Synthesis and antifungal activities of some aryl(benzofuran-2-yl)ketoximes

Article abstract of DOI:10.1016/S0014-827X(02)01257-0

In this study, some aryl(benzofuran-2-yl)ketoximes and their ethers and esters were synthesised. The structure elucidation of the compounds was performed by IR, ¹H NMR and mass spectroscopic data and elemental analyses results. Antifungal activ

Full text of DOI:10.1016/S0014-827X(02)01257-0

Il Farmaco 57 (2002) 609–612
www.elsevier.com/locate/farmac
Synthesis and antifungal activities of some
aryl(benzofuran-2-yl)ketoximes
a,
a
a
a
8
S¸eref Demirayak *, Umit Uc¸ucu , Kadriye Benkli , Nalan Gu¨ndog˘du-Karaburun ,
Ahmet C¸ ag˘rı Karaburun a, Derya Akar a, Muhammed Karabacak a, Nuri Kiraz b
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu Uni6ersity, 26470 Eskis¸ehir, Turkey
b Department of Microbiology, Faculty of Medicine, Osmangazi Uni6ersity, 26100 Eskis¸ehir, Turkey
Received 12 March 2002; accepted 15 March 2002
Abstract
In this study, some aryl(benzofuran-2-yl)ketoximes and their ethers and esters were synthesised. The structure elucidation of the
1
compounds was performed by IR, H NMR and mass spectroscopic data and elemental analyses results. Antifungal activities of
´
the compounds were examined and notable activity was obtained. © 2002 Editions scientifiques et me´dicales Elsevier SAS. All
rights reserved.
Keywords: Aryl(benzofuran-2-yl)ketoximes; Antifungal activity
1. Introduction
were uncorrected. Spectroscopic data were recorded on
the following instruments, IR: Schimadzu 435 IR spec-
trophotometer, 1H NMR: Bruker DPX 400 NMR spec-
trometer in DMSO-d6 using TMS as internal standard.
Analyses for C, H, N were within 0.4% of the theoreti-
cal values. Aryl(benzofuran-2-yl)ketones were prepared
according to the literature method [6].
The reaction sequences depicted in Scheme 1 were
followed to obtain the new derivatives. Some characte-
ristics of the compounds were given in Table 1.
The increase in fungal infections in recent years,
directed the studies on imidazole and triazole structured
antifungal drugs [1,2]. After it was discovered that
oxiconazole, i.e. carrying both azole and oxime residue,
is a very effective antifungal agent, oximes became of
interest. During our literature researches we had ob-
served that benzophenone oximes were effective against
phytopathogenic fungi both in vitro and in vivo [1]. It
was proved that the activity increased when one of the
aryl residues was heteroaryl [3–5] (i.e. pyridine or
furane). Besides, it was reported that free oximes and
their ethers or esters showed notably higher activities
[4]. In consideration of all these findings, in this study,
we aimed to obtain aryl(benzofuran-2-yl)ketoximes and
their ethers and esters and test their antifungal activity.
2.1. Aryl(benzofuran-2-yl)ketoximes (2)
The suitable aryl(benzofuran-2-yl)ketone (1), (5
mmol), hydroxylamine hydrochloride (7 mmol) and
anhydrous sodium acetate (7 mmol) were refluxed in
ethanol for 3 h. The reaction mixture was cooled. The
crystalline raw product was filtered and recrystallised
from ethanol.
2. Chemistry
2a IR (KBr) wmax (cm−1): 3192 (OꢀH), 1639–1512
(CꢁN, CꢁC), 1H NMR (400 MHz) (DMSO-d6) l
(ppm): 7.16–7.75 (10H, m, ArꢀH), 12.30 (1H, s, OꢀH).
2c IR (KBr) wmax (cm−1): 3202 (OꢀH), 1642–1510
(CꢁN, CꢁC), 1H NMR (400 MHz) (DMSO-d6) l
(ppm): 3.80 (3H, s, ArꢀOCH3), 6.78 (2H, d, j:8.82 Hz,
ArꢀH), 7.20–7.74 (7H, m, ArꢀH), 12.32 (1H, s, OꢀH).
Melting points were determined by using an Elec-
trothermal 9100 digital melting point apparatus and
* Correspondence and reprints
E-mail address: sdemiray@anadolu.edu.tr (S¸. Demirayak).
´
0014-827X/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0014-827X(02)01257-0

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S¸. Demirayak et al. / Il Farmaco 57 (2002) 609–612
2.2. Aryl(benzofuran-2-yl)-O-alkylketoximes (3)
ArꢀH), 7.13–7.49 (2H, m, ArꢀH), 7.38 (2H, d, j: 8.65
Hz, ArꢀH), 7.43–7.61 (2H, m, ArꢀH).
The suitable aryl(benzofuran-2-yl)ketone (1), (5
mmol), derivative of alkylhydroxylamine (7 mmol) and
anhydrous sodium acetate (7 mmol) were refluxed in
ethanol for 3 h. The reaction mixture was cooled. The
crystalline raw product was filtered and recrystallised
from ethanol.
3f IR (KBr) wmax (cm−1): 1645–1500 (CꢁN, CꢁC), 1H
NMR (400 MHz) (DMSO-d6) l (ppm): 1.12 and 1.26
(3H, two t, NꢀOꢀCH2ꢀCH3), 3.81(3H, s, ArꢀOCH3),
4.09 and 4.18 (2H, two q, NꢀOꢀCH2ꢀCH3), 6.41 (1H, s,
ArꢀH), 6.90–7.61 (8H, m, ArꢀH).
3g IR (KBr) wmax (cm−1): 1645–1500 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 3.84 and
3.96 (3H, two s, NꢀOꢀCH3), 6.36 (1H, s, ArꢀH), 7.01–
7.50 (8H, m, ArꢀH), EI MS: m/z: 285.24 [M+], 254.10,
219.43, 205.26, 62.51 (100%).
3a IR (KBr) wmax (cm−1): 1642–1510 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 3.95 and
4.07 (3H, two s, NꢀOꢀCH3), 6.96–7.65 (10H, m,
ArꢀH), EI MS: m/z: 251.10 [M+], 236.60, 76.10
(100%).
3h IR (KBr) wmax (cm−1): 1645–1500 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 1.10 and
1.23 (3H, two t, NꢀOꢀCH2ꢀCH3), 4.12 and 4.22 (2H,
two q, NꢀOꢀCH2ꢀCH3), 6.36 (1H, s, ArꢀH), 7.04–7.54
(8H, m, ArꢀH).
3e IR (KBr) wmax (cm−1): 1645–1500 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 3.79 and
3.80 (3H, two s, ArꢀOCH3), 4.00 and 4.10 (3H, two s,
NꢀOꢀCH3), 6.56 (1H, s, ArꢀH), 6.93 (2H, d, j: 8.71 Hz,
Scheme 1.

S¸. Demirayak et al. / Il Farmaco 57 (2002) 609–612
611
Table 1
2.4. Aryl(benzofuran-2-yl)ketoxime acetates (5a,c,e,g)
Some characteristics of the compounds
The suitable aryl(benzofuran-2-yl)ketoxime (2), was
refluxed with an excess of acetic anhydride for 1 h. The
reaction mixture was poured into water and neutralised
with sodium bicarbonate solution. The precipitate
formed was filtered and crystallised from ethanol.
5a IR (KBr) wmax (cm−1): 1640–1490 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 2.00 and
2.10 (3H, two s, NꢀOꢀCOCH3), 6.79 (1H, s, ArꢀH),
7.16–7.75 (9H, m, ArꢀH), EI MS: m/z: 279.05 [M+],
236.86, 42.83 (100%).
Comp.
M.p. (°C)
Yield
(%)
Formulae
Molecular
weight
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
5d
5e
5f
122–124 a
162–165
154–156
75
80
72
82
52
58
68
70
68
62
72
70
45
55
48
60
52
65
48
55
65
60
40
62
55
55
65
58
C15H11NO2
C16H13NO2
C16H13NO3
C15H10ClNO2
237.2
251.2
267.2
271.6
251.2
265.2
265.2
279.3
281.2
295.3
285.7
299.7
327.3
361.8
341.3
375.8
357.3
391.8
361.8
396.2
279.2
341.3
293.3
355.3
309.3
371.3
313.7
375.7
166–169
b
C
16H13NO2
b
b
b
C17H15NO2
C17H15NO2
C18H17NO2
C17H15NO3
114–116
97–99
121–123
122–123
67–69
71–72
109–110
95–97
108–109
88–90
132–133
136–137
141–143
69–71
104–106
80–82
87–89
5c IR (KBr) wmax (cm−1): 1625–1510 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 2.12 and
2.33 (3H, two s, ArꢀCH3), 3.85 and 3.86 (3H, two s,
NꢀOꢀCOCH3), 6.95–7.80 (9H, m, ArꢀH).
C
18H17NO3
C16H12ClNO2
17H14ClNO2
C22H17NO2
22H16ClNO2
C23H19NO2
23H18ClNO2
C
C
2.5. Aryl(benzofuran-2-yl)ketoxime benzoates (5b,d,f,h)
C
C23H19NO3
C23H18ClNO3
C22H16ClNO2
C22H15Cl2NO2
C17H13NO3
The suitable aryl(benzofuran-2-yl)ketoxime (2), (2
mmol) and benzoic anhydride (3 mmol) were refluxed
in tetrahydrofurane for 2 h. The solvent was evapo-
rated. The precipitate formed was crystallised from
ethanol.
C
22H15NO3
C18H15NO3
23H17NO3
C18H15NO4
C
5b IR (KBr) wmax (cm−1): 1625–1510 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 7.22–7.84
(15H, m, ArꢀH).
102–103
99–101
98–100
C
C
23H17NO4
17H12ClNO3
5g
5h
5f IR (KBr) wmax (cm−1): 1625–1510 (CꢁN, CꢁC), 1H
NMR (400 MHz) (DMSO-d6) l (ppm): 3.92 (3H, s,
ArꢀOCH3), 7.15–7.80 (14H, m, ArꢀH).
C22H14ClNO3
a Lit. m.p. 118 °C [7].
b Oily.
5h IR (KBr) wmax (cm−1): 1638–1510 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 7.21–7.86
(14H, m, ArꢀH), EI MS: m/z: 375.65 [M+], 253.90,
104.65 (100%).
2.3. Aryl(benzofuran-2-yl)ketoxime ethers (4)
The suitable aryl(benzofuran-2-yl)ketoxime (2), (2
mmol), an appropriate alkylhalide (benzyl bromide or
4-chlorobenzylchloride) (2 mmol) and potassium car-
bonate (2 mmol) were refluxed in acetone for 8 h. The
solvent was evaporated and the residue was washed and
crystallised from ethanol.
3. Antifungal activity
All the compounds were evaluated in vitro for anti-
fungal activity. Antifungal susceptibility testing was
done by using macrobroth dilution test, in accordance
with the National Committee for Clinical Laboratory
Standards [8]. Results are given as minimal inhibitory
concentrations (MIC) in mg/ml in Table 2.
4d IR (KBr) wmax (cm−1): 1635–1515 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 2.02 and
2.17 (3H, two s, ArꢀCH3), 5.02 and 5.17 (2H, two s,
ArꢀCH2ꢀ), 7.06–7.60 (13H, m, ArꢀH).
4f IR (KBr) wmax (cm−1): 1645–1500 (CꢁN, CꢁC), 1H
NMR (400 MHz) (DMSO-d6) l (ppm): 3.82 (3H, s,
ArꢀOCH3), 5.24 and 5.35 (2H, two s, ArꢀCH2ꢀ), 6.78
(1H, s, ArꢀH), 7.01–7.78 (12H, m, ArꢀH).
4. Results and discussion
4g IR (KBr) wmax (cm−1): 1620–1495 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 5.07 and
5.21 (2H, two s, ArꢀCH2ꢀ), 7.01–7.62 (14H, m, ArꢀH).
4h IR (KBr) wmax (cm−1): 1645–1500 (CꢁN, CꢁC),
1H NMR (400 MHz) (DMSO-d6) l (ppm): 5.10 and
5.20 (2H, two s, ArꢀCH2ꢀ), 6.79 (1H, s, ArꢀH), 7.16–
7.75 (12H, m, ArꢀH), EI MS: m/z: 396.40 [M+],
364.00, 292.81, 175.14, 124.26 (100%).
4.1. Chemistry
Aryl(benzofuran-2-yl)ketoxime derivatives were syn-
thesised as outlined in the scheme. The ketones, 1, were
obtained in Modified Rap–Sto¨rmer reaction condition
[6]. O-Alkylketoximes were obtained by using two dif-
ferent methods. While ketones were reacted with O-
methyl or O-ethyl-hydroxylamine in the first method, in

612
S¸. Demirayak et al. / Il Farmaco 57 (2002) 609–612
Table 2
able antifungal activity. Some of our compounds’ MIC
Antifungal activities of the compounds (mg/ml)
values are determined as 1 or 2 mg/ml which is almost
equal to those of the controls’. Nevertheless, the most
significant compound is appeared to be 2a with a MIC
value lower than the control, i.e. 0.5 mg/ml. Highly
effective compounds, 2a–d and 3a–h, should be charac-
terised as, non-substituted or substituted with a small
alkyl group on the oxime residue. As mentioned above,
the lowest MIC value obtained from the compound 2a,
which has the simplest structure of its group in analogy
with this generalisation. However, this relationship
could not be observed in oxime esters of acetyl and
benzoyl derivatives.
Comp.
C. albicans
Comp.
C. albicans
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
4d
0.5
2
2
4
2
4
1
4
2
4
2
1
16
16
16
16
4e
4f
4g
4h
5a
5b
5c
5d
5e
5f
5g
5h
O
16
16
32
8
4
4
8
4
64
8
16
16
1
C
F
2
1
Acknowledgements
Authors are grateful to Anadolu University Research
Fund for the support of this work.
O, Oxiconazole; C, Clotrimazol; F, Fluconazole.
the second method, oxime derivatives, 2, were reacted
with benzylbromide or 4-chlorobenzylchloride. Acetates
or benzoates, 5, were prepared by reacting 2 with acetic
anhydride or benzoic anhydride, respectively. As ex-
pected the presence of E and Z isomers of the oxime
derivatives was confirmed by thin layer chromatogra-
phy and NMR spectra. Thus, in the NMR spectra
aliphatic protons resonated in two different groups with
corresponding integral values. However, aromatic pro-
tons were observed as multipled peaks.
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broth dilution method using Candida albicans strains.
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and fluconazole were used as control. The MIC values
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