In vitro anti-Candida activity of certain new 3-(1H-Imidazol-1-yl)propan-1- one oxime esters

Article abstract of DOI:10.3390/molecules181012208

Anti-Candida activities of certain new oximes 4a-d and their respective aromatic esters 5a-l are reported. The tested compounds 4a-d and 5a-l exhibited better anti-Candida profiles than fluconazole. Compound 5j, namely (E)-3-(1H-imidazol-1-yl)-1- phenylpropan-1-one O-4-chlorobenzoyl oxime emerged as the most active congener, with a MIC value of 0.0054 μmol/mL being more potent than both fluconazole (MIC > 1.6325 μmol/mL) and miconazole (MIC value = 0.0188 μmol/mL) as a new anti-Candida albicans agent.

Full text of DOI:10.3390/molecules181012208

Molecules 2013, 18, 12208-12221; doi:10.3390/molecules181012208
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
In Vitro Anti-Candida Activity of Certain New
3-(1H-Imidazol-1-yl)propan-1-one Oxime Esters
Mohamed I. Attia 1,2,*, Azza S. Zakaria 3,4, Maha S. Almutairi 1 and Soraya W. Ghoneim 1
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451,
Saudi Arabia
2
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries
Research Division, National Research Centre, Dokki, Giza 12622, Egypt
3
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451,
Saudi Arabia
4
Department of Microbiology, Faculty of Pharmacy, Alexandria University, Alexandria 21500,
Egypt
* Author to whom correspondence should be addressed; E-Mail: mattia@ksu.edu.sa.
Received: 1 September 2013; in revised form: 19 September 2013 / Accepted: 23 September 2013 /
Published: 30 September 2013
Abstract: Anti-Candida activities of certain new oximes 4a–d and their respective
aromatic esters 5a–l are reported. The tested compounds 4a–d and 5a–l exhibited better
anti-Candida profiles than fluconazole. Compound 5j, namely (E)-3-(1H-imidazol-1-yl)-1-
phenylpropan-1-one O-4-chlorobenzoyl oxime emerged as the most active congener,
with a MIC value of 0.0054 µmol/mL being more potent than both fluconazole
(MIC > 1.6325 µmol/mL) and miconazole (MIC value = 0.0188 µmol/mL) as a new
anti-Candida albicans agent.
Keywords: synthesis; Mannich reaction; azoles; oxime esters; anti-Candida
1. Introduction
Fungal infections have recently emerged as a growing threat to human health, especially in patients
with weakened or compromised immune systems [1,2]. The organisms most often responsible for
invasive fungal infection are Candida and Aspergillus species [3]. Candida infections are adverse in
their manifestations, varying from superficial skin problems, chronic infection of the nails, mouth,

Molecules 2013, 18
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throat or vagina to frequently fatal systemic diseases that involve the lungs, heart, gastrointestinal tract,
central nervous system and other organs [4]. These infections are considered to be opportunistic in
nature, since some aspect of the host’s defense system is impaired in some way. In spite of the large
number of the available antifungal agents, the medical need is still largely unmet and therefore, efforts
to discover new antifungal agents are a must. This is largely due to the perceived threat of emerging
new pathogenic fungi and resistance of many strains to existing therapy [5–7].
Five major classes of the clinically used antifungal drugs are available, namely polyenes (such as
amphotericin B and nystatin), echinocandins (such as caspofungin), allylamines (such as naftifine and
terbinafine), fluoropyrimidines (such as 5-fluorocytosine) and azoles (such as miconazole, fluconazole
and oxiconazole) (Figure 1) [8–10]. Azole antifungal drugs remain the mainstay of therapy for
candidal life-threatening fungal infections due to their safety profile and high therapeutic index [11].
The mechanism of action of azole antifungals relies on their ability to inhibit Cyt-P450 dependent
sterol 14α-demethylase through binding to the heme cofactor of the cytochrome CYP51 leading to
inhibition of sterols synthesis in fungi [4,12].
Figure 1. Azole antifungal agents used in clinical therapy.
Cl
Cl
R
N
N
N
O
Cl
Cl
O
N
N
N
N
Cl
Cl
Cl
Oxiconazole
Clotrimazole
R = H: Econazole
R = Cl: Miconazole
N
S
N
N
Cl
OH
N
Cl
O
NH2
N
N
F
N
N
F
N
Cl
O
N
H
F
Fluconazole
Tioconazole
5-Flucytosine
An evaluation of the literature exposed that some potent clinically used azole antifungals are derived
from oxime-containing scaffolds [13]. Additionally, most of the available imidazole-containing antifungal
agents have a two carbon atom spacer between the imidazole pharmacophore and an aromatic moiety,
whereas limited information is available about imidazole-containing antifungals having a three-carbon
atom linker between the imidazole pharmacophore and the aromatic moiety [14,15]. Moreover,
Walker et al. reported that some aryl and aralkyl esters of 2-(1H-imidazol-1-yl)-1-phenylethanols
displayed more anti-Candida albicans activity than miconazole [16].

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Based upon the aforementioned premises, we became interested in the development of new
imidazole-containing drug-like anti-Candida agents incorporating oxime functionality, exemplified by
compounds 4a–d as well as their respective aromatic esters, compounds 5a–l.
2. Results and Discussion
2.1. Chemistry
The pivotal ketones 3a–d were prepared using the synthetic strategy outlined in Scheme 1.
Thus, the appropriate acetophenone 1a–d was reacted with dimethylamine hydrochloride and
paraformaldehyde in the presence of a catalytic amount of concentrated hydrochloric acid to yield
Mannich base hydrochlorides 2a–d. Imidazole was alkylated with the appropriate Mannich base 2a–d to
give ketones 3a–d in good yields (Scheme 1).
Scheme 1. Synthesis of the ketones 3a–d.
O
O
O
N
N(CH3)2 .HCl
CH3
N
i
ii
R
R
R
1a-d
2a-d
3a-d
Compound No.
1a, 2a, 3a
R
H
1b, 2b, 3b
1c, 2c, 3c
4-Cl
4-OCH3
4-CH3
1d, 2d, 3d
Reagents and conditions: (i) HN(CH3)2.HCl, (CH2O)n, conc. HCl, ethanol, reflux, 2 h; (ii) imidazole, water,
reflux, 5 h.
Ketones 3a–d were allowed to react with hydroxylamine hydrochloride in the presence of
potassium hydroxide to yield oximes 4a–d. X-ray crystallography is a decisive analytical tool
which can confirm the configuration of the produced oximes 4a–d. Accordingly, the assigned
(E)-configuration of compounds 4a–d was established via single crystal X-ray structure of the oxime
4a (Figure 2) [17].
The produced oximes 4a–d were subjected to esterification with the appropriate carboxylic acid
derivatives using ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl) in the
presence of 4-dimethylaminopyridine (DMAP) to yield the target compounds 5a–l (Scheme 2). The
1
chemical structures of oximes 4a–d and the title compounds 5a–l were confirmed via IR, H-NMR,
13C-NMR and mass spectral data.

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Figure 2. ORTEP diagram of the title compound 4a drawn at 50% ellipsoids for
non-hydrogen atoms.
Scheme 2. Synthesis of the target compounds 5a–l.
R1
O
N
O
O
NOH
N
i
ii
N
N
N
N
N
R
R
R
3a-d
4a-d
5a-l
Compound No.
R
R1
3a, 4a, 5a
H
C6H5
3b, 4b, 5b
4-Cl
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
3c, 4c, 5c
4-OCH3
3d, 4d, 5d
4-CH3
H
5e
5f
H
4-CH3-C6H4
4-CF3-C6H4
5g
5h
5i
H
H
4-OCH3-C6H4
H
3,4,5-(OCH3)3-C6H2
4-Cl-C6H4
5j
H
5k
5l
H
3-Cl-C6H4
H
2-Cl-C6H4
Reagents and conditions: (i) H2NOH·HCl, KOH, ethanol, reflux, 18 h.; (ii) an appropriate carboxylic acid,
EDCI·HCl, DMAP, DCM, rt, 18 h.
2.2. In Vitro Anti-Candida Activity and SARs
Fluconazole is the gold standard azole antifungal and used clinically as the first line of treatment for
fungal infections, especially those caused by C. albicans. However, its extensive medical use has led to

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the emergence of resistance [18]. The in vitro anti-Candida activity of the synthesized
imidazole-containing oximes 4a–d and their respective aromatic esters 5a–l was evaluated against two
clinical isolates of Candida, C. albicans and C. tropicalis, which are resistant to fluconazole
(MIC > 1.6325 µmol/mL). The test compounds 4a–d and 5a–l incorporate a three-carbon atom bridge
between the imidazole pharmacophore and the aromatic moiety to gain insight about anti-Candida
activity of this type of compounds. The anti-Candida activities, expressed as diameter of the inhibition
zone (DIZ) and minimum inhibition concentration (MIC) for the oximes 4a–d, the target compounds
5a–l as well as for the reference drugs fluconazole and miconazole, are summarized in Table 1.
Table 1. Anti-Candida activity of oximes 4a–d and the target compounds 5a–l against
Candida albicans and Candida tropicalis.
Compound No
Candida albicans
Candida tropicalis
DIZ ± SD *
MIC (µmol/mL) **
0.5807
DIZ ± SD *
MIC (µmol/mL) **
0.5807
4a
21 ± 1.0
13 ± 0.6
9 ± 1.15
8 ± 1.0
20 ± 0.5
8 ± 1.0
4b
0.5019
0.5019
4c
0.5099
8 ± 1.0
0.2549
4d
0.5456
8 ± 1.0
0.5456
5a
11 ± 1.2
18 ± 1.1
16 ± 0.4
18 ± 0.9
16 ± 0.9
7 ± 1.0
0.3919
8 ± 1.0
0.7837
5b
0.0805
12 ± 1.0
16 ± 1.2
14 ± 0.5
14 ± 0.6
8 ± 1.0
0.6439
5c
0.3257
0.3257
5d
0.1699
0.3398
5e
0.3708
0.3708
5f
0.3752
0.1876
5g
13 ± 0.6
24 ± 1.1
17 ± 1.1
25 ± 1.0
20 ± 0.9
12 ± 1.0
15 ± 0.5
38 ± 1.1
0.6454
14 ± 1.0
17 ± 1.0
14 ± 0.5
25 ± 1.2
14 ± 0.5
12 ± 0.7
16 ± 0.5
24 ± 0.5
0.3227
5h
0.0112
0.3582
5i
0.3053
0.3053
5j
5k
0.0054
0.1767
0.0221
0.7069
5l
0.7069
0.3535
Fluconazole
Miconazole
>1.6325
0.0188
>1.6325
0.0024
* The arithmetic mean of the inhibition zone diameters in mean ± standard deviation in mm. ** The lowest
concentration of the compound that produced 80% microbial growth inhibition (μmol/mL).
The preliminary anti-Candida potential of the test compounds 4a–d and 5a–l was evaluated using
the DIZ assay and the results are presented in Table 1. The test compounds displayed a promising
anti-Candida activity (DIZ = 7–25 mm) where compound 5j was the most active congener (DIZ = 25 ± 1
and 25 ± 1.2 mm against C. albicans and C. tropicalis, respectively).
The oxime 4a exhibited good anti-Candida activity (MIC value = 0.5807 µmol/mL) toward both
C. albicans and C. tropicalis, being more potent than fluconazole (MIC value > 1.6325 µmol/mL) but
weaker than miconazole (MIC value = 0.0188 and 0.0024 µmol/mL for C. albicans and C. tropicalis,
respectively). Substitution of the aromatic ring of 4a with substituents endowed with different electronic
and steric properties like chloro, methoxy and/or methyl groups gave compounds 4b, 4c and 4d,

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respectively, aiming to enhance its anti-Candida activity. Unfortunately, the anti-Candida activity of 4a did
not improve significantly, except for compound 4c toward C. tropicalis (MIC value = 0.2549 µmol/mL).
De Vita et al. reported that the presence of a second aromatic ring could enhance the antifungal
activity of azoles [19]. Consequently, the respective aromatic esters 5a–l of the oximes 4a–d were
prepared and biologically evaluated as new anti-Candida agents. Esterification of the hydroxyl
group of 4a with benzoic acid gave compound 5a which displayed better anti-Candida activity
(MIC value = 0.3919 µmol/mL) than that of 4a toward C. albicans. Moreover, esterification of the
hydroxyl group of the oximes 4b–d with 4-chlorobenzoic acid gave the respective esters 5b–d.
Compounds 5b–d showed better anti-Candida profile than their respective oximes 4b–d, where
compound 5b is the most active congener with a MIC value of 0.0805 µmol/mL toward C. albicans.
Substitution of the aromatic ester functionality of 5a with fluoride, methyl and/or trifluoromethyl groups
gave compounds 5e–g which exhibited anti-Candida albicans activity comparable with that of 5a, except
for compound 5g (MIC value = 0.6454 µmol/mL) which was weaker than 5a. Compounds 5e–g
displayed better anti-Candida tropicalis profiles than that of 5a where compound 5f is the most active
candidate with a MIC value of 0.1876 µmol/mL.
Substitution of the aromatic ester functionality of 5a with a group endowed with negative inductive
effect and positive mesomeric properties like a methoxy group gave compound 5h, which showed a
comparable anti-Candida albicans profile (MIC value = 0.0112 µmol/mL) with that of miconazole (MIC
value = 0.0188 µmol/mL) and was about 145-fold more potent than fluconazole (MIC > 1.6325 µmol/mL).
This result encouraged us to synthesize the trimethoxy analogue of 5a, compound 5i. Unfortunately,
5i exhibited weaker anti-Candida albicans (MIC value = 0.3053 µmol/mL) than that of 5h.
Compound 5j emerged as the most active congener in the whole series of synthesized compounds
against both C. albicans and C. tropicalis. Compound 5j, the 4-chloro analogue of 5a, exhibited about
3.5-fold and 300-fold more potency than miconazole and the gold standard azole antifungal,
fluconazole, respectively, as a drug-like anti-Candida albicans agent. The positional isomers of
compound 5j, compounds 5k and 5l, displayed weaker anti-Candida activity than that of 5j.
3. Experimental
3.1. Chemistry
3.1.1. General
Melting points were determined on a Gallenkamp melting point apparatus, and are uncorrected.
Infrared (IR) spectra were recorded as KBr disks using the Perkin Elmer FT-IR Spectrum BX
apparatus. NMR spectra were carried out on a Bruker NMR spectrometer operating at 500 MHz for 1H
13
and 125.76 MHz for C at the Research Center, College of Pharmacy, King Saud University, Saudi
Arabia. TMS was used as internal standard and chemical shift values were recorded in ppm on δ scale.
1
The H-NMR data were represented as follows: chemical shifts, multiplicity (s. singlet, d. doublet, t.
triplet, m. multiplet, br. broad) and number of protons. The 13C-NMR data were represented as
chemical shifts and type of carbon. Mass spectra were measured on Agilent Triple Quadrupole 6410 QQQ
LC/MS with an electrospray ionization (ESI) source. Silica gel thin layer chromatography (TLC) plates
from Merck (silica gel precoated aluminium plates with a 245 nm fluorescent indicator) were used for thin

Molecules 2013, 18
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layer chromatography. Visualization was performed by illumination with UV light source (254 nm).
Column chromatography was carried out on silica gel 60 (0.063–0.200 mm) obtained from Merck and
chloroform/methanol (9:0.5) was used as a solvent system.
3.1.2. General Procedure for Preparation of the Ketones 3a–d
The appropriate acetophenone 1a–d (200 mmol), dimethylamine hydrochloride (270 mmol) and
paraformaldehyde (90 mmol) were heated to reflux in absolute ethanol (35 mL) in the presence of
catalytic amount of concentrated hydrochloric acid (0.5 mL). Reflux of the reaction mixture was continued
under stirring for two hours, cooled and acetone (200 mL) was added. The formed Mannich base
hydrochlorides 2a–d were precipitated, filtered off and dried. Subsequently, compounds 2a–d (100 mmol)
were dissolved in water (100 mL) and imidazole (200 mmol) was added. The reaction mixture was
heated to reflux for five hours, cooled and the precipitated solids were collected by filtration to give
ketones 3a–d which were pure enough to be used in the next step.
3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one (3a). Synthesis of 3a was previously reported [14].
1-(4-Chlorophenyl)-3-(1H-imidazol-1-yl)propan-1-one (3b). Synthesis of 3b was previously reported [15].
3-(1H-Imidazol-1-yl)-1-(4-methoxyphenyl)propan-1-one (3c). Synthesis of 3c was previously
reported [20].
3-(1H-Imidazol-1-yl)-1-(4-methylphenyl)propan-1-one (3d). Synthesis of 3d was previously reported [21].
3.1.3. General Procedure for Preparation of the Oximes 4a–d
A mixture of the appropriate ketone 3a–d (10 mmol), hydroxylamine hydrochloride (20 mmol), and
KOH (20 mmol) in ethanol (10 mL) was heated to reflux under stirring for 18 h. The reaction mixture
was allowed to cool to room temperature and the insoluble solids were filtered off. The filtrate was
concentrated under vacuum and the residue was poured onto ice-cold water (15 mL). The precipitated
solids were collected by filtration and dried to give oximes 4a–d which were subsequently subjected to
the esterification step without any further purification.
(1E)-N-Hydroxy-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (4a). [17] Yield 70%; colourless solid
mp. 155–157 °C (ethanol); IR (KBr): ν (cm−1) 3508 (OH), 3149, 3002, 2703, 1644 (C=N), 1600, 1573,
1
1221, 758; H-NMR (CDCl3): δ 3.31 (t, J = 7.1 Hz, 2H, -CH2-CH2-N), 4.28 (t, J = 7.1 Hz, 2H,
-CH2-CH2-N), 6.96 (s, 1H, -N-CH=CH-N=), 7.07 (s, 1H, -N-CH=CH-N=), 7.29–7.49 (m 5H, Ar-H),
7.58 (s, 1H, -N-CH=N-); 13C-NMR (CDCl3): δ 28.3 (-CH2-CH2-N), 41.8 (-CH2-CH2-N), 119.1
(-N-CH=CH-N=), 126.1, 128.8, 128.9 (-N-CH=CH-N=, Ar-CH), 135.1, 137.0 (Ar-C), 139.5
(-N-CH=N-), 155.4 (C=N-OH); MS m/z (ESI): 216.0 [M + 1]+.
(1E)-1-(4-Chlorophenyl)-N-hydroxy-3-(1H-imidazol-1-yl)propan-1-imine (4b). The synthesis and
characterization of 4b were previously reported [22].

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(1E)-N-Hydroxy-3-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)propan-1-imine (4c). Yield 65%; pale
yellow solid mp. 136–138 °C (ethanol); IR (KBr): ν (cm−1) 3512 (OH), 3135, 3026, 2632, 1648 (C=N),
1
1680, 1566, 1228, 752; H-NMR (CDCl3): δ 3.26 (t, J = 6.5 Hz, 2H, -CH2-CH2-N), 3.83 (s, 3H,
OCH3), 4.28 (t, J = 7.1 Hz, 2H, -CH2-CH2-N), 6.89 (d, J = 7.5 Hz, 2H, Ar-H), 6.97 (s, 1H,
-N-CH=CH-N=), 7.08 (s, 1H, -N-CH=CH-N=), 7.44 (d, J = 7.5 Hz, 2H, Ar-H), 7.58 (s, 1H, -N-CH=N-);
13C-NMR (CDCl3): δ 28.9 (-CH2-CH2-N), 43.6 (-CH2-CH2-N), 55.4 (OCH3), 114.0 (Ar-CH), 119.1
(-N-CH=CH-N=), 127.4, 127.9, 129.1 (-N-CH=CH-N=, Ar-CH, Ar-C), 137.1 (-N-CH=N-), 155.4
(C=N-OH), 160.5 (Ar-C); MS m/z (ESI): 246.0 [M + 1]+.
(1E)-N-Hydroxy-3-(1H-imidazol-1-yl)-1-(4-methylphenyl)propan-1-imine (4d). Yield 65%; white solid
mp. 147–149 °C (ethanol); IR (KBr): ν (cm−1) 3509 (OH), 3119, 2702, 1639 (C=N), 1679, 1512, 1230,
738; 1H-NMR (CDCl3): δ 2.27 (s, 3H, CH3), 3.18 (t, J = 7.0 Hz, 2H, -CH2-CH2-N), 4.18 (t, J = 7.0 Hz,
2H, -CH2-CH2-N), 6.88 (s, 1H, -N-CH=CH-N=), 6.99 (s, 1H, -N-CH=CH-N=), 7.08 (d, J = 7.8 Hz,
2H, Ar-H), 7.30 (d, J = 7.9 Hz, 2H, Ar-H), 7.49 (s, 1H, -N-CH=N-); 13C-NMR (CDCl3): δ 21.3 (CH3),
28.9 (-CH2-CH2-N), 43.6 (-CH2-CH2-N), 119.1 (-N-CH=CH-N=), 125.9, 129.1, 129.4 (-N-CH=CH-N=,
Ar-CH), 132.6, 137.1, 139.4 (-N-CH=N-, Ar-C), 154.7 (C=N-OH); MS m/z (ESI): 230.0 [M + 1]+.
3.1.4. General Procedure for the Synthesis of the Target Oxime Esters 5a–l
A solution of the appropriate carboxylic acid (7 mmol) and EDCI·HCl (7.3 mmol) was stirred in
DCM (75 mL) in the presence of DMAP (400 mg). The appropriate oxime 4a–d (6.9 mmol) was added
to the stirred reaction mixture and stirring was continued for further 18 h at room temperature. The
reaction mixture was washed successively with water (2 × 20 mL), 10% NaHCO3 solution (2 × 15 mL),
and water (2 × 15 mL). The organic layer was separated, dried (Na2SO4) and evaporated under
reduced pressure and the residue was purified either by recrystallisation (for solids) or by column
chromatography (for oils).
(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-benzoyl oxime (5a). Yield 41%; colourless viscous oil;
1
IR (KBr): ν (cm−1) 3115, 2943, 1746 (C=O), 1650 (C=N), 1510, 1243, 735; H-NMR (CDCl3):
δ (ppm) = 3.38 (t, J = 7.1 Hz, 2H, -CH2-CH2-N), 4.21 (t, J = 7.1 Hz, 2H, -CH2-CH2-N), 6.84 (s, 1H,
-N-CH=CH-N=), 6.95 (s, 1H, -N-CH=CH-N=), 7.36-7.46 (m, 6H, -N-CH=N-, Ar-H), 7.55-7.60 (m, 2H,
Ar-H), 7.96 (d, J = 7.6 Hz, 2H, Ar-H.); 13C-NMR (CDCl3): δ 31.0 (-CH2-CH2-N), 43.7 (-CH2-CH2-N),
118.8 (-N-CH=CH-N=), 127.3, 128.6, 128.8, 129.1, 129.6, 130.0, 131.3 (-N-CH=CH-N=, Ar-CH,
Ar-C), 133.0, 133.8, 136.9 (-N-CH=N-, Ar-CH, Ar-C), 163.4 (C=N), 163.5 (C=O); MS m/z (ESI):
320.1 [M + 1]+.
(E)-1-(4-Chlorophenyl)-3-(1H-imidazol-1-yl)propan-1-one O-4-chlorobenzoyl oxime (5b). Yield 56%;
white solid mp. 132–134 °C (isopropanol); IR (KBr): ν (cm−1) 3107, 1744 (C=O), 1650 (C=N), 1560,
1513, 1261, 748; 1H-NMR (CDCl3): δ (ppm) = 3.43 (t, J = 6.9 Hz, 2H, -CH2-CH2-N), 4.29 (t, J = 6.9 Hz,
2H, -CH2-CH2-N), 6.89 (s, 1H, -N-CH=CH-N=), 7.02 (s, 1H, -N-CH=CH-N=), 7.41 (d, J = 8.5 Hz,
2H, Ar-H.), 7.49–7.51 (m, 3H, -N-CH=N-, Ar-H), 7.60 (d, J = 8.5 Hz, 2H, Ar-H.), 7.94 (d, J = 8.5 Hz,
2H, Ar-H); 13C-NMR (CDCl3): δ 30.8 (-CH2-CH2-N), 43.7 (-CH2-CH2-N), 118.8 (-N-CH=CH-N=),

Molecules 2013, 18
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126.9, 128.5, 129.2, 129.4, 130.0, 130.9, 131.2, (-N-CH=CH-N=, Ar-CH, Ar-C), 136.9, 137.8, 140.4
(-N-CH=N-, Ar-C), 162.5 (C=N), 162.6 (C=O); MS m/z (ESI): 388.0 [M ]+.
(E)-3-(1H-Imidazol-1-yl)-1-(4-methoxyphenyl)propan-1-one O-4-chlorobenzoyl oxime (5c). Yield
70%; white solid mp. 131–133 °C (isopropanol); IR (KBr): ν (cm−1) 3123, 2366, 1758 (C=O), 1684
1
(C=N), 1564, 1514, 1252, 747; H-NMR (CDCl3): δ (ppm) = 3.44 (t, J = 6.9 Hz, 2H, -CH2-CH2-N),
3.87 (OCH3), 4.32 (t, J = 7.0 Hz, 2H, -CH2-CH2-N), 6.92 (s, 1H, -N-CH=CH-N=), 6.96 (d, J = 8.8 Hz,
2H, Ar-H.), 7.09 (s, 1H, -N-CH=CH-N=), 7.49 (d, J = 8.6 Hz, 2H, Ar-H.), 7.67 (d, J = 9.0 Hz, 2H,
Ar-H.), 7.77 (s, 1H, -N-CH=N-), 7.94 (d, J = 8.6 Hz, 2H, Ar-H); 13C-NMR (CDCl3): δ 30.5
(-CH2-CH2-N), 44.2 (-CH2-CH2-N), 55.5 (OCH3), 114.5 (Ar-CH), 119.1 (-N-CH=CH-N=), 128.5,
128.9, 129.2, 130.9, 131.2, (-N-CH=CH-N=, Ar-CH, Ar-C), 136.8, 140.2 (-N-CH=N-, Ar-C), 162.3,
162.8, 162.9 (C=N, C=O, Ar-C); MS m/z (ESI): 384.2 [M + 1]+
(E)-3-(1H-Imidazol-1-yl)-1-(4-methylphenyl)propan-1-one O-4-chlorobenzoyl oxime (5d). Yield 58%;
white solid mp. 142–144 °C (isopropanol); IR (KBr): ν (cm−1) 3065, 1744 (C=O), 1654 (C=N), 1646,
1
1559, 1508, 1254, 749; H-NMR (CDCl3): δ (ppm) = 2.42 (s, 3H, CH3), 3.46 (t, J = 6.9 Hz, 2H,
-CH2-CH2-N), 4.31 (t, J = 6.9 Hz, 2H, -CH2-CH2-N), 6.91 (s, 1H, -N-CH=CH-N=), 7.09 (s, 1H,
-N-CH=CH-N=), 7.27 (d, J = 7.9 Hz, 2H, Ar-H.), 7.49 (d, J = 8.5 Hz, 2H, Ar-H.), 7.62 (d, J = 8.0 Hz,
2H, Ar-H.), 7.79 (s, 1H, -N-CH=N-), 7.94 (d, J = 8.5 Hz, 2H, Ar-H); 13C-NMR (CDCl3): δ 21.5 (CH3),
30.6 (-CH2-CH2-N), 44.2 (-CH2-CH2-N), 119.1 (-N-CH=CH-N=), 127.2, 128.4, 128.5, 129.2, 129.9,
130.9, 131.2, (-N-CH=CH-N=, Ar-CH, Ar-C), 136.8, 140.2, 142.1 (-N-CH=N-, Ar-C.), 162.7 (C=N),
163.3 (C=O); MS m/z (ESI): 368.2 [M + 1]+.
(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-4-fluorobenzoyl oxime (5e). Yield 62%; pale
yellow solid mp. 114–116 °C (isopropanol); IR (KBr): ν (cm−1) 3115, 2848, 1746 (C=O), 1660 (C=N),
1571, 1249, 739; 1H-NMR (CDCl3): δ (ppm) = 3.46 (t, J = 7.0 Hz, 2H, -CH2-CH2-N), 4.29 (t, J = 7.0 Hz,
2H, -CH2-CH2-N), 6.91 (s, 1H, -N-CH=CH-N=), 7.02 (s, 1H, -N-CH=CH-N=), 7.18–7.21 (m, 2H,
Ar-H), 7.43–7.52 (m, 4H, -N-CH=N-, Ar-H), 7.68 (d, J = 7.4 Hz, 2H, Ar-H.), 8.03–8.05 (m, 2H,
3
Ar-H); C-NMR (CDCl3): δ 30.9 (-CH2-CH2-N), 43.8 (-CH2-CH2-N), 116.1 (d, J = 22.1 Hz, Ar-CH),
118.8 (-N-CH=CH-N=), 124.9, (d, J = 2.6 Hz, Ar-C), 127.3, 129.1, 129.8, 131.4 (-N-CH=CH-N=,
Ar-CH), 132.2 (d, J = 9.4 Hz, Ar-CH), 132.8, 136.9 (-N-CH=N-, Ar-C), 162.5 (C=N), 163.5 (C=O),
167.1 (d, J = 254.0 Hz, Ar-C); MS m/z (ESI): 338.2 [M + 1]+.
(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-4-methylbenzoyl oxime (5f). Yield 62%; pale
yellow solid mp. 125–127 °C (isopropanol); IR (KBr): ν (cm−1) 3115, 2964, 1736 (C=O), 1647 (C=N),
1
1605, 1506, 1248, 750; H-NMR (CDCl3): δ (ppm) = 2.37 (s, 3H, CH3), 3.36 (t, 2H, J = 7.1 Hz,
-CH2-CH2-N), 4.21 (t, 2H, J = 7.0 Hz -CH2-CH2-N), 6.84 (s, 1H, -N-CH=CH-N=), 6.94 (s, 1H,
-N-CH=CH-N=), 7.23 (d, J = 7.8 Hz, 2H, Ar-H), 7.35–7.41 (m, 4H, -N-CH=N-, Ar-H), 7.59 (d, J = 7.0
13
Hz, 2H, Ar-H.), 7.85 (d, J = 8.0 Hz, 2H, Ar-H); C-NMR (CDCl3): δ 21.8 (CH3), 31.1 (-CH2-CH2-N),
43.7 (-CH2-CH2-N), 118.8 (-N-CH=CH-N=), 125.8, 127.2, 129.0, 129.5, 129.6, 130.1, 131.2, 133.1
(-N-CH=CH-N=, Ar-CH, Ar-C), 136.9 (-N-CH=N-), 144.7 (Ar-C), 163.2 (C=N), 163.5 (C=O); MS m/z
(ESI): 334.0 [M + 1]+.

Molecules 2013, 18
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(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-4-(trifluoromethyl)benzoyl oxime (5g). Yield 39%;
white solid mp. 125–127 °C (isopropanol); IR (KBr): ν (cm−1) 3050, 2360, 1750 (C=O), 1653 (C=N),
1559, 1507, 1264, 737; 1H-NMR (CDCl3): δ (ppm) = 3.47–3.49 (m, 2H, -CH2-CH2-N), 4.29–4.32 (m,
2H, -CH2-CH2-N), 6.91 (s, 1H, -N-CH=CH-N=), 7.05 (s, 1H, -N-CH=CH-N=), 7.36–7.55 (m, 4H,
-N-CH=N-, Ar-H), 7.71–7.72 (m, 2H, Ar-H), 7.79 (d, J = 8.0 Hz, 2H, Ar-H.), 8.13 (d, J = 8.0 Hz, 2H,
13
Ar-H); C-NMR (CDCl3): δ 30.8 (-CH2-CH2-N), 43.8 (-CH2-CH2-N), 118.8 (-N-CH=CH-N=), 125.8
(d, J = 3.4 Hz, CF3), 125.9, 127.3, 128.6, 129.2, 129.8, 130.0, 131.6, 132.6 (-N-CH=CH-N=, Ar-CH,
Ar-C), 135.6, 136.9 (-N-CH=N-, Ar-C), 162.4 (C=N), 164.0 (C=O); MS m/z (ESI): 388.1 [M + 1]+.
(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-4-methoxybenzoyl oxime (5h). Yield 40%; off
white solid mp. 108–110 °C (isopropanol); IR (KBr): ν (cm−1) 3117, 2968, 1735 (C=O), 1650 (C=N),
1
1602, 1507, 1248, 765; H-NMR (CDCl3): δ (ppm) = 3.46 (t, J = 6.9 Hz, 2H, -CH2-CH2-N), 3.91 (s,
3H, OCH3), 4.30 (t, J = 6.9 Hz, 2H, -CH2-CH2-N), 6.94 (s, 1H, -N-CH=CH-N=), 7.01 (d, J = 8.8 Hz,
2H, Ar-H), 7.10 (s, 1H, -N-CH=CH-N=), 7.45–7.50 (m, 4H, -N-CH=N-, Ar-H), 7.67 (d, J = 7.0 Hz,
2H, Ar-H.), 8.01 (d, J = 8.8 Hz, 2H, Ar-H); 13C-NMR (CDCl3): δ 31.0 (-CH2-CH2-N), 43.7
(-CH2-CH2-N), 55.6 (OCH3), 114.1 (Ar-CH), 118.8 (-N-CH=CH-N=), 120.7, 127.2, 129.0, 130.0,
131.2, 131.7, 133.1 (-N-CH=CH-N=, Ar-CH, Ar-C), 136.9 (-N-CH=N-), 162.9 (C=N), 163.2 (Ar-C),
164.0 (C=O); MS m/z (ESI): 350.0 [M + 1]+.
(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-3,4,5-trimethoxybenzoyl oxime (5i). Yield 53%;
white solid mp. 135–137 °C (isopropanol); IR (KBr): ν (cm−1) 3103, 2938, 1742 (C=O), 1645 (C=N),
1
1593, 1503, 1231, 749; H-NMR (CDCl3): δ (ppm) = 3.45 (t, J = 6.8 Hz, 2H, -CH2-CH2-N), 3.92
(s, 6H, 2 × OCH3), 3.94 (s, 3H, OCH3), 4.28 (t, J = 6.8 Hz, 2H, -CH2-CH2-N), 6.91 (s, 1H, -N-CH=CH-N=),
7.02 (s, 1H, -N-CH=CH-N=), 7.27–7.50 (m, 6H, -N-CH=N-, Ar-H), 7.67 (d, J = 7.0 Hz, 2H, Ar-H.);
13C-NMR (CDCl3): δ 30.9 (-CH2-CH2-N), 43.6 (-CH2-CH2-N), 56.5 (2 × OCH3), 61.0 (OCH3), 106.9
(Ar-CH), 118.6 (-N-CH=CH-N=), 123.5, 127.3, 129.1, 130.1, 131.3, 132.9 (-N-CH=CH-N=, Ar-CH,
Ar-C), 136.8 (-N-CH=N-), 142.9, 153.2 (Ar-C), 163.2 (C=N), 163.6 (C=O); MS m/z (ESI): 410.1 [M + 1]+.
(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-4-chlorobenzoyl oxime (5j). Yield 54%; colourless
crystals mp. 126–128 °C (isopropanol); IR (KBr): ν (cm−1) 3115, 2970, 1743 (C=O), 1648 (C=N),
1508, 1249, 736; 1H-NMR (CDCl3): δ (ppm) = 3.44 (t, J = 6.7 Hz, 2H, -CH2-CH2-N), 4.27 (t, J = 6.7 Hz,
2H, -CH2-CH2-N), 6.90 (s, 1H, -N-CH=CH-N=), 7.02 (s, 1H, -N-CH=CH-N=), 7.45–7.50 (m, 6H,
-N-CH=N-, Ar-H), 7.68 (d, J = 8.4 Hz, 2H, Ar-H.), 7.95 (d, J = 8.4 Hz, 2H, Ar-H); 13C-NMR (CDCl3):
δ 30.9 (-CH2-CH2-N), 43.7 (-CH2-CH2-N), 118.7 (-N-CH=CH-N=), 127.1, 127.3, 129.1, 129.2, 130.1,
130.9, 131.4, 132.8 (-N-CH=CH-N=, Ar-CH, Ar-C), 136.9 (-N-CH=N-), 140.2 (Ar-C.), 162.7 (C=N),
163.7 (C=O); MS m/z (ESI): 354.1 [M + 1]+.
(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-3-chlorobenzoyl oxime (5k). Yield 61%; pale
1
yellow viscous oil; IR (KBr): ν (cm−1) 3113, 1751 (C=O), 1654 (C=N), 1510, 1282, 739; H-NMR
(DMSO-d6): δ (ppm) = 3.52 (br. s, 2H, -CH2-CH2-N), 4.30 (br. s, 2H, -CH2-CH2-N), 6.80 (s, 1H,
-N-CH=CH-N=), 7.17 (s, 1H, -N-CH=CH-N=), 7.51–7.82 (m, 8H, -N-CH=N-, Ar-H), 8.00 (d, J = 1.5 Hz,
13
2H, Ar-H.); C-NMR (DMSO-d6): δ 30.1 (-CH2-CH2-N), 43.0 (-CH2-CH2-N), 119.3 (-N-CH=CH-N=),

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127.3, 128.1, 128.5, 128.9, 130.3, 130.9, 131.1, 132.9, 133.6, 133.7 (-N-CH=CH-N=, Ar-CH, Ar-C),
137.1 (-N-CH=N-), 161.7 (C=N), 164.8 (C=O); MS m/z (ESI): 354.1 [M]+.
(E)-3-(1H-Imidazol-1-yl)-1-phenylpropan-1-one O-2-chlorobenzoyl oxime (5l). Yield 60%; white solid
mp. 118–120 °C (isopropanol); IR (KBr): ν (cm−1) 3054, 1763 (C=O), 1658 (C=N), 1640, 1511, 1265,
1
739; H-NMR (DMSO-d6): δ (ppm) = 3.45 (br. s, 2H, -CH2-CH2-N), 4.25 (br. s, 2H, -CH2-CH2-N),
6.80 (s, 1H, -N-CH=CH-N=), 7.08 (s, 1H, -N-CH=CH-N=), 7.51-7.67 (m, 7H, -N-CH=N-, Ar-H), 7.75 (d,
J = 6.9 Hz, 2H, Ar-H.), 7.90 (d, J = 7.2 Hz, 1H, Ar-H.); 13C-NMR (DMSO-d6): δ 30.2 (-CH2-CH2-N), 43.0
(-CH2-CH2-N), 119.2 (-N-CH=CH-N=), 127.3, 127.6, 128.5, 128.8, 128.9, 130.9, 131.1, 131.3, 131.9,
132.8, 133.7 (-N-CH=CH-N=, Ar-CH, Ar-C), 137.1 (-N-CH=N-), 162.2 (C=N), 164.6 (C=O); MS m/z
(ESI): 354.1 [M]+.
3.2. Anti-Candida Activity
3.2.1. Anti-Candida Agents
Miconazole was purchased from Sigma-Aldrich Co. (St. Louis, MO, USA) and fluconazole from
Shouguang-Fukang Pharmaceutical Ltd. (Shandong, China). The antifungal discs (containing 25 µg
fluconazole and/or 10 µg miconazole) were purchased from ROSCO (Neo-Sensitabs, Taastrup, Denmark).
Dimethyl sulfoxide (100%) was used to dissolve stock solutions of miconazole, fluconazole and/or
the synthesized compounds 4a–d and 5a–l to obtain an initial concentration of 1000 µg/mL. These
stock solutions were then diluted to the desired concentration with sterile distilled water. Miconazole
and fluconazole antifungal discs were stored at –80 °C until used.
3.2.2. Media
Liquid RPMI 1640 medium supplemented with L-glutamine was purchased from Sigma-Aldrich
Co. (St. Louis, MO, USA) and was added to 2% sodium bicarbonate and 0.165 M morpholine- propane
sulfonic acid (MOPS) from Dojindo Laboratories (Kumamoto, Japan) then adjusted to pH 7.0. Sabouraud
Dextrose Agar (SDA) and Brain Heart Infusion Broth (BHI) from Difco Laboratories (Detroit, MI, USA).
Potato dextrose agar (PDA) was purchased from Eiken Chemical Co. Ltd. (Tokyo, Japan).
3.2.3. Organisms
Two clinical isolates of Candida species were obtained from King Khaled Hospital, Riyadh, Saudi
Arabia. One was identified as C. albicans and the other as C. tropicalis. The yeasts were stored at –70 °C
in BHI with glycerol 5% until tested.
3.2.4. Preparation of Inocula
Preparation of inocula for the broth microdilution testing was performed in accordance with CLSI
documents M27-A2 [23] with RPMI 1640 medium. Yeast isolates were subcultured at 35 °C for 48 h
on PDA plates. Candida cells were then recovered and suspended in 5 mL of sterile saline. The
turbidity of each suspension was adjusted to a 0.5 McFarland standard (corresponding to 1–3 × 106 to
5–3 × 106 CFU/mL) at a wavelength of 530 nm according to the reported method [23]. Each

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suspension was diluted 1,000-fold with sterile RPMI 1640 medium to give a final inoculum of 1–3 × 103 to
5–3× 103 CFU/mL.
3.2.5. Disk Diffusion Assay
The disk diffusion assay was performed as described previously [24]. Colonies obtained from the
Candida strains under test were suspended in sterile saline and adjusted to a 0.5 McFarland standard
(corresponding to 5 × 106 CFU/mL). An aliquot of 100 µL of each yeast suspension was spread
uniformly onto SDA plates. Six mm Whatmann filter paper disks were impregnated with 1000 µg of
the synthesized compounds 4a–d and 5a–l and were allowed to dry. Then they were placed onto the
surface of the inoculated agar plates together with the standard antifungal discs which were then
incubated at 35 °C. Diameters of inhibition zones were measured at 24 h.
3.2.6. Antifungal Susceptibility Studies
The MIC of the reference standards and/or the synthesized compounds 4a–d and 5a–l were
determined with a microdilution test (M27-A2 Protocol), according to the reference method of the
CLSI. The previously prepared yeast inocula (100 µL) were added to each well of 96-well flat-bottom
microdilution plates; each well contained 100 µL of twofold serial dilutions of the standard or the
synthesized compounds 4a–d and 5a–l ranging from 1 µg/mL to 500 µg/mL in RPMI 1640 medium.
Readings were measured at 490 nm with a microplate ELISA reader after each plate was incubated at
35 °C for 48 h. The MICs for the reference standards and/or the synthesized compounds were
determined with 80% growth inhibition at the end point relative to the turbidity of the growth control.
4. Conclusions
Anti-Candida activities of certain new imidazole-containing oximes 4a–d and their respective
aromatic esters 5a–l have been reported. The synthesized compounds 4a–d and 5a–l exhibited
anti-Candida activity better than that of the gold standard antifungal drug, fluconazole. Compound 5j
emerged as the most active congener among the all synthesized compounds, being about 3.5-fold and
300-fold more potent than miconazole and fluconazole, respectively. Compound 5j could be considered
as a prodrug and could serve as a new lead for anti-Candida agents.
Acknowledgments
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at
King Saud University for its funding of this research through the Research Group Project no.
RGP-VPP-196.
Conflicts of Interests
The authors have declared that there is no conflict of interests.

Molecules 2013, 18
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