Synthesis of some novel triazole derivatives and investigation of their antimicrobial activities

Article abstract of DOI:10.1080/00397911.2010.501475

The aim of this study is to synthesize new triazole derivatives and investigate their antimicrobial activities. 4-Amino-5-(2-cyclohexylethyl)-3-[N- (benzothiazole-2-yl)aceta mido]thio-4H-1,2,4-triazole and 4-amino-5-[2-(4- hydroxyphenyl)ethyl]-3-[N-(benzo

Full text of DOI:10.1080/00397911.2010.501475

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Synthesis of Some Novel Triazole
Derivatives and Investigation of Their
Antimicrobial Activities
Mehlika Dilek Altıntop a , Zafer Asım Kaplancıklı a , Gülhan Turan-
Zitouni a , Ahmet Özdemir a , Fatih Demirci b , Gökalp İşcan b
&
Gilbert Revial c
a Faculty of Pharmacy, Department of Pharmaceutical Chemistry,
Anadolu University, Eskişehir, Turkey
b Faculty of Pharmacy, Department of Pharmacognosy, Anadolu
University, Eskişehir, Turkey
c Laboiratoire de Transformations Chimiques et Pharmaceutiques,
UMR-CNRS 7084, Paris, France
Published online: 25 May 2011.
To cite this article: Mehlika Dilek Altntop , Zafer Asm Kaplanckl , Glhan Turan-Zitouni , Ahmet
zdemir , Fatih Demirci , Gkalp can & Gilbert Revial (2011) Synthesis of Some Novel Triazole
Derivatives and Investigation of Their Antimicrobial Activities, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:15, 2234-2250,
DOI: 10.1080/00397911.2010.501475
To link to this article: http://dx.doi.org/10.1080/00397911.2010.501475
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Synthetic Communications1, 41: 2234–2250, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.501475
SYNTHESIS OF SOME NOVEL TRIAZOLE DERIVATIVES
AND INVESTIGATION OF THEIR ANTIMICROBIAL
ACTIVITIES
Mehlika Dilek Altıntop,1 Zafer Asım Kaplancıklı,1
1
Gu¨lhan Turan-Zitouni, Ahmet Ozdemir, Fatih Demirci,
1
2
¨
2
Gokalp Is¸can, and Gilbert Revial
3
˙
¨
1Faculty of Pharmacy, Department of Pharmaceutical Chemistry,
Anadolu University, Eskis¸ehir, Turkey
2Faculty of Pharmacy, Department of Pharmacognosy, Anadolu University,
Eskis¸ehir, Turkey
3Laboiratoire de Transformations Chimiques et Pharmaceutiques,
UMR-CNRS 7084, Paris, France
GRAPHICAL ABSTRACT
Abstract The aim of this study is to synthesize new triazole derivatives and investigate their
antimicrobial activities. 4-Amino-5-(2-cyclohexylethyl)-3-[N-(benzothiazole-2-yl)aceta
mido]thio-4H-1,2,4-triazole and 4-amino-5-[2-(4-hydroxyphenyl)ethyl]-3-[N-(benzothia-
zole-2-yl)acetamido]thio-4H-1,2,4-triazole derivatives were prepared by the reaction of
2-chloro-N-(benzothiazole-2-yl)acetamides with 4-amino-5-(2-cyclohexylethyl)-2,4-dihydro-
3H-1,2,4-triazol-3-thione and 4-amino-5-[2-(4-hydroxyphenyl)ethyl]-2,4-dihydro-3H-1,2,4-
triazol-3-thione, respectively. The structures of these compounds were elucidated by infrared,
1H NMR, 13C NMR, mass spectra, and elemental analysis. The synthesized compounds were
screened for their antimicrobial activities against various Candida species and pathogenic bac-
teria. Compound IIIg and compound IIIi were found to be the most potent derivatives against
Candida species and tested bacteria, respectively.
Keywords Antimicrobial activity; benzothiazole; triazole
Received March 17, 2010.
Address correspondence to Zafer Asım Kaplancıklı, Faculty of Pharmacy, Department of
Pharmaceutical Chemistry, Anadolu University, 26470 Eskis¸ehir, Turkey. E-mail: zakaplan@anadolu.edu.tr
2234

NOVEL TRIAZOLE DERIVATIVES
2235
INTRODUCTION
Systemic fungal infections have emerged as important causes of morbidity and
mortality in immunocompromised patients. The incidence of systemic fungal infec-
tions has increased dramatically, due mainly to Candida species, over the past two
decades.[1–6]
The greatly increased incidence of life-threatening fungal infections has
resulted in a corresponding increase in demand for new agents to treat these
infections.
It is obvious from the literature that azoles are the most widely used and stud-
ied class of antifungal agents. Azoles are mainly inhibitors of cytochrome P450-
dependent 14a-demethylase, which catalyzes the removal of the 14a-methyl group
of lanosterol in the ergosterol biosynthetic pathway. The selective inhibition of this
enzyme results in the depletion of ergosterol and accumulation of lanosterol and
other 14a -methylsterols in the fungal cell membrane. This disrupts the structure
of the cell membrane in fungi and causes the increased membrane permeability
and inhibition of fungal growth.[7–9]
Azoles, especially triazole antifungal agents, play a leading role in the treat-
ment of systemic fungal infections because of their broad spectrum and improved
safety profile, but the widespread use of these compounds has led to the development
of resistance in recent years. As a consequence of this situation, antifungal drug
research is mainly focused on the development of more effective antifungal azoles
with fewer adverse effects.[9,10]
The development of resistance to antibiotics has also led to the failure of the
treatment of bacterial infections, which are responsible for the bulk of nosocomial
infections. To overcome this serious problem, which is considered as the inevitable
consequence of the widespread use of these agents, the development of new drugs
has gained great importance.[11]
Among triazole derivatives, 1,2,4-triazoline-3-thiones have received consider-
able attention because of their importance in synthetic chemistry. Herein, the com-
pounds that have triazoline-3-thione structure (IIa and b) were synthesized via the
fusion of thiocarbohydrazide and appropriate propionic acids.[12,13]
Table 1. Some properties of the synthesized compounds
Compound
R
R0
Melting point (ꢀC)
Yield (%)
IIa
IIb
—
—
Cyclohexyl
164–165
238–240
172–174
239–242
220–224
215–218
169–170
218–222
228–232
223–226
220–223
219–221
75
80
70
75
70
72
70
72
79
71
74
75
4-hydroxyphenyl
Cyclohexyl
Cyclohexyl
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
H
Cl
CH3
OCH3
OC2H5
H
Cyclohexyl
Cyclohexyl
Cyclohexyl
4-hydroxyphenyl
4-hydroxyphenyl
4-hydroxyphenyl
4-hydroxyphenyl
4-hydroxyphenyl
Cl
CH3
OCH3
OC2H5

2236
M. D. ALTINTOP ET AL.
In this study, we describe the discovery of new triazole derivatives (Table 1),
which were tested in vitro against various Candida species and bacteria and com-
pared with ketoconazole and chloramphenicol, respectively.
RESULTS AND DISCUSSION
Initially, 2-chloro-N-(benzothiazol-2-yl)acetamides were synthesized via
nucleophilic acyl substitution reaction of 2-aminobenzothiazoles with chloroacetyl
chloride in the presence of triethylamine.[14] The compounds, as new starting
materials that have triazoline-3-thione structure (IIa and b), were obtained by heat-
ing thiocarbohydrazide with the appropriate propionic acids according to the
procedure.[15] The desired compounds (IIIa–j) were prepared by reacting 2-chloro-N-
(benzothiazol-2-yl)acetamides with appropriate triazoline-3-thiones (IIa and b)
under basic conditions. The presence of a base favors the thiol form, which is prone
to nucleophilic substitution reactions. These reactions are summarized in Scheme 1,
and the ring-closure reaction is considered to proceed as shown in Scheme 2.
The compounds that have triazoline-3-thione structure (IIa and b) may exist in
two tautomeric forms, namely thione and thiol forms.[16] In the infrared (IR) spectra,
Scheme 1. Synthesis of triazole derivatives.

NOVEL TRIAZOLE DERIVATIVES
2237
Scheme 2. Proposed mechanism of the ring closure.
the absence of a band at 2600–2550 cmꢁ1 due to the S-H stretching vibration
confirms that the thione form predominates over the thiol form in the solid state.
Acetamide derivatives (IIIa–j) have a strong, characteristic band in the region
1700–1650 cmꢁ1 due to the C O stretching vibration. The asymmetric and sym-
=
metric stretching bands for aliphatic C-H group occur at 2925–2920 cmꢁ1 and
2850–2845 cmꢁ1 respectively. The aromatic C-H stretching vibration of the
compounds (IIIa–j) gives rise to a band at 3100–3000 cmꢁ1
.
1
In the H NMR spectra of the compounds that have triazoline-3-thione struc-
ture (IIa and b), the signals due to the NH protons, which are observed at
13–14 ppm, are considered as a proof of the predominance of the thione form over
the thiol form.

2238
M. D. ALTINTOP ET AL.
Scheme 3. Proposed mass fragmentation of compound IIIa.
In the 1H NMR spectra of acetamide derivatives (IIIa–j), the signal due to the
amide proton appears at 12–13 ppm. In their 13C NMR spectra (IIIa–j), the signal
due to the amide carbon is observed at 167–168 ppm.
In the mass spectra of all compounds (IIIa–j), we cannot see the molecular ion
peak because of the ease of C-S bond cleavage. For the compounds containing the
cyclohexane ring, except for compound IIId, the main fragmentation proceeds via
amide bond cleavage. The base peaks in their spectra correspond to 2-aminoben-
zothiazole moiety, whereas the base peak at m=z 130 in the spectrum of compound
IIId belongs to a triazole moiety. On the other hand, the phenolic compounds (IIIf–j)
undergo benzylic cleavage, resulting in the hydroxy tropylium ion at m=z 107, which
corresponds to the base peak. The next fragmentation arises by the loss of CO, lead-
ing to a line at m=z 77. The proposed fragmentation pathways of some compounds
are shown in Schemes 3–7.
The in vitro activities of the compounds (IIIa–j) were determined by the micro-
broth dilution method. All compounds (IIIa–j) showed less antimicrobial potency
than ketoconazole and chloramphenicol (Table 2). Among these compounds, it is
clear that compounds IIIg and IIIi are the most potent derivatives against Candida
species and tested bacteria, respectively.

NOVEL TRIAZOLE DERIVATIVES
2239
Scheme 4. Proposed mass fragmentation of compound IIa.
CONCLUSION
In conclusion, we synthesized new triazole derivatives and evaluated their
in vitro antimicrobial activities against various Candida species and bacteria. The
results indicate that compound IIIg is the most effective compound against Candida
species among these compounds. This outcome confirms that the phenol and the
chlorine substituent on benzothiazole ring may have a considerable influence
on antifungal activity. Compound IIIi is the most potent derivative against tested
bacteria.

2240
M. D. ALTINTOP ET AL.
Scheme 5. Proposed mass fragmentation of compound IIIf.
EXPERIMENTAL
Chemistry
All reagents were purchased from commercial suppliers and were used without
further purification. Melting points (mp) were determined on a Electrothermal 9100
melting-point apparatus and are uncorrected. Infrared spectra (IR) were recorded on
a Shimadzu 8400 Fourier transform (FT)–IR spectrophotometer. Proton nuclear
magnetic resonance (1H NMR) spectra were recorded on Bruker 400- and
500-MHz spectrometers. Carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on a Bruker 100-MHz spectrometer. Chemical shifts were expressed
in parts per million (ppm), and tetramethylsilane (TMS) was used as an internal
standard. Mass spectra were recorded on a VG Quattro mass spectrometer. Elemen-
tal analyses were performed on a Perkin-Elmer EAL 240 analyzer. Thin-layer
chromatography (TLC) was performed on glass plates precoated with silica gel 60
F254 (Merck).
N-(Benzothiazol-2-yl)-2-chloroacetamides (Ia–e)
Chloroacetyl chloride (0.1 mol) was added dropwise with stirring to a mixture
of 2-aminobenzothiazole=6-substituted-2-aminobenzothiazole (0.1 mol) and triethy-
lamine in toluene at 0–5 ꢀC. The solvent was evaporated under reduced pressure.

NOVEL TRIAZOLE DERIVATIVES
2241
Scheme 6. Proposed mass fragmentation of compound IIb.
The residue was washed with water to remove triethylamine hydrochloride and
crystallized from ethanol.[13]
4-Amino-5-(2-cyclohexylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-thione
(IIa)
A mixture of 3-cyclohexylpropionic acid (0.1 mol) and thiocarbohydrazide
(0.1 mol) was heated in an oil bath at 160–170 ꢀC for 2 h. It was then dispersed with
hot water and collected by filtration. The product was crystallized from ethanol.
IR (KBr) nmax (cmꢁ1): 3286.81, 3225.09, 3165.29 (N-H stretching), 2922.25 (ali-
phatic C-H asymmetric stretching), 2848.96 (aliphatic C-H symmetric stretching),
=
1622.19, 1564.32, 1473.66 (C N stretching), 1338.64, 1288.49, 1259.56 (C-N and
=
C S stretching).

2242
M. D. ALTINTOP ET AL.
Scheme 7. Proposed mass fragmentation of compound Ia.
1H NMR (500 MHz) (DMSO-d6) d (ppm): 0.84–0.93 (2H, m, cyclohexane H),
1.09–1.28 (4H, m, cyclohexane H), 1.38–1.73 (7H, m, cyclohexane H, cyclohexane-
CH2), 2.65 (2H, t, CH2-triazole), 5.53 (2H, s, NH2), 13.44 (1H, s, N-H).
4-Amino-5-[2-(4-hydroxyphenyl)ethyl]-2,4-dihydro-3H-1,2,4-triazol-3-
thione (IIb)
IIb was prepared as IIa using 3-(4-hydroxyphenyl)propionic acid.

NOVEL TRIAZOLE DERIVATIVES
2243
Ba
Table 2. Antimicrobial activities of the compounds as MIC values (mg=mL)
Organism
IIIa IIIb IIIc IIId IIIe IIIf IIIg IIIh IIIi IIIj
Aa
C. albicans (Clin. isol.)
C. albicans (ATCC90028)
C. tropicalis
0.5
0.5
1
1
1
1
1
1
1
1
2
2
1
2
2
2
1
1
1
1
1
1
1
2
2
1
2
1
2
0.5 0.5
1
0.5
1
0.5 0.5 0.25 0.5
0.5
1
1
1
0.0625
0.0625
nt
nt
1
1
1
1
1
1
1
2
1
1
1
1
0.5
0.25
1
1
1
0.25
1
1 nt
0.5 0.5
nt 0.03
nt
C. krusei
1
1
1
1
1
1
2
1
1
1
1
0.03
0.007
0.03
0.03
nt
nt
C.parapsilosis
C. albicans (NRRL Y-12983)
C. glabrata
1
0.25 0.5
1
1
1
2
1
1
2
1
1
1
1
1
1
1
1
1
1
1
nt
1
1
1
1
2
2
1
2
2
1
1
1
2
1
1
2
2
1
nt
1
0.5
2
nt
E. coli
S. aureus
2
0.03125
0.0156
0.25
0.03125
0.0078
0.03125
1
2
nt
P. aeruginosa
E. aerogenes
B. subtilis
1
1
nt
2
2
nt
2
2
nt
MRSA
2
2
nt
aA, ketoconazole; B, chloramphenicol; nt, not tested.
IR (KBr) nmax (cmꢁ1): 3319.60, 3269.45, 3207.73 (N-H and O-H stretching),
=
1612.54, 1566.25, 1514.17, 1489.10, 1435.09 (C N and C C stretching), 1344.43,
=
=
1220.98, 1178.55 (C-N and C S stretching), 827.49 (1,4-disubstituted benzene C-H
out of plane deformation).
1H NMR (500 MHz) (DMSO-d6) d (ppm): 2.83 (4H, m, CH2-triazole, phenol-
CH2), 5.57 (2H, s, NH2), 6.66 (2H, d, phenol H3, H5), 7.03 (2H, phenol H2, H6), 9.20
(1H, s, O-H), 13.43 (1H, s, N-H).
4-Amino-5-(2-cyclohexylethyl)-3-[N-(benzothiazole-
2-yl)acetamido]thio-4H-1,2,4-triazole (IIIa)
A mixture of N-(benzothiazol-2-yl)-2-chloroacetamide (2 mmol) and appropri-
ate triazole (2 mmol) in acetone was stirred at room temperature for 8 h in the pres-
ence of potassium carbonate, and then triethylamine was added. The mixture was
stirred at room temperature for 30 h and filtered. The residue was washed with water
and crystallized from ethanol.
IR (KBr) nmax (cmꢁ1): 3435.34, 3352.39 (amine N-H stretching), 3217.37
(amide N-H stretching), 3057.27 (aromatic C-H stretching), 2922.25 (aliphatic C-H
asymmetric stretching), 2848.96 (aliphatic C-H symmetric stretching), 1683.91
=
=
=
(amide C O stretching), 1600.97, 1554.68, 1446.66 (C N and C C stretching),
1332.86, 1261.49, 1172.76, 1020.38 (C-N stretching), 875.71, 754.19 (C-H out of
plane deformation), 671.25 (C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 0.80–0.95 (2H, m, cyclohexane H),
1.05–1.30 (4H, m, cyclohexane H), 1.40–1.75 (7H, m, cyclohexane H, cyclohexane-
CH2), 2.68 (2H, t, J ¼ 7.8 Hz, CH2-triazole), 4.22 (2H, s, S-CH2), 5.88 (2H, s,
NH2), 7.29 (1H, t, J ¼ 7.7 Hz, benzothiazole H6), 7.42 (1H, t, J ¼ 7.7 Hz, benzothia-
zole H5), 7.75 (1H, d, J ¼ 8.0 Hz, benzothiazole H7), 7.93 (1H, d, J ¼ 8.0 Hz,
benzothiazole H4), 12.60 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 21.08 (CH2, CH2-triazole), 25.71
(2CH2, cyclohexane), 26.12 (CH2, cyclohexane), 32.46 (2CH2, cyclohexane), 33.44

2244
M. D. ALTINTOP ET AL.
(CH2, cyclohexane-CH2), 34.77 (CH2, S-CH2), 36.57 (CH, cyclohexane C1), 120.56
(CH, benzothiazole C7), 121.50 (CH, benzothiazole C4), 123.49 (CH, benzothiazole
C6), 125.97 (CH, benzothiazole C5), 131.48 (C, benzothiazole C7a), 148.50 (C,
triazole C5), 150.41 (C, benzothiazole C3a), 156.68 (C, triazole C3), 157.66 (C,
=
benzothiazole C2), 167.51 (C, C O).
MS (EI) m=z (%): 226 (44), 190 (18), 168 (28), 150 (100), 130 (94), 84 (22).
Anal. calc. for C19H24N6OS2: C, 54.78; H, 5.81; N, 20.17. Found: C, 54.82; H,
5.80; N, 20.20.
4-Amino-5-(2-cyclohexylethyl)-3-[N-(6-chlorobenzothiazole-2-
yl)acetamido]thio-4H-1,2,4-triazole (IIIb)
Compound IIIb was synthesized according to the method described for IIIa
4-amino-5-
using
N-(6-chlorobenzothiazol-2-yl)-2-chloroacetamide
and
(2-cyclohexylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIa).
IR (KBr) nmax (cmꢁ1): 3433.41, 3342.75 (amine N-H stretching), 3198.08
(amide N-H stretching), 3061.13 (aromatic C-H stretching), 2922.25 (aliphatic C-H
asymmetric stretching), 2850.88 (aliphatic C-H symmetric stretching), 1683.91
=
=
=
(amide C O stretching), 1604.83, 1556.61, 1442.80 (C N and C C stretching),
1338.64, 1263.42, 1172.76, 1097.53 (C-N stretching), 812.06, 756.12 (C-H out of
plane deformation), 686.68 (C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 0.80–0.95 (2H, m, cyclohexane H),
1.05–1.30 (4H, m, cyclohexane H), 1.45–1.75 (7H, m, cyclohexane H, cyclohexane-
CH2), 2.66 (2H, t, J ¼ 7.8 Hz, CH2-triazole), 4.23 (2H, s, S-CH2), 5.89 (2H, s,
NH2), 7.46 (1H, d, J ¼ 8.6 Hz, benzothiazole H5), 7.75 (1H, d, J ¼ 8.6 Hz, benzothia-
zole H7), 8.10 (1H, s, benzothiazole H4), 12.70 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 20.99 (CH2, CH2-triazole), 25.68
(2CH2, cyclohexane), 26.09 (CH2, cyclohexane), 32.43 (2CH2, cyclohexane), 33.37
(CH2, cyclohexane-CH2), 34.55 (CH2, S-CH2), 36.52 (CH, cyclohexane C1), 121.38
(CH, benzothiazole C7), 121.79 (CH, benzothiazole C4), 126.46 (CH, benzothiazole
C5), 127.68 (C, benzothiazole C6), 133.13 (C, benzothiazole C7a), 147.39 (C, ben-
zothiazole C3a), 150.42 (C, triazole C5), 156.63 (C, triazole C3), 158.53 (C, benzothia-
=
zole C2), 167.78 (C, C O).
MS (EI) m=z (%): 226 (21), 184 (100), 155 (32), 130 (65), 84 (32), 66 (34).
Anal. calc. for C19H23ClN6OS2: C, 50.60; H, 5.14; N, 18.63. Found: C, 50.62;
H, 5.16; N, 18.63.
4-Amino-5-(2-cyclohexylethyl)-3-[N-(6-methylbenzothiazole-2-
yl)acetamido]thio-4H-1,2,4-triazole (IIIc)
Compound IIIc was synthesized according to the method described for IIIa
4-amino-5-
using
N-(6-methylbenzothiazol-2-yl)-2-chloroacetamide
and
(2-cyclohexylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIa).
IR (KBr) nmax (cmꢁ1): 3429.55, 3338.89 (amine N-H stretching), 3184.58 (amide
N-H stretching), 3063.06 (aromatic C-H stretching), 2920.32 (aliphatic C-H asym-
metric stretching), 2850.88 (aliphatic C-H symmetric stretching), 1683.91 (amide
=
C O stretching), 1612.54, 1564.32, 1460.16 (C N and C C stretching), 1330.93,
=
=

NOVEL TRIAZOLE DERIVATIVES
2245
1261.49, 1170.83, 1026.16 (C-N stretching), 812.06, 746.48 (C-H out of plane
deformation), 669.32 (C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 0.83–0.95 (2H, m, cyclohexane H),
1.05–1.35 (4H, m, cyclohexane H), 1.50–1.77 (7H, m, cyclohexane H, cyclohexane-C-
H2), 2.41 (3H, s, CH3), 2.67 (2H, t, J ¼ 7.8 Hz, CH2-triazole), 4.19 (2H, s, S-CH2),
5.85 (2H, s, NH2), 7.22 (1H, d, J ¼ 8.2 Hz, benzothiazole H5), 7.62 (1H, d, J ¼ 8.2 Hz,
benzothiazole H7), 7.69 (1H, s, benzothiazole H4), 12.54 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 20.97 (CH3), 21.08 (CH2, CH2-
triazole), 25.70 (2CH2, cyclohexane), 26.10 (CH2, cyclohexane), 32.45 (2CH2,
cyclohexane), 33.43 (CH2, cyclohexane-CH2), 34.78 (CH2, S-CH2), 36.57 (CH, cyclo-
hexane C1), 120.17 (CH, benzothiazole C7), 121.05 (CH, benzothiazole C4), 127.28
(CH, benzothiazole C5), 131.62 (C, benzothiazole C7a), 132.95 (C, benzothiazole
C6), 146.46 (C, benzothiazole C3a), 150.39 (C, triazole C5), 156.67 (C, triazole C3),
=
156.74 (C, benzothiazole C2), 167.29 (C, C O).
MS (EI) m=z (%): 226 (31), 164 (100), 155 (83), 130 (73), 98 (23), 84 (45), 66
(53), 55 (24).
Anal. calc. for C20H26N6OS2: C, 55.79; H, 6.09; N, 19.52. Found: C, 55.82; H,
6.12; N, 19.54.
4-Amino-5-(2-cyclohexylethyl)-3-[N-(6-methoxybenzothiazole-2-
yl)acetamido]thio-4H-1,2,4-triazole (IIId)
Compound IIId was synthesized according to the method described for IIIa
4-amino-5-
using
N-(6-methoxybenzothiazol-2-yl)-2-chloroacetamide
and
(2-cyclohexylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIa).
IR (KBr) nmax (cmꢁ1): 3425.69, 3317.67 (amine N-H stretching), 3194.23
(amide N-H stretching), 3070.78 (aromatic C-H stretching), 2920.32 (aliphatic C-H
asymmetric stretching), 2847.03 (aliphatic C-H symmetric stretching), 1681.98
=
=
=
(amide C O stretching), 1610.61, 1564.32, 1465.95 (C N and C C stretching),
1332.86, 1259.56, 1170.83, 1062.81 (C-N stretching), 810.13, 746.48 (C-H out of
plane deformation), 671.25 (C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 0.83–0.95 (2H, m, cyclohexane H),
1.05–1.35 (4H, m, cyclohexane H), 1.50–1.80 (7H, m, cyclohexane H, cyclohexane-C-
H2), 2.67 (2H, t, J ¼ 7.8 Hz, CH2-triazole), 3.81 (3H, s, O-CH3), 4.21 (2H, s, S-CH2),
5.90 (2H, s, NH2), 7.04 (1H, d, J ¼ 8.6 Hz, benzothiazole H5), 7.57 (1H, s, benzothia-
zole H7), 7.66 (1H, d, J ¼ 8.6 Hz, benzothiazole H4), 12.43 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 21.00 (CH2, CH2-triazole), 25.67
(2CH2, cyclohexane), 26.09 (CH2, cyclohexane), 32.42 (2CH2, cyclohexane), 33.39
(CH2, cyclohexane-CH2), 34.56 (CH2, S-CH2), 36.52 (CH, cyclohexane C1), 55.59
(CH3), 104.70 (CH, benzothiazole C7), 114.93 (CH, benzothiazole C5), 121.21
(CH, benzothiazole C4), 132.76 (C, benzothiazole C7a), 142.58 (C, benzothiazole
C3a), 150.47 (C, triazole C5), 155.63 (C, benzothiazole C6), 156.17 (C, triazole C3),
=
156.62 (C, benzothiazole C2), 167.26 (C, C O).
MS (EI) m=z (%): 226 (44), 180 (65), 165 (78), 155 (61), 143 (21), 130 (100), 55
(20).
Anal. calc. for C20H26N6O2S2: C, 53.79; H, 5.87; N, 18.82. Found: C, 53.81; H,
5.90; N, 18.80.

2246
M. D. ALTINTOP ET AL.
4-Amino-5-(2-cyclohexylethyl)-3-[N-(6-ethoxybenzothiazole-2-
yl)acetamido]thio-4H-1,2,4-triazole (IIIe)
Compound IIIe was synthesized according to the method described for IIIa
and
using N-(6-ethoxybenzothiazol-2-yl)-2-chloroacetamide
(2-cyclohexylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIa).
4-amino-5-
IR (KBr) nmax (cmꢁ1): 3423.76 (amine N-H stretching), 3221.23 (amide N-H
stretching), 3076.56 (aromatic C-H stretching), 2922.25 (aliphatic C-H asymmetric
=
stretching), 2850.88 (aliphatic C-H symmetric stretching), 1676.20 (amide C O stretch-
=
=
ing), 1602.90, 1581.68, 1458.23 (C N and C C stretching), 1259.56, 1057.03 (C-N
stretching), 813.99, 744.55 (C-H out of plane deformation), 669.32 (C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 0.80–0.95 (2H, m, cyclohexane H),
1.05–1.30 (4H, m, cyclohexane H), 1.36 (3H, t, J ¼ 6.9 Hz, O-CH2-CH3), 1.50–1.75
(7H, m, cyclohexane H, cyclohexane-CH2), 2.67 (2H, m, CH2-triazole), 4.07 (2H,
q, J ¼ 6.9 Hz, O-CH2-CH3), 4.21 (2H, s, S-CH2), 5.90 (2H, s, NH2), 7.02 (1H, dd,
J ¼ 8.8, 2.4 Hz, benzothiazole H5), 7.54 (1H, d, J ¼ 2.4 Hz, benzothiazole H7), 7.64
(1H, d, J ¼ 8.8 Hz, benzothiazole H4), 12.54 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 14.65 (CH3), 21.00 (CH2, CH2-tria-
zole), 25.67 (2CH2, cyclohexane), 26.09 (CH2, cyclohexane), 32.43 (2CH2, cyclohex-
ane), 32.52 (CH2, cyclohexane-CH2), 33.39 (CH2, S-CH2), 36.52 (CH, cyclohexane
C1), 63.58 (CH2, O-CH2-CH3), 105.34 (CH, benzothiazole C7), 115.27 (CH, ben-
zothiazole C5), 121.20 (CH, benzothiazole C4), 132.74 (C, benzothiazole C7a),
142.50 (C, benzothiazole C3a), 150.46 (C, triazole C5), 155.40 (C, benzothiazole
=
C6), 155.58 (C, triazole C3), 156.61 (C, benzothiazole C2), 167.24 (C, C O).
MS (EI) m=z (%): 221 (61), 206 (70), 193 (100), 165 (37), 130 (14), 66 (17).
Anal. calc. for C21H28N6O2S2: C, 54.76; H, 6.13; N, 18.24. Found: C, 54.76; H,
6.15; N, 18.22.
4-Amino-5-[2-(4-hydroxyphenyl)ethyl]-3-[N-(Benzothiazole-
2-yl)acetamido]thio-4H-1,2,4-triazole (IIIf)
Compound IIIf was synthesized according to the method described for IIIa
using N-(benzothiazol-2-yl)-2-chloroacetamide and 4-amino-5-[2-(4-hydroxyphenyl)
ethyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIb).
IR (KBr) nmax (cmꢁ1): 3350.46 (amine N-H stretching), 3286.81 (O-H stretch-
ing), 3182.65 (amide N-H stretching), 3059.20 (aromatic C-H stretching), 2926.11 (ali-
phatic C-H asymmetric stretching), 2852.81 (aliphatic C-H symmetric stretching),
=
=
=
1683.91 (amide C O stretching), 1602.90, 1560.46, 1448.59 (C N and C C stretch-
ing), 1338.64 (C-N stretching), 1228.70 (C-O stretching), 1172.76 (C-N stretching),
875.71 (C-H out of plane deformation), 819.77 (1,4-disubstituted benzene C-H out
of plane deformation), 758.05 (C-H out of plane deformation), 673.18 (C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 2.90 (4H, m, CH2-triazole,
phenol-CH2), 4.27 (2H, s, S-CH2), 5.95 (2H, s, NH2), 6.70 (2H, d, J ¼ 8.4 Hz, phenol
H3, H5), 7.06 (2H, J ¼ 8.4 Hz, phenol H2, H6), 7.31 (1H, t, J ¼ 7.3 Hz, benzothiazole
H6), 7.44 (1H, t, J ¼ 7.3 Hz, benzothiazole H5), 7.78 (1H, d, J ¼ 8.0 Hz, benzothiazole
H7), 7.98 (1H, d, J ¼ 7.8 Hz, benzothiazole H4), 9.21 (1H, m, O-H), 12.66 (1H, m,
N-H).

NOVEL TRIAZOLE DERIVATIVES
2247
13C NMR (100 MHz) (DMSO-d6) d (ppm): 26.01 (CH2, phenol-CH2), 31.21
(CH2, CH2-triazole), 34.60 (CH2, S-CH2), 115.09 (2CH, phenol C3, C5), 120.61
(CH, benzothiazole C7), 121.68 (CH, benzothiazole C4), 123.61 (CH, benzothiazole
C6), 126.13 (CH, benzothiazole C5), 129.15 (2CH, phenol C2, C6), 130.95 (C, ben-
zothiazole C7a), 131.45 (C, phenol C1), 148.50 (C, benzothiazole C3a), 150.69 (C, tria-
zole C5), 155.58 (C, phenol C4), 155.97 (C, triazole C3), 157.76 (C, benzothiazole C2),
=
167.57 (C, C O).
MS (EI) m=z (%): 236 (29), 150 (13), 130 (20), 107 (100), 77 (11).
Anal. calc. for C19H18N6O2S2: C, 53.51; H, 4.25; N, 19.70. Found: C, 53.50; H,
4.29; N, 19.71.
4-Amino-5-[2-(4-hydroxyphenyl)ethyl]-
3-[N-(6-chlorobenzothiazole-2-yl)acetamido]thio-4H-1,2,4-triazole
(IIIg)
Compound IIIg was synthesized according to the method described for IIIa
using N-(6-chlorobenzothiazol-2-yl)-2-chloroacetamide and 4-amino-5-[2-(4-
hydroxyphenyl)ethyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIb).
IR (KBr) nmax (cmꢁ1): 3336.96 (amine N-H stretching), 3196.15 (amide N-H
stretching), 3066.92 (aromatic C-H stretching), 2924.18 (aliphatic C-H asymmetric
=
stretching), 2852.81 (aliphatic C-H symmetric stretching), 1685.84 (amide C O
=
=
stretching), 1604.83, 1554.68, 1442.80 (C N and C C stretching), 1338.64, 1259.56,
1172.76, 1099.46 (C-N stretching), 819.77 (1,4-disubstituted benzene C-H out of plane
deformation), 756.12 (C-H out of plane deformation), 684.75 (C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 2.89 (4H, m, CH2-triazole,
phenol-CH2), 4.26 (2H, s, S-CH2), 5.94 (2H, s, NH2), 6.69 (2H, d, J ¼ 7.3 Hz, phenol
H3, H5), 7.06 (2H, J ¼ 7.3 Hz, phenol H2, H6), 7.45 (1H, d, J ¼ 8.0 Hz, benzothiazole
H5), 7.75 (1H, d, J ¼ 8.0 Hz, benzothiazole H7), 8.11 (1H, s, benzothiazole H4), 9.22
(1H, m, O-H), 12.85 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 25.99 (CH2, phenol-CH2), 31.19
(CH2, CH2-triazole), 34.58 (CH2, S-CH2), 115.08 (2CH, phenol C3, C5), 121.39
(CH, benzothiazole C7), 121.78 (CH, benzothiazole C4), 126.46 (CH, benzothiazole
C5), 127.65 (CH, benzothiazole C6), 129.14 (2CH, phenol C2, C6), 130.93 (C,
benzothiazole C7a), 133.16 (C, phenol C1), 147.41 (C, benzothiazole C3a), 150.66
(C, triazole C5), 155.57 (C, phenol C4), 155.96 (C, triazole C3), 158.70 (C, benzothia-
=
zole C2), 167.85 (C, C O).
MS (EI) m=z (%): 236 (34), 184 (17), 130 (25), 107 (100), 77 (11).
Anal. calc. for C19H17ClN6O2S2: C, 49.51; H, 3.72; N, 18.23. Found: C, 49.53;
H, 3.74; N, 18.26.
4-Amino-5-[2-(4-hydroxyphenyl)ethyl]-
3-[N-(6-methylbenzothiazole-2-yl)acetamido]thio-4H-1,2,4-triazole
(IIIh)
Compound IIIh was synthesized according to the method described for IIIa
4-amino-5-
using
[2-(4-hydroxyphenyl)ethyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIb).
N-(6-methylbenzothiazol-2-yl)-2-chloroacetamide
and

2248
M. D. ALTINTOP ET AL.
IR (KBr) nmax (cmꢁ1): 3346.61 (amine N-H stretching), 3284.88 (O-H stretch-
ing), 3194.23 (amide N-H stretching), 3066.92 (aromatic C-H stretching), 2926.11
(aliphatic C-H asymmetric stretching), 2858.60 (aliphatic C-H symmetric stretching),
=
=
=
1676.20 (amide C O stretching), 1608.69, 1564.32, 1458.23 (C N and C C stretch-
ing), 1336.71, 1255.70, 1174.69 (C-N stretching), 817.85 (1,4-disubstituted benzene
C-H out of plane deformation), 746.48 (C-H out of plane deformation), 671.25
(C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 2.41 (3H, s, CH3), 2.89 (4H, m,
CH2-triazole, phenol-CH2), 4.25 (2H, s, S-CH2), 5.93 (2H, s, NH2), 6.69 (2H, d,
J ¼ 8.4 Hz, phenol H3, H5), 7.06 (2H, J ¼ 8.4 Hz, phenol H2, H6), 7.26 (1H, d,
J ¼ 8.3 Hz, benzothiazole H5), 7.65 (1H, d, J ¼ 8.3 Hz, benzothiazole H7), 7.75
(1H, s, benzothiazole H4), 9.20 (1H, m, O-H), 12.60 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 20.95 (CH3), 26.00 (CH2, phenol-
CH2), 31.20 (CH2, CH2-triazole), 34.56 (CH2, S-CH2), 115.08 (2CH, phenol C3,
C5), 120.24 (CH, benzothiazole C7), 121.27 (CH, benzothiazole C4), 127.46 (CH,
benzothiazole C5), 129.15 (2CH, phenol C2, C6), 130.95 (C, benzothiazole C7a),
131.59 (C, benzothiazole C6), 133.09 (C, phenol C1), 146.46 (C, benzothiazole
C3a), 150.67 (C, triazole C5), 155.58 (C, phenol C4), 155.95 (C, triazole C3), 156.85
=
(C, benzothiazole C2), 167.40 (C, C O).
MS (EI) m=z (%): 236 (41), 164 (11), 130 (26), 107 (100), 77 (12).
Anal. calc. for C20H20N6O2S2: C, 54.53; H, 4.58; N, 19.08. Found: C, 54.52; H,
4.57; N, 19.10.
4-Amino-5-[2-(4-hydroxyphenyl)ethyl]-
3-[N-(6-methoxybenzothiazole-2-yl)acetamido]thio-4H-1,2,4-triazole
(IIIi)
Compound IIIi was synthesized according to the method described for IIIa
4-amino-5-
using
[2-(4-hydroxyphenyl)ethyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIb).
N-(6-methoxybenzothiazol-2-yl)-2-chloroacetamide
and
IR (KBr) nmax (cmꢁ1): 3354.32 (amine N-H stretching), 3190.37 (amide N-H
stretching), 3082.35 (aromatic C-H stretching), 2933.83 (aliphatic C-H asymmetric
=
stretching), 2866.32 (aliphatic C-H symmetric stretching), 1676.20 (amide C O
=
=
stretching), 1604.83, 1581.68, 1462.09 (C N and C C stretching), 1334.78,
1257.63 (C-N stretching), 1224.84 (C-O stretching), 1172.76, 1022.31 (C-N stretch-
ing), 825.56 (1,4-disubstituted benzene C-H out of plane deformation), 746.48
(C-H out of plane deformation), 669.32 (C-S stretching).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 2.90 (4H, m, CH2-triazole,
phenol-CH2), 3.81 (3H, s, O-CH3), 4.24 (2H, s, S-CH2), 5.94 (2H, s, NH2), 6.70
(2H, d, J ¼ 7.8 Hz, phenol H3, H5), 7.05 (3H, t, J ¼ 7.9 Hz, phenol H2, H6, benzothia-
zole H5), 7.57 (1H, s, benzothiazole H7), 7.67 (1H, d, J ¼ 8.8 Hz, benzothiazole H4),
9.21 (1H, m, O-H), 12.49 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 26.00 (CH2, phenol-CH2), 31.21
(CH2, CH2-triazole), 34.53 (CH2, S-CH2), 55.58 (CH3), 104.71 (CH, benzothiazole
C7), 114.93 (CH, benzothiazole C5), 115.08 (2CH, phenol C3, C5), 121.22 (CH, ben-
zothiazole C4), 129.15 (2CH, phenol C2, C6), 130.95 (C, benzothiazole C7a), 132.77
(C, phenol C1), 142.59 (C, benzothiazole C3a), 150.69 (C, triazole C5), 155.58 (C,

NOVEL TRIAZOLE DERIVATIVES
2249
phenol C4), 155.67 (C, benzothiazole C6), 155.96 (C, triazole C3), 156.18 (C,
=
benzothiazole C2), 167.24 (C, C O).
MS (EI) m=z (%): 236 (38), 180 (12), 165 (14), 130 (25), 107 (100), 77 (12).
Anal. calc. for C20H20N6O3S2: C, 52.62; H, 4.42; N, 18.41. Found: C, 52.60; H,
4.45; N, 18.45.
4-Amino-5-[2-(4-hydroxyphenyl)ethyl]-
3-[N-(6-ethoxybenzothiazole-2-yl)acetamido]thio-4H-1,2,4-triazole
(IIIj)
Compound IIIj was synthesized according to the method described for IIIa
and
using
N-(6-ethoxybenzothiazol-2-yl)-2-chloroacetamide
4-amino-5-
[2-(4-hydroxyphenyl)ethyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione (IIb).
IR (KBr) nmax (cmꢁ1): 3421.83, 3356.25 (amine N-H stretching), 3200.01
(amide N-H stretching), 3074.63 (aromatic C-H stretching), 2980.12 (aliphatic
CH3 C-H stretching), 2931.90 (aliphatic CH2 C-H stretching), 1676.20 (amide
=
=
=
C O stretching), 1606.76, 1516.10, 1460.16 (C N and C C stretching), 1338.64,
1257.63, 1055.10 (C-N stretching), 823.63 (1,4-disubstituted benzene C-H out of
plane deformation), 742.62 (C-H out of plane deformation).
1H NMR (400 MHz) (DMSO-d6) d (ppm): 1.34 (3H, t, J ¼ 7.0 Hz, O-CH2-
CH3), 2.90 (4H, m, CH2-triazole, phenol-CH2), 4.06 (2H, q, J ¼ 7.0 Hz, O-CH2-
CH3), 4.24 (2H, s, S-CH2), 5.94 (2H, s, NH2), 6.70 (2H, d, J ¼ 8.6 Hz, phenol H3,
H5), 7.03 (3H, m, phenol H2, H6, benzothiazole H5), 7.54 (1H, d, J ¼ 2.6 Hz, ben-
zothiazole H7), 7.65 (1H, d, J ¼ 8.8 Hz, benzothiazole H4), 9.21 (1H, m, O-H),
12.40 (1H, m, N-H).
13C NMR (100 MHz) (DMSO-d6) d (ppm): 14.65 (CH3), 26.00 (CH2, phenol-
CH2), 31.21 (CH2, CH2-triazole), 34.54 (CH2, S-CH2), 63.58 (CH2, O-CH2-CH3),
105.34 (CH, benzothiazole C7), 115.08 (2CH, phenol C3, C5), 115.28 (CH, benzothia-
zole C5), 121.21 (CH, benzothiazole C4), 129.15 (2CH, phenol C2, C6), 130.94 (C,
benzothiazole C7a), 132.76 (C, phenol C1), 142.51 (C, benzothiazole C3a), 150.68
(C, triazole C5), 155.41 (C, benzothiazole C6), 155.58 (C, phenol C4), 155.63 (C,
=
triazole C3), 155.96 (C, benzothiazole C2), 167.22 (C, C O).
MS (EI) m=z (%): 236 (39), 165 (11), 130 (26), 107 (100), 77 (11).
Anal. calc. for C21H22N6O3S2: C, 53.60; H, 4.71; N, 17.86. Found: C, 53.57; H,
4.68; N, 17.83.
Microbiology
A modified microbroth dilution method was carried out according to the
National Committee for Clinical Laboratory Standards (NCCLS) and a previous
work.[17,18] Ketoconazole and chloramphenicol were used as reference drugs.
The compounds IIIa–j were tested in vitro against C. albicans (clinical isolate,
Eskisehir Osmangazi University, Faculty of Medicine, Eskisehir, Turkey), C. albicans
(ATCC 90028), C. tropicalis (NRRL Y-12968), C. krusei (NRRL Y-7179),
C. parapsilosis (NRRL Y-12696), C. albicans (NRRL Y-12983), C. glabrata (clinical
isolate, Eskisehir Osmangazi University, Faculty of Medicine, Eskisehir, Turkey),
Escherichia coli (NRRL B-3008), Staphylococcus aureus (ATCC 6538), Pseudomonas

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M. D. ALTINTOP ET AL.
aeruginosa (ATCC 27853), Enterobacter aerogenes (NRRL 3567), Bacillus subtilis
(NRRL B-4378), methicillin-resistant Staphylococcus aureus (clinical isolate,
Eskisehir Osmangazi University, Faculty of Medicine, Eskisehir, Turkey).
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