of combination of anti-
fungal agents with rationale to attain synergistic or additive ef-
fects, is still higher than ignorable amounts and antagonistic
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.58 (3H, s,
CH3), 7.39–7.43 (1H, m, Ar-H), 7.56–7.60 (1H, m, Ar-H),
7.65–7.69 (3H, m, Ar-H), 7.88 (1H, d, Ar-H), 8.01–8.04 (2H,
d, j: 8.51 Hz, Ar-H). ES-MS: m/z: Positive polarity: 271
(M + 1) (100%).
1c IR (KBr) υmax (cm−1): 1643 (C=O), 1640–1552 (C=N,
1
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.45 (3H, s,
CH3), 2.54 (3H, s, Ar-CH3), 7.37–7.39 (1H, dd, j: 1.41 Hz, j:
8.58 Hz, Ar-H), 7.55–7.69 (5H, m, Ar-H), 7.96–7.99 (2H, m,
Ar-H).
1f IR (KBr) υmax (cm−1): 1641 (C=O), 1638–1550 (C=N,
1
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.56 (3H, s,
CH3), 7.59 (1H, dd, j: 2.11 Hz, j: 8.86 Hz, Ar-H), 7.66–7.68
(2H, d, j: 8.54 Hz, Ar-H), 7.74 (1H, d, Ar-H), 8.01–8.03 (3H,
m, Ar-H).
4.1.2. Aryl [(3-imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-
yl)] ketones (3)
a) The suitable aryl (3-methyl-benzofuran-2-yl) ketone (1)
(5 mmol), NBS (5 mmol) and benzoyl peroxide (5 mmol) were
refluxed in carbontetrachloride for 5 hours. The solvent was
evaporated; the residue was washed with water then cold etha-
nol. No further purification was done and the product was used
in the second step.

N. Gündoğdu-Karaburun et al. / European Journal of Medicinal Chemistry 41 (2006) 651–656
653
Scheme 1. Synthesis of the compounds.
b) The suitable aryl [3-(bromomethyl)benzofuran-2-yl] ke-
tone (2) (5 mmol), imidazole or 1,2,4-triazole (5.5 mmol) and
potassium carbonate (5 mmol) were refluxed in acetone for
2 hours. The solvent was evaporated and the raw product was
crystallised from ethanol.
triazole-H and Ar-H), 8.75 (1H, s, triazole-H). ES-MS: m/z:
Positive polarity: 337.9 (M + 1) (75%), 286.2 (100%).
4.1.3. Aryl (3-methyl-benzofuran-2-yl) ketoximes (4)
The suitable aryl (3-methyl-benzofuran-2-yl) ketone (1)
(5 mmol), hydroxylamine hydrochloride (7 mmol) and anhy-
drous sodium acetate (7 mmol) were refluxed in ethanol for
3 hours. The reaction mixture was cooled. The crystalline of
raw product was filtered and recrystallised from ethanol.
4b IR (KBr) υmax (cm−1): 3254 (O–H), 1629–1521 (C=N,
C=C). 1H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.15 and
2.20 (3H, two s, CH3), 7.27–7.39 (2H, m, Ar-H), 7.42–7.48
(4H, m, Ar-H), 7.52–7.56 (1H, m, Ar-H), 7.64–7.71 (1H, m,
Ar-H), 11.95 and 12.26 (1H, two s, OH).
3a IR (KBr) υmax (cm−1): 1647 (C=O), 1638–1553 (C=N,
1
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 5.77 (2H, s,
–CH2–), 6.47–6.60 (2H, m, Ar-H), 6.86–6.98 (3H, m, Ar-H),
7.06–7.16 (4H, m, Ar-H), 7.89–8.10 (3H, m, imidazole-H). ES-
MS: m/z: Positive polarity: 303 (M + 1) (100%).
3f IR (KBr) υmax (cm−1): 1643 (C=O), 1640–1564 (C=N,
1
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 5.92 (2H, s,
–CH2–), 7.59–7.63 (3H, m, Ar-H), 7.71–7.75 (2H, m, Ar-H),
7.80–7.82 (1H, d, Ar-H), 7.99 (1H, s, Ar-H), 8.05–8.07 (2H, m,

654
N. Gündoğdu-Karaburun et al. / European Journal of Medicinal Chemistry 41 (2006) 651–656
Table 1
Some characteristics of the compounds
Compounds
R1
R2
R3
X
M.p.
(°C)
202
Yield
(%)
63
Molecular formula
(Anal. C, H, N)
C16H12O2
Molecular
weight
1a
1b
1c
1d
1e
1f
H
H
H
–
236.27
270.72
250.30
284.74
270.72
305.16
266.30
300.74
302.34
303.32
336.78
337.77
336.78
337.77
371.23
372.21
251.29
285.73
265.31
299.76
285.73
320.18
281.31
315.76
317.35
318.34
351.80
352.78
351.80
352.78
386.24
387.23
H
H
Cl
H
–
105
84
70
64
67
68
65
62
64
64
57
62
54
57
61
70
68
71
81
65
68
72
76
64
68
45
46
43
52
53
55
50
53
C16H11ClO2
CH3
CH3
Cl
Cl
H
H
–
C17H14O2
H
Cl
H
–
121
103
123
85
C17H13ClO2
H
–
C
16H11ClO2
16H10Cl2O2
H
Cl
H
–
C
1g
1h
3a
3b
3c
3d
3e
3f
OCH3
OCH3
H
–
C17H14O3
H
Cl
H
–
117
168
160
186
203
94
C17H13ClO3
H
CH
N
CH
N
CH
N
CH
N
–
C19H14N2O2
C18H13N3O2
C19H13ClN2O2
H
H
H
H
H
Cl
Cl
H
H
H
C18H12ClN3O2
Cl
Cl
Cl
Cl
H
H
C19H13ClN2O2
C18H12ClN3O2
C19H12Cl2N2O2
C18H11Cl2N3O2
H
H
163
280
250
113a
125a
134
144
157
180
121
134
121
124
140
138
179
262
247
198
3g
3h
4a
4b
4c
4d
4e
4f
H
Cl
Cl
H
H
H
C16H13NO2
H
H
Cl
H
–
C16H12ClNO2
C17H15NO2
CH3
CH3
Cl
Cl
H
H
–
H
Cl
H
–
C17H14ClNO2
H
–
C16H12ClNO2
H
Cl
H
–
C16H11Cl2NO2
C17H15NO3
4g
4h
5a
5b
5c
5d
5e
5f
OCH3
OCH3
H
–
H
Cl
H
–
C17H14ClNO3
H
CH
N
CH
N
CH
N
CH
N
C
C
C
C
C
C
C
C
19H15N3O2
H
H
H
18H14N4O2
H
H
Cl
Cl
H
19H14ClN3O2
18H13ClN4O2
19H14ClN3O2
18H13ClN4O2
19H13Cl2N3O2
18H12Cl2N4O2
H
H
Cl
Cl
Cl
Cl
H
H
H
5g
5h
H
Cl
Cl
H
a
Ref. [16].
4c IR (KBr) υmax (cm−1): 3221 (O–H), 1634–1546 (C=N,
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.12 (3H, s,
CH3), 7.32–7.41 (2H, dq, j: 1.93 Hz, j: 8.72 Hz, Ar-H), 7.44–
7.60 (3H, m, Ar-H), 7.74–7.80 (2H, dd, Ar-H), 13.62 (1H, bs,
OH).
1
CH3), 2.43 (3H, s, Ar-CH3), 7.11–7.18 (2H, dq, j: 1.32 Hz, j:
8.4 Hz, Ar-H), 7.23–7.35 (1H, d, Ar-H), 7.38–7.48 (5H, m, Ar-
H), 12.61 (1H, s, OH). ES-MS: m/z: Positive polarity: 266
(M + 1) (100%), Negative polarity: 264 (M – 1) (100%).
4d IR (KBr) υmax (cm−1): 3272 (O–H), 1616–1568 (C=N,
C=C). 1H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.14 and
2.22 (3H, two s, CH3), 2.40 and 2.43 (3H, two s, Ar-CH3),
7.13–7.19 (2H, dq, j: 1.34 Hz, j: 8.45 Hz, Ar-H), 7.34–7.36
(1H, d, Ar-H), 7.40–7.48 (3H, m, Ar-H), 7.51–7.54 (1H, m,
Ar-H), 11.94 and 12.26 (1H, two s, OH).
4h IR (KBr) υmax (cm−1): 3250 (O–H), 1623–1595 (C=N,
C=C). 1H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.12 and
2.16 (3H, two s, CH3), 3.77 and 3.80 (3H, two s, Ar-OCH3),
6.86–7.08 (2H, dq, j: 2.07 Hz, j: 8.6 Hz, Ar-H), 7.11–7.17 (2H,
dd, Ar-H), 7.42–7.58 (3H, m, Ar-H), 11.80 and 12.18 (1H, two
s, OH). ES-MS: m/z: Positive polarity: 316 (M + 1) (100%),
Negative polarity: 314 (M – 1) (100%).
4.1.4. Aryl [(3-imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-
yl)] ketoximes (5)
4e IR (KBr) υmax (cm−1): 3123 (O–H), 1621–1552 (C=N,
C=C). 1H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.13 and
2.15 (3H, two s, CH3), 7.32–7.53 (5H, m, Ar-H), 7.58–7.60
(1H, d, Ar-H), 7.74–7.80 (2H, dd, Ar-H), 11.93 and 12.23
(1H, two s, OH).
The suitable aryl [(3-imidazol-1-yl/triazol-1-ylmethyl)ben-
zofuran-2-yl)] ketone (3) (5 mmol), hydroxylamine hydrochlor-
ide (7 mmol) and anhydrous sodium acetate (7 mmol) were
refluxed in ethanol for 3 hours. The reaction mixture was
cooled. The crystalline of raw product was filtered and recrys-
tallised from ethanol.
4f IR (KBr) υmax (cm−1): 3216 (O–H), 1628–1553 (C=N,
1
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 2.20 (3H, s,

N. Gündoğdu-Karaburun et al. / European Journal of Medicinal Chemistry 41 (2006) 651–656
655
Table 2
Twice MIC readings were performed by each chemical agent.
For the antimycotic assays the compounds were dissolved in
DMSO. Further dilutions of the compounds and standard
drug in test medium were prepared at the required quantities
of 100, 75, 50, 25, 12.5, 5, 1, 0.5 μg ml–1 concentrations with
Sabouraud dextrose broth. In order to ensure that the solvent
per se had no effect on yeast growth, a control test was also
performed containing inoculated broth supplemented with
only DMSO at the same dilutions used in our experiments
and found inactive in culture medium. All the compounds
were tested for their in vitro growth inhibitory activity
against the yeast C. albicans (NRRL Y-27077), C. albicans
(clinical isolate obtained from Faculty of Medicine, Osman-
gazi University, Eskişehir, Turkey) and C. glabrata (ATCC
36583).
Antifungal activities of the compounds as MIC (μg ml–1
)
Compounds
C. albicans
C. albicans
C. glabrata
(NRRL Y-27077) (Clinical isolate) (ATCC 36583)
1a
1b
1c
1d
1e
1f
1g
1h
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
5d
5e
5f
5g
5h
25
25
50
50
25
25
25
50
25
25
25
25
25
25
25
25
25
5
12.5
5
5
5
12.5
5
12.5
12.5
25
25
25
25
12.5
12.5
12.5
25
25
50
50
50
25
25
50
25
25
25
25
25
25
25
25
5
5
5
5
12.5
12.5
12.5
12.5
5
12.5
12.5
12.5
12.5
5
12.5
5
12.5
5
5
5
5
5
5
5
5
5
5
12.5
5
Ketoconazole was used as control drug. The observed data
on the antifungal activity of the compounds and the control
drug are given in Table 2.
25
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
25
25
25
25
25
25
12.5
4.2.1. Antifungal assay
The cultures were obtained from Sabouraud dextrose broth
(Difco) at pH 7 and the twofold serial dilutions technique was
applied. The final inoculum size was 5 × 103 CFU ml–1 for
antifungal assay. A set of tubes containing only inoculated
broth was kept as controls. For the antifungal assay after incu-
bation for 24 h at 35 °C, the last tube with no growth of yeast
was recorded to represent the MIC expressed in μg ml–1. Every
experiment in the antifungal assays was replicated twice in or-
der to define the MIC values.
12.5
12.5
5
Ketoconazole
12.5
Acknowledgements
Authors are grateful to Anadolu University, Commission of
Scientific Research Projects for the support of this work.
5a IR (KBr) υmax (cm−1): 3115 (O–H), 1643–1525 (C=N,
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 5.42 (2H, s,
1
–CH2–), 6.83–8.09 (12H, m, Ar-H), 12.64 (1H, s, OH).
References
5c IR (KBr) υmax (cm−1): 3126 (O–H), 1635–1534 (C=N,
1
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 5.32 (2H, s,
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–CH2–), 7.06–8.39 (11H, m, Ar-H), 12.87 (1H, s, OH). ES-
MS: m/z: Positive polarity: 352 (M + 1) (100%).
5e IR (KBr) υmax (cm−1): 3118 (O–H), 1638–1510 (C=N,
C=C). 1H-NMR (400 MHz) (DMSO-d6) δ (ppm): 5.28 and
5.42 (2H, two s, –CH2–), 6.86–7.91 (11H, m, Ar-H), 12.37
and 12.80 (1H, two s, OH). ES-MS: m/z: Positive polarity:
352 (M + 1) (100%).
5f IR (KBr) υmax (cm−1): 3124 (O–H), 1636–1517 (C=N,
1
C=C). H-NMR (400 MHz) (DMSO-d6) δ (ppm): 5.63 (2H, s,
–CH2–), 7.35–7.47 (5H, m, Ar-H), 7.56–7.58 (1H, d, Ar-H),
7.69–7.70 (1H, d, Ar-H), 7.98 (1H, s, Ar-H), 8.67 (2H, s, tria-
zole-H), 12.51 (1H, s, OH). ES-MS: m/z: Positive polarity: 353
(M + 1) (42%), 286.2 (100%), Negative polarity: 351 (M – 1)
(100%).
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