Synthesis of some oxadiazole derivatives as new anticandidal agents

Article abstract of DOI:10.3390/molecules16097662

In this study, 5-[(pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole-2(3H)-thione (3) was synthesized via the ring closure reaction of 2-(pyrimidin-2-ylthio) acetohydrazide (2) with carbon disulphide. New oxadiazole derivatives 4a-f were obtained by the nucleop

Full text of DOI:10.3390/molecules16097662

Molecules 2011, 16, 7662-7671; doi:10.3390/molecules16097662
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Some Oxadiazole Derivatives as
New Anticandidal Agents
Zafer Asim Kaplancikli
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir,
Turkey; E-Mail: zakaplan@anadolu.edu.tr; Tel.: +90-222-3350580/3776; Fax: +90-222-3350750
Received: 25 July 2011; in revised form: 23 August 2011 / Accepted: 6 September 2011 /
Published: 7 September 2011
Abstract: In this study, 5-[(pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole-2(3H)-thione (3)
was synthesized via the ring closure reaction of 2-(pyrimidin-2-ylthio)acetohydrazide (2)
with carbon disulphide. New oxadiazole derivatives 4a-f were obtained by the nucleophilic
substitution reaction of compound 3 with various phenacyl bromides. The chemical
1
structures of the compounds were elucidated by IR, H-NMR, 13C-NMR and FAB+-MS
spectral data and elemental analyses. The newly synthesized derivatives 4a-f were tested in
vitro by using a microbroth dilution method against C. albicans (clinical isolate,
Osmangazi University, Faculty of Medicine, Eskişehir, Turkey), C. albicans (ATCC
90028), C. glabrata (clinical isolate, Osmangazi University, Faculty of Medicine,
Eskişehir, Turkey), C. tropicalis (NRRL Y-12968), C. krusei (NRRL Y-7179),
C. parapsilosis (NRRL Y- 12696), C. albicans (NRRL Y-12983), C. glabrata (clinical
isolate, Anadolu University, Faculty of Science, Department of Biology, Eskişehir,
Turkey). Among these compounds, compound 4a was found to be the most potent
derivative (MIC = 0.007–0.06 versus ketoconazole: 0.001–0.007 mg/mL) against Candida
species, except C. tropicalis and C. krusei when compared with the standard antifungal
ketoconazole.
Keywords: oxadiazole; pyrimidine; anticandidal activity
1. Introduction
The incidence of invasive fungal infections, particularly those related to Candida species, has
increased worldwide over the past two decades. It is obvious that Candida has emerged as one of the

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Molecules 2011, 16
leading causes of nosocomial bloodstream infections. Although there are some antifungal agents
currently available, the treatment of invasive fungal infections still remains a challenging problem due
to the development of resistance accompanying the widespread use of these drugs. As a consequence
of this situation, medicinal chemists have focused on the development of more effective agents for the
treatment of invasive fungal infections caused by resistant organisms [1-5].
Oxadiazoles have gained great importance in medicinal chemistry owing to their broad spectrum
and metabolic profile [6]. Many studies have confirmed that oxadiazole derivatives possess antifungal
activity [7-14]. Among oxadiazole derivatives, 1,3,4-oxadiazolin-2-thiones have received a great deal
of attention in heterocyclic chemistry as versatile intermediates due to the fact that the thiol group on
oxadiazole ring undergoes nucleophilic substitution reactions readily [15,16].
Pyrimidine derivatives have been found to possess anticandidal activity. Voriconazole, which is an
azole derivative bearing pyrimidine group, is widely used as an antifungal agent for the treatment of
candidiasis [5,17-19]. On the other hand, some researchers have also carried out considerable research
for novel antifungal agents bearing thioether moiety. The prominent compounds bearing thioether
group are butoconazole and sulconazole, all of which are widely used as antifungal drugs for the
treatment of candidiasis [20-22].
In the present study, new oxadiazole derivatives bearing two important functional moieties, namely
pyrimidine and thioether, were synthesized and furthermore, their anticandidal effects were elaborated.
2. Results and Discussion
Initially, 5-[(pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole-2(3H)-thione (3) was obtained by the ring
closure reaction of the acid hydrazide 2 with carbon disulphide in the presence of potassium
hydroxide. The target compounds 4a-f were synthesized via the nucleophilic substitution reaction of
5-[(pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole-2(3H)-thione (3) with various phenacyl bromides.
These reactions are summarized in Scheme 1 and some properties of the compounds are given in
Table 1.
1
The structures of the compounds 4a-f were confirmed by IR, H-NMR, 13C-NMR and FAB-MS
spectral data and Elemental analyses. In the IR spectra of all compounds 4a-f, all derivatives have a
strong, characteristic band in the region 1685–1675 cm−1 due to the C=O stretching vibration. The
bands due to C=C and C=N stretching vibrations are observed in the region 1620–1400 cm−1.
Table 1. Some properties of the compounds (4a-f).
Molecular
formula
Molecular
weight
344
Compound
R
Yield (%)
M.p. (°C)
4a
4b
4c
4d
4e
4f
H
p-Cl
p-NO2
m-NO2
m-Cl
75
85
95
92
84
88
112-114
106-108
145-149
79-80
89-90
75-77
C15H12N4O2S2
C15H11ClN4O2S2
C15H11N5O4S2
C15H11N5O4S2
C15H11ClN4O2S2
C15H10Cl2N4O2S2
378,5
389
389
378,5
413
2,4-Cl

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Molecules 2011, 16
Scheme 1. The synthetic protocol of the compounds (4a-f).
N
N
NH2NH2
H
O
N
N
S
NH2
N
S
O
O
1
2
CS2/KOH
N
N
H
N
N
N
S
O
SH
O
N
S
O
S
N
N
3
Br
R
N
N
N
S
O
S
R
N
O
4a-f
1
In the H NMR spectra of all compounds 4a-f, the signals due to the -S-CH2- protons directly
attached to oxadiazole ring and carbonyl group appeared at 4.67–4.72 ppm and 4.91–5.17 ppm,
respectively. The pyrimidine ring protons were observed in the region 7.25–8.72 ppm. The other
aromatic protons were observed at expected regions.
In their 13C-NMR spectra of 4a-f, the signals due to the carbonyl carbons were observed at
191–193 ppm. The oxadiazole ring carbons appeared at 163.61–165.77 ppm. The aromatic carbons
were observed in the expected regions.

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Molecules 2011, 16
In the mass spectra of all compounds 4a-f, the M+1 peak was observed. All compounds gave
satisfactory elemental analysis.
All compounds were tested in vitro against C. albicans (clinical isolate, Osmangazi University,
Faculty of Medicine, Eskişehir, Turkey), C. albicans (ATCC 90028), C. glabrata (clinical isolate,
Osmangazi University, Faculty of Medicine, Eskişehir, Turkey), C. tropicalis (NRRL Y-12968),
C. krusei (NRRL Y-7179), C. parapsilosis (NRRL Y- 12696), C. albicans (NRRL Y-12983),
C. glabrata (clinical isolate, Anadolu University, Faculty of Science, Department of Biology,
Eskişehir, Turkey) and compared with ketoconazole (Table 2).
Table 2. Anticandidal activities of novel compounds (4a-f) as MIC values (mg/mL).
4a
4b
4c
4d
4e
4f
Ref.
A
B
C
D
E
F
0.015
0.03
0.03
0.015
0.007
0.06
0.06
0.06
0.015
0.03
0.125
0.015
0.03
0.06
0.06
0.03
0.06
0.03
0.06
0.015
0.015
0.03
0.06
0.03
0.125
0.06
0.06
0.06
0.125
0.06
0.125
0.06
0.015
0.03
0.125
0.06
0.03
0.06
0.06
0.03
0.03
0.06
0.06
0.06
0.015
0.06
0.06
0.015
0.007
0.007
0.003
0.001
0.001
0.001
0.001
0.001
G
H
A: C. albicans (clinical isolate, Osmangazi University, Faculty of Medicine, Eskişehir, Turkey),
B: C. albicans (ATCC 90028), C: C. albicans (NRRL Y-12983), D:C. glabrata (clinical isolate,
Osmangazi University, Faculty of Medicine, Eskişehir, Turkey), E: C. glabrata (clinical isolate,
Anadolu University, Faculty of Science, Department of Biology, Eskişehir, Turkey), F: C. krusei
(NRRL Y-7179), G: C. parapsilosis (NRRL Y- 12696), H: C. tropicalis (NRRL Y-12968),
Ref.: Ketoconazole.
The biological results indicate that C. albicans (clinical isolate) is the most susceptible fungus to
compounds 4a, 4b and 4e. These compounds exhibit the strongest inhibitory activity against
C. albicans (clinical isolate) with a MIC value of 0.015 mg/mL, when compared with the standard
antifungal ketoconazole, which exhibits inhibitory activity with a MIC value of 0.007 mg/mL. This
outcome confirms that phenyl and chlorophenyl groups may have a considerable influence on
antifungal activity against the tested clinical C. albicans isolate. It can be attributed to + π effect of
phenyl and chlorophenyl groups. Compounds 4c and 4d exhibit lower inhibitory activity against
C. albicans (clinical isolate) which may be due to—π effect of the nitro substituent.
The standard strain C. albicans (ATCC 90028) showed an inhibition range with MIC values of
0.03–0.06 mg/mL of the tested compounds 4a-f suggesting moderate inhibitory activity compared to
the clinical isolate versus ketoconazole. The other tested C. albicans strain (NRRL Y-12983) was less
susceptible to the tested compounds, with the MIC = 0.03–0.125 mg/mL.
The tested compounds 4a-c showed strong inhibitory activity (0.03 mg/mL) against and C. glabrata
(clinical isolate, Eskisehir Osmangazi University, Eskişehir, Turkey), and relatively good inhibition
was also observed in compounds 4d-f with an inhibition value of 0.06 mg/mL. However, compound
4a exhibits the most potent inhibitory activity among the tested substances against C. glabrata (clinical
isolate, Anadolu University, Faculty of Science, Department of Biology, Eskişehir, Turkey) with a
MIC value of 0.007 mg/mL, whereas ketoconazole exhibits inhibitory activity with a MIC value of

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Molecules 2011, 16
0.001 mg/mL. The Candida species was susceptible to compounds 4b-f with MIC values of
0.015–0.125 mg/mL.
Compound 4c is the most potent (MIC = 0.03 mg/mL) derivative against C. krusei (NRRL Y-7179).
It is obvious that p-nitro group has an important impact on antifungal activity against C. krusei. Other
tested compounds showed an inhibition effect with MIC 0.06 mg/mL.
The standard strain C. parapsilosis (NRRL Y- 12696) was inhibited by all tested compounds
relatively well, with an MIC value of 0.06 mg/mL, except compound 4d with an MIC value of
0.125 mg/mL, whereas ketoconazole showed an inhibition concentration of 0.001 mg/mL.
Compound 4f exhibits the highest antifungal activity (MIC 0.015 mg/mL) against C. tropicalis
(NRRL Y-12968) compared to ketoconazole (MIC 0.001 mg/mL) among the tested compounds
against this pathogen. It is apparent that there is a positive correlation between antifungal activity
against C. tropicalis and 2,4-dichlorophenyl substituent.
3. Experimental
3.1. General
All reagents were used as purchased from commercial suppliers without further purification.
Melting points were determined on an Electrothermal 9100 digital melting point apparatus and were
uncorrected (Electrothermal, Essex, UK). Spectroscopic data were recorded on the following
instruments: IR, Shimadzu 435 IR spectrophotometer (Shimadzu, Tokyo, Japan) 1H-NMR (400 MHz)
and 13C-NMR (100 MHz) Bruker (Avance DRX-400) NMR spectrometer (Bruker Bioscience,
Billerica, MA, USA) in DMSO-d6 using TMS as internal standard; MS-FAB, VG Quattro mass
spectrometer (Fisons Instruments Vertriebs GmbH, Mainz, Germany). Elemental analyses were
performed on a Perkin Elmer EAL 240 elemental analyser (Perkin-Elmer, Norwalk, CT, USA).
3.2. General Procedure for Synthesis of the Compounds
Ethyl 2-(pyrimidin-2-ylthio)acetate (1). A mixture of 2-mercaptopyrimidine (0.05 mol) and ethyl
chloroacetate (0.05 mol) in the presence of potassium carbonate (0.05 mol) in acetone (100 mL) was
refluxed for 10 h. The reaction mixture was cooled, filtered and the crude product was solved in water
and then extracted with ether [17].
2-(Pyrimidin-2-ylthio)acetohydrazide (2). A mixture of the ester (1, 0.05 mol) and hydrazine hydrate
(0.1 mol) in ethanol (100 mL) was stirred at room temperature for 3 hours and then filtered [17].
5-[(pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole-2(3H)-thione (3). A mixture of the hydrazide (2)
(0.01 mol) and carbon disulfide (10 mL) in the presence of potassium hydroxide (0.01 mol) in ethanol
(15 mL) was refluxed for 10 h. The solution was cooled and acidified to pH 5-6 with hydrochloric acid
solution and crystallized from ethanol [17].
2-[5-[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazol-2-ylthio]acetophenone
derivatives
4a-f.
5-
[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole-2(3H)-thione (3) (0.01 mol) and appropriate phenacyl

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Molecules 2011, 16
bromide (0.01 mol) in acetone (15 mL) were stirred at room temperature for 8 hours and filtered. The
residue was crystallized from ethanol.
2-[5-[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazol-2-ylthio]acetophenone (4a). IR (KBr) νmax (cm−1):
1
3057 (aromatic C-H), 1683 (C=O), 1605, 1551, 1440 (C=N and C=C). H-NMR: 4.68 (2H, s, CH2-
oxadiazole), 5.08 (2H, s, CH2-CO), 7.25 (1H, dd, pyrimidine), 7.56–7.60 (2H, dd, phenyl), 7.69 (1H,
13
dd, phenyl), 8.01–8.03 (2H, d, phenyl), 8.65–8.66 (2H, d, pyrimidine); C-NMR: 31.17 (CH2, CH2-
oxadiazole), 40.93 (CH2, CH2-CO), 118.41 (CH, pyrimidine), 128.89 (2CH, phenyl), 129.36 (2CH,
phenyl), 134.44 (CH, phenyl), 135.45 (C, phenyl), 158.51 (CH, pyrimidine), 158.61 (CH, pyrimidine),
163.88 (C, oxadiazole), 165.64 (C, oxadiazole), 169.11 (C, pyrimidine), 192.75 (C, C=O); Anal. For
C15H12N4O2S2 calculated: C, 52.31; H, 3.51; N, 16.27; found: C, 52.30; H, 3.52; N, 16.25; MS (FAB)
[M+1]+: m/z 345.
2-[5-[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazol-2-ylthio]-4′-chloroacetophenone (4b). IR (KBr)
ν
max (cm−1): 3066 (aromatic C-H), 1685 (C=O), 1615, 1560, 1445 (C=N and C=C). 1H-NMR: 4.67 (2H,
s, CH2-oxadiazole), 5.06 (2H, s, CH2-CO), 7.25 (1H, dd, pyrimidine), 7.61–7.67 (2H, d,
13
4-chlorophenyl), 7.99–8.05 (2H, d, 4-chlorophenyl), 8.65–8.71 (2H, d, pyrimidine); C-NMR: 31.10
(CH2, CH2-oxadiazole), 40.80 (CH2, CH2-CO), 118.40 (CH, pyrimidine), 129.48 (2CH,
4-chlorophenyl), 130.81 (2CH, 4-chlorophenyl), 134.15 (C, 4-chlorophenyl), 139.39 (C,
4-chlorophenyl), 158.51 (2CH, pyrimidine), 163.88 (C, oxadiazole), 165.68 (C, oxadiazole), 169.90
(C, pyrimidine), 191.93 (C, C=O); Anal. For C15H11ClN4O2S2 calculated: C, 47.55; H, 2.93; N, 14.79;
found: C, 47.52; H, 2.90; N, 14.81; MS (FAB) [M+1]+: m/z 379.
2-[5-[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazol-2-ylthio]-4′-nitroacetophenone (4c). IR (KBr) νmax
(cm−1): 3067 (aromatic C-H), 1685 (C=O), 1604, 1554, 1442 (C=N and C=C). 1H-NMR: 4.72 (2H, s,
CH2-oxadiazole), 5.13 (2H, s, CH2-CO), 7.25 (1H, dd, pyrimidine), 8.15–8.26 (2H, d, 4-nitrophenyl),
8.28–8.42 (2H, d, 4-nitrophenyl), 8.60–8.71 (2H, d, pyrimidine); 13C-NMR: 33.51 (CH2,
CH2-oxadiazole), 41.05 (CH2, CH2-CO), 118.41 (CH, pyrimidine), 124.41 (2CH, 4-nitrophenyl),
130.34 (2CH, 4-nitrophenyl), 140.10 (C, 4-nitrophenyl), 150.75 (C, 4-nitrophenyl), 158.52
(CH, pyrimidine), 158.61 (CH, pyrimidine), 163.61 (C, oxadiazole), 165.77 (C, oxadiazole), 169.09
(C, pyrimidine), 192.29 (C, C=O); Anal. For C15H11N5O4S2 calculated: C, 46.27; H, 2.85; N, 17.98;
found: C, 46.30; H, 2.82; N, 18.00; MS (FAB) [M+1]+: m/z 390.
2-[5-[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazol-2-ylthio]-3′-nitroacetophenone (4d). IR (KBr) νmax
1
(cm−1): 3067 (aromatic C-H), 1684 (C=O), 1605, 1555, 1440 (C=N and C=C). H-NMR: 4.67 (2H, s,
CH2-oxadiazole), 5.17 (2H, s, CH2-CO), 7.26 (1H, dd, pyrimidine), 7.87–7.91 (1H, dd, 3-nitrophenyl),
8.43–8.54 (2H, d, 3-nitrophenyl), 8.59–8.61 (1H, s, 3-nitrophenyl), 8.63–8.72 (2H, d, pyrimidine);
13C-NMR: 31.15 (CH2, CH2-oxadiazole), 40.82 (CH2, CH2-CO), 118.39 (CH, pyrimidine), 123.26
(CH, 3-nitrophenyl), 128.55 (CH, 3-nitrophenyl), 131.22 (CH, 3-nitrophenyl), 135.06 (CH,
3-nitrophenyl), 136.66 (C, 3-nitrophenyl), 148.52 (C, 3-nitrophenyl), 158.51 (CH, pyrimidine), 158.61
(CH, pyrimidine), 163.61 (C, oxadiazole), 165.77 (C, oxadiazole), 169.10 (C, pyrimidine), 191.72
(C, C=O); Anal. For C15H11N5O4S2 calculated: C, 46.27; H, 2.85; N, 17.98; found: C, 46.28; H, 2.86;
N, 17.99; MS (FAB) [M+1]+: m/z 390.

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Molecules 2011, 16
2-[5-[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazol-2-ylthio]-3′-chloroacetophenone (4e). IR (KBr)
1
νmax (cm−1): 3065 (aromatic C-H), 1685 (C=O), 1614, 1555, 1445 (C=N and C=C). H-NMR: 4.67
(2H, s, CH2-oxadiazole), 5.07 (2H, s, CH2-CO), 7.25 (1H, dd, pyrimidine), 7.59-7.66 (1H, dd,
3-chlorophenyl), 7.68-7.79 (1H, d, 3-chlorophenyl), 7.84-7.85 (1H, d, 3-chlorophenyl), 7.92-8.04 (1H,
s, 3-chlorophenyl), 8.60-8.71 (2H, d, pyrimidine); 13C-NMR: 31.20 (CH2, CH2-oxadiazole), 40.77
(CH2, CH2-CO), 118.39 (CH, pyrimidine), 127.53 (CH, 3-chlorophenyl), 128.58 (CH,
3-chlorophenyl), 129.21 (CH, 3-chlorophenyl), 131.35 (CH, 3-chlorophenyl), 134.10 (C,
3-chlorophenyl), 137.27 (C, 3-chlorophenyl), 158.50 (CH, pyrimidine), 158.61 (CH, pyrimidine),
163.70 (C, oxadiazole), 165.71 (C, oxadiazole), 169.00 (C, pyrimidine), 191.93 (C, C=O); Anal. For
C15H11ClN4O2S2 calculated: C, 47.55; H, 2.93; N, 14.79; found: C, 47.52; H, 2.90; N, 14.80; MS
(FAB) [M+1]+: m/z 379.
2-[5-[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazol-2-ylthio]-2′,4′-dichloroacetophenone (4f). IR (KBr)
ν
max (cm−1): 3065 (aromatic C-H), 1685 (C=O), 1620, 1552, 1415 (C=N and C=C). 1H-NMR: 4.68 (2H,
s, CH2-oxadiazole), 4.91 (2H, s, CH2-CO), 7.27 (1H, dd, pyrimidine), 7.53–7.64 (2H,
2,4-dichlorophenyl), 7.73–7.88 (1H, d, 2,4-dichlorophenyl), 8.61–8.70 (2H, d, pyrimidine); 13C-NMR:
33.58 (CH2, CH2-oxadiazole), 42.71 (CH2, CH2-CO), 118.53 (CH, pyrimidine), 128.26 (CH,
2,4-dichlorophenyl), 128.55 (CH, 2,4-dichlorophenyl), 130.93 (C, 2,4-dichlorophenyl), 131.51 (CH,
2,4-dichlorophenyl), 135.23 (C, 2,4-dichlorophenyl), 137.59 (C, 2,4-dichlorophenyl), 158.54 (CH,
pyrimidine), 158.61 (CH, pyrimidine), 163.47 (C, oxadiazole), 165.77 (C, oxadiazole), 169.11
(C, pyrimidine), 193.73 (C, C=O); Anal. For C15H10Cl2N4O2S2 calculated: C, 43.59; H, 2.44; N, 13.56;
found: C, 43.60; H, 2.45; N, 13.53; MS (FAB) [M+1]+: m/z 414.
3.3. Microbiology
3.3.1. Anticandidal Evaluation
A modified microbroth dilution method was carried out according to the procedure [23,24]. The
compounds 4a-f were tested in vitro against C. albicans (clinical isolate, Osmangazi University,
Faculty of Medicine, Eskişehir, Turkey), C. albicans (ATCC 90028), C. albicans (NRRL Y-12983),
C. glabrata (clinical isolate, Osmangazi University, Faculty of Medicine, Eskişehir, Turkey),
C. glabrata (clinical isolate, Anadolu University, Faculty of Science, Department of Biology,
Eskişehir, Turkey), C. krusei (NRRL Y-7179), C. parapsilosis (NRRL Y- 12696), C. tropicalis
(NRRL Y-12968).
Microorganisms were stored in 15% glycerol containing micro-test tubes at −86 °C. All Candida
strains were inoculated on Sabouraud Dextrose Agar (SDA) prior to the experiments at 37 °C. After
sufficient growth, Candida spp. were then transferred to Mueller Hinton Broth (MHB) for further
incubation under the same conditions for another 24 h.
3.3.2. Microbroth Dilution Assay
The test compounds and the antifungal standard were first dissolved in dimethyl sulfoxide (DMSO)
which was used to prepare the stock solutions at an initial concentration of 2 mg/mL. Serial dilution
series were prepared in MHB (10 mL) with an equal amount of the test samples. The last row was

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Molecules 2011, 16
filled only with water as growth control for the microorganism. Overnight grown microorganism
suspensions were first diluted in double strength MHB and standardized to 1 × 108 CFU/mL (using
McFarland No: 0.5) under sterile conditions. Then each microorganism suspension was pippetted into
each well and incubated at 37 °C for 24 h. Ketoconazole was used as a standard antifungal agent
against Candida spp. Sterile distilled water and medium served as a positive growth control. The first
well without turbidity was assigned as the minimum inhibitory concentration (MIC, in mg/mL).
4. Conclusions
In conclusion, the syntheses of new oxadiazole derivatives were described, which were also tested
in vitro against various clinical and standard Candida species for their antifungal effects.
5-[(Pyrimidin-2-ylthio)methyl]-1,3,4-oxadiazole-2(3H)-thione (3) was obtained via the ring closure
reaction of the acid hydrazide 2 with carbon disulphide. New oxadiazole derivatives were prepared by
the nucleophilic substitution reaction of compound 3 with appropriate phenacyl bromides. Among
these compounds, the non-substituted compound 4a is the most potent derivative (MIC:
0.007–0.06 mg/mL) against Candida species except C. tropicalis and C. krusei.
Within the tested yeasts, C. albicans (clinical isolate) seems to be the most susceptible strain to
compounds 4a, 4b and 4e. These compounds exhibit inhibitory activity with a MIC value of 0.015 mg/mL,
whereas ketoconazole exhibits inhibitory activity with a MIC value of 0.007 mg/mL. This could result
from increased lipophilicity associated with phenyl and chlorophenyl groups. Compound 4f exhibits
the highest antifungal activity against C. tropicalis (NRRL Y-12968). It is clear that the 2,4-
dichlorophenyl substituent has an important impact on antifungal activity against C. tropicalis.
Compound 4c is the most effective derivative against C. krusei (NRRL Y-7179). It is apparent that the
p-nitro group may have a considerable influence on antifungal activity against this species.
Conflict of Interest
The author reports no conflicts of interest. The author alone is responsible for the content and
writing of the paper.
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Sample Availability: Samples of the compounds 4a-f are available from the author.
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