Synthesis and antimicrobial activity of 4-phenyl/cyclohexyl-5-(1- phenoxyethyl)-3-[N-(2-thiazolyl)acetamido]thio-4H-1,2,4-triazole derivatives

Article abstract of DOI:10.1016/j.ejmech.2005.01.007

The increasing clinical importance of drug-resistant fungal and bacterial pathogens has lent additional urgency to microbiological research and new antimicrobial compound development. For this purpose, new thiazole derivatives of triazoles were synthesize

Full text of DOI:10.1016/j.ejmech.2005.01.007

European Journal of Medicinal Chemistry 40 (2005) 607–613
www.elsevier.com/locate/ejmech
Short communication
Synthesis and antimicrobial activity
of 4-phenyl/cyclohexyl-5-(1-phenoxyethyl)-
3-[N-(2-thiazolyl)acetamido]thio-4H-1,2,4-triazole derivatives
Gülhan Turan-Zitouni a,*, Zafer Asım Kaplancıklı a, Mehmet TahaYıldız b,
Pierre Chevallet c, Demet Kaya d
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskis¸ehir, Turkey
b Department of Biology, Faculty of Science, Anadolu University, 26470 Eskis¸ehir, Turkey
c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Montpellier University, LAAP, CNRS-UMR 5810, 34000 Montpellier, France
d
˙
Department of Microbiology, Faculty of Medicine, Izzet Baysal University, Düzce, Turkey
Received 27 May 2004; received in revised form 30 December 2004; accepted 12 January 2005
Available online 02 March 2005
Abstract
The increasing clinical importance of drug-resistant fungal and bacterial pathogens has lent additional urgency to microbiological research
and new antimicrobial compound development. For this purpose, new thiazole derivatives of triazoles were synthesized and evaluated for
antifungal and antibacterial activity.
The reaction of propionic acid hydrazides with various aryl/alkyl isothiocyanates gave thiosemicarbazides which furnished the mercaptot-
riazoles by alkali cyclization. The 4-phenyl/cyclohexyl-5-(1-phenoxyethyl)-3-[N-(2-thiazolyl)acetamido]thio-4H-1,2,4-triazole derivatives
were synthesized by reacting the mercaptotriazoles with 2-chloro-N-(2-thiazolyl)acetamide. The chemical structures of the compounds were
elucidated by IR, 1H-NMR, FAB+-MS spectral data. Their antimicrobial activities against Candida albicans (two strains), Candida glabrata,
Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa were investigated. The results showed that some of the compounds have
very strong antifungal activity.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Thiazole; Triazole; Antifungal activity; Antibacterial activity
1. Introduction
fungals may be regarded as a new class providing truly effec-
tive drugs those are reported to inhibit fungi by blocking the
biosynthesis of certain fungal lipids, especially ergosterol in
cell membranes, and by additional mechanisms [4,5]. The
imidazole antifungals, such as clotrimazole, miconazole, and
ketoconazole, showed good topical activity, but were only of
limited value for systematic administration. Triazole deriva-
tives are the other major chemical group of antifungal azole
derivatives. Nowadays, the most frequently used triazoles are
fluconazole and itraconazole. They posses a broad spectrum
of antifungal activity and reduced toxicity when compared
with the imidazole antifungals [6–11].
The development of resistance to current antibacterial
therapy continues to search for more effective agents. In addi-
tion, primary and opportunistic fungal infections continue to
increase rapidly because of the increased number of immu-
nocompromised patients (AIDS, cancer and transplants). Sev-
eral reviews have appeared illustrating the problems encoun-
tered by today’s infectious disease clinicians [1–3].
As known, not only biochemical similarity of the human
cell and fungi forms a handicap for selective activity, but also
the easily gained resistance is the main problem encountered
in developing safe and efficient antifungals. The azole anti-
Triazoles, in particular, substituted-1,2,4-triazoles and the
open-chain thiosemicarbazide counterparts of 1,2,4-triazole,
are among the various heterocycles that have received the most
attention during the last two decades as potential antimicro-
* Corresponding author. Tel.: +90 222 335 0580/3642; fax: +90 222 335
0750.
E-mail address: gturan@anadolu.edu.tr (G. Turan-Zitouni).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.01.007

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G. Turan-Zitouni et al. / European Journal of Medicinal Chemistry 40 (2005) 607–613
bial agents [12–22]. Substitutions including thio [23,24], alky-
lthio and alkenylthio [25,26] derivatives have been carried
out primarily at the 3-position of the 1,2,4-triazole ring, as
potential antimicrobial agents those will overcome the above
mentioned resistance problems.
In view of these data, we aimed the synthesis of new 1,2,4-
triazole derivatives as novel antimicrobial agents. The triaz-
oles contain thiazole ring system and, in additionally, some
of these thiazoles include ester residue. Thiazole moiety was
selected as it is well known with its antimicrobial activity
[27–30] and ester residue, i.e. easily hydrolyze to acid func-
tion, was especially preferred refer to the data discussed as a
part of the effect of acidic functions on nonspecific antifun-
gal agents [31].
zine hydrate [33,34]. The condensation of the acid hydrazides
(II) with appropriate phenyl/cyclohexyl isothiocyanate
resulted in the formation of 1-(2-phenoxypropionyl)-4-
phenyl/cyclohexyl-3-thiosemicarbazides (III) [35,36].
The thiosemicarbazides, on refluxing with 2 N sodium
hydroxide solution, were cyclized into corresponding
4-phenyl/cyclohexy-5-(1-phenoxyethyl)-2,4-dihydro-3H-
1,2,4-triazol-3-thione (IVa–e) in which, two of them (IVd
and IVe) are reported for the first time [36–38]. Treatment of
equimolar quantities of these triazoles with 2-chloro-N-(2-
thiazolyl)acetamides (I) in the presence of anhydrous potas-
sium carbonate resulted in the formation of the title com-
pounds (Va–o). Some characterizations of IVa–e and Va–o
were given in Table 1.
2. Chemistry
3. Biology
The synthetic route of compounds is outlined in Scheme
1. In the present work, 2-chloro-N-(2-thiazolyl)acetamides
(I) were prepared for the first time by reacting 2-amino-
thiazoles with chloroacetyl chloride in accordance with the
method described in Ref. [32].
3.1. Antimicrobial activity
Antimicrobial activities of compounds were tested using
microbroth dilution method [39,40]. Tested microorganism
strains were; Candida albicans (NRRL Y-27077), Candida
glabrata (ATCC 36583), C. albicans (isolate obtained from
The 2-phenoxypropionic acid hydrazides (II) were pre-
pared by reacting ethyl 2-phenoxypropionates with hydra-
Scheme 1. The general synthesis reactions.

G. Turan-Zitouni et al. / European Journal of Medicinal Chemistry 40 (2005) 607–613
609
Table 1
Some characterizations of the compounds
Compounds
IVa
IVb
IVc
IVd
IVe
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
Vj
Vk
Vl
Vm
Vn
R1
R2
R3
M.p. (°C)
171–173
136–138
183–185
177–179
194–196
202–204
235–238
140–142
222–224
177–179
190–191
208–210
206–208
175–177
161–164
218–220
153–155
201–203
232–234
188–190
Yield (%)
50
Molecular formula
–
H
C6H5
C6H5
C6H5
C6H11
C6H11
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H11
C6H11
C6H11
C6H11
C6H11
C6H11
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
16H15N3OS
–
Cl
55
16H14ClN3OS
17H17N3OS
–
CH3
H
52
–
46
16H21N3OS
–
CH3
H
45
17H23N3OS
H
73
21H19N5O2S2
24H23N5O4S2
25H25N5O4S2
21H18ClN5O2S2
24H22ClN5O4S2
25H24ClN5O4S2
22H21N5O2S2
25H25N5O4S2
26H27N5O4S2
21H25N5O2S2
24H29N5O4S2
25H31N5O4S2
22H27N5O2S2
25H31N5O4S2
26H33N5O4S2
COOC2H5
CH2COOC2H5
H
H
65
H
72
Cl
62
COOC2H5
CH2COOC2H5
H
Cl
72
Cl
65
CH3
CH3
CH3
H
71
COOC2H5
CH2COOC2H5
H
68
63
72
COOC2H5
CH2COOC2H5
H
H
68
H
69
CH3
CH3
CH3
72
COOC2H5
CH2COOC2H5
75
Vo
81
Faculty of Medicine, Osmangazi University), Escherichia coli
(ATCC 10798), Staphylococcus aureus (ATCC 6538),
Pseudomonas aeruginosa (ATCC 7700). Chloramphenicol
and ketoconazole were used as control drugs. The observed
data on the antimicrobial activity of the compounds and con-
trol drugs were given in Table 2.
4. Results, discussion and conclusion
In the present work, five triazolinethiones (IVa–e) (two of
them original) and 15 new compounds (Va–o) which are thio-
ether derivatives of IV were synthesized. The structures of
the obtained compounds were elucidated by spectral data.
Table 2
MIC values of the compounds as µg ml–1
Compounds
IVa
IVb
IVc
IVd
IVe
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
Vj
C. albicans (a)
C. albicans (b)
16
C. glabrata
E. coli
100
100
100
100
100
100
100
100
400
100
100
100
100
200
200
100
100
100
200
200
–
S. aureus
200
200
200
200
200
200
200
200
400
100
200
200
200
200
200
>400
200
200
200
200
–
P. aeruginosa
100
200
100
100
100
100
100
100
400
100
100
100
100
200
200
100
100
100
200
200
–
16
2
8
>16
16
1
1
0.25
8
16
0.5
16
>16
4
>16
>16
>16
>16
>16
>16
>16
8
0.125
8
8
4
8
4
>16
8
8
8
16
8
>16
16
16
16
16
16
16
>16
8
16
>16
16
16
16
>16
>16
4
>16
>16
16
Vk
Vl
Vm
Vn
Vo
>16
>16
>16
>16
4
8
16
8
A
B
–
–
50
12.5
200
A: Ketoconazole, B: chloramphenicol.
a C. albicans (NRRL Y-27077).
b C. albicans (isolate obtained from Faculty of Medicine, Osmangazi University).

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G. Turan-Zitouni et al. / European Journal of Medicinal Chemistry 40 (2005) 607–613
According to the IR spectroscopic data of the compounds
As we consider all results obtained from antifungal and
antibacterial tests together we can say that entire compounds
tested are more active towards fungi then bacteria.
IVa–e which have triazoline-3-thione structure, the observa-
tion of C=S stretching bands at 1399–1373 cm–1 and the
absence of an absorption about in 2600–2550 cm–1 region
cited [41] for SH group have proved that these compounds
were in the thionic form. NH stretching bands of IVa–e were
observed at 3421–3088 cm–1 region. The IR spectra of thio-
ether derivatives (Va–o) showed characteristic C=O (amide)
stretching bands in 1700–1660 cm–1 region. In addition, com-
pounds which are including ester group, showed characteris-
tic C=O (ester) bands in 1745–1715 cm–1 region.
5. Experimental
5.1. Chemistry
All melting points (m.p.) were determined in open capil-
laries on a Gallenkamp apparatus and are uncorrected. The
purity of the compounds was routinely checked by thin layer
chromatography (TLC) using silica gel 60G (Merck). Spec-
troscopic data were recorded by the following instruments.
IR: Shimadzu IR-435 spectrophotometer; 1H-NMR: Bruker
250 MHz spectrometer, MS-FAB: VG Quattro Mass spec-
trometer. Elemental analyses were recorded on Perkin Elmer
EAL 240 spectrometer.
In the 1H-NMR spectra of compounds IV, NH peaks were
observed as singlets at about 13.70–14.04 ppm region. There-
fore, it was proved that they were found in thionic form. In
thioether derivatives (V), the signal due to COCH2 methyl-
ene protons, presented in all compounds, appeared at 4.05–
4.30 ppm, as singlets. NHCO proton was observed at 12.45–
12.90 ppm as a singlet or broad band. All the other aromatic
and aliphatic protons were observed at expected regions.
Mass spectra (MS (FAB)) of compounds showed a M +
1 peaks, in agreement with their molecular formula.
The most important part of the results was those which are
obtained from antifungal activity screening. Most of the com-
pounds were effective against C. albicans (NRRLY-27077).
When compared with ketoconazole; especially IVb, IVc, IVe
showed strong, Vc similar to reference agent, and IVa, VId,
Va, Vd, Vf, Vg, Vh, Vi, Vk, Vl, Vm moderate activity.
Similar results obtained from C. glabrata. Compounds
IVb, IVc, IVe, Vc and Vd show great, IVa, VId, Va, Vb, Ve,
Vf, Vn, Vm similar and Vg, Vh, Vi, Vj, Vk and Vo moderate
activity when compared with ketoconazole.
5.1.1. General procedure for synthesis of the compounds
5.1.1.1. 2-Chloro-N-(2-thiazolyl)acetamides (I). Chloro-
acetyl chloride (20 mmol) and triethylamine (20 mmol) were
added to a solution of 2-amino-4-substituted-thiazole
(20 mmol) in anhydrous benzene and the mixture was treated
as described in literature.
5.1.1.2. 2-Phenoxypropionic acid hydrazides (II). These com-
pounds were prepared according to the previously reported
method, by reacting ethyl 2-phenoxypropionates with hydra-
zine hydrate.
5.1.1.3. 1-(2-Phenoxypropionyl)-4-phenyl/cyclohexyl-3-
thiosemicarbazides (III). Equimolar quantities of acid
hydrazide (30 mmol) and phenyl/cyclohexyl isothiocyanate
in 25 ml of absolute ethanol were refluxed for 3–5 h. The
resulting solid was filtered and recrystallized from ethanol.
SAR observations showed that triazolethiols are more
active then their thioether derivatives. Besides this, the most
effective derivatives of triazolethiols were p-methylphenoxy
derivatives.
The only resistant strain against almost all of the com-
pounds, except IVa, IVc, Vf, Vh, Vk, was the clinic isolate
of C. albicans. Among these five active compounds, the most
and the only effective compound against clinic isolate of C.
albicans was Vf, which includes chlorine subsistent on phe-
noxy moiety while other effective compounds does not have.
However, it was also observed that the ester substations on
the thiazole ring had no determining influence on the antifun-
gal activity.
5.1.1.4. 4-Phenyl/cyclohexy-5-(1-phenoxyethyl)-2,4-dihydro-
3H-1,2,4-triazol-3-thione (IVa–e). Suitable substituted thi-
osemicarbazides (III) (20 mmol) were dissolved in 2 N
sodium hydroxide and the resulting solution was heated under
reflux for 3 h. The solution was cooled and acidified to pH
2–3 with hydrochloric acid solution and recrystallized from
ethanol.
The result of antibacterial screening of newly prepared
compounds IVe and Va–o expressed as the MIC are summa-
rized in Table 2. The antibacterial assessment revealed that
the compounds posses only a moderate or slight activity. The
MIC values are generally within the range of 100–400 µg ml–1,
most of often between 100 and 200 µg ml–1 against all evalu-
ated strains. By comparing their MIC values with chloram-
phenicol, the compounds were less active against E. coli and
S. aureus. On the other hand the compounds exhibited com-
parable or better activities against P. aeruginosa then those
of chloramphenicol.
5.1.1.5. 4-Phenyl/cyclohexyl-5-(1-phenoxyethyl)-3-[N-(2-
thiazolyl)acetamido]thio-4H-1,2,4-triazole (Va–o). A mix-
ture of the 2-chloro-N-(2-thiazolyl)acetamides (I) (10 mmol),
appropriate triazoles (IV) and anhydrous potassium carbon-
ate in acetone was mixtured at room temperature for 6 h. The
mixture was filtered, the filtrate was evaporated until dry-
ness. The residue was washed with water and recrystallized
from ethanol.
IVa:
IR (KBr) tmaks (cm–1): 3099 (N–H), 1589–1408 (C=C and
C=N), 1374 (C=S), 1238–1134 (C–O).

G. Turan-Zitouni et al. / European Journal of Medicinal Chemistry 40 (2005) 607–613
611
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.45 (3H, d
[J = 6.44 Hz], CH–CH3), 5.30 (1H, q [J = 6.43 Hz], CH–CH3),
6.60 (2H, d [J = 7.85 Hz], C2, C6 protons of O-phenyl), 6.85
(1H, t [J = 7.33 Hz], C4 proton of O-phenyl), 7.20 (2H, d
[J = 7.50 Hz], C3, C5 protons of O-phenyl), 7.35–7.50 (5H,
m, protons of N-phenyl), 14.00 (1H, s, N–H).
MS (FAB) [M + 1]: m/z 298.
O-phenyl), 7.25–755 (7H, m, protons of N-phenyl and C4, C5
protons of thiazole), 12.45 (1H, s, N–H).
MS (FAB) [M + 1]: m/z 438.
Anal. Calc. for C21H19N5O2S2: C, 57.65; H, 4.38; N, 16.01.
Found: C, 57.45; H, 4.55; N, 16.20.
Vb:
IR (KBr) tmaks (cm–1): 3120 (NH), 1721 (ester C=O), 1664
(amide C=O), 1580–1463 (C=C and C=N), 1231–1098
(C–O).
Anal. Calc. for C16H15N3OS: C, 64.62; H, 5.08; N, 14.13.
Found: C, 64.30; H, 5.20; N, 14.25.
IVb:
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.30 (3H, t
[J = 7.10 Hz], COO–CH2–CH3), 1.60 (3H, d [J = 6.46 Hz],
CH–CH3), 4.20 (2H, s, S–CH2), 4.30 (2H, q [J = 7.05 Hz],
COO–CH2–CH3), 5.50 (1H, q [J = 6.48 Hz], CH–CH3), 6.70
(2H, d [J = 7.86 Hz], C2, C6 protons of O-phenyl), 6.90 (1H,
t [J = 7.35], C4 proton of O-phenyl), 7.20 (2H, t [J = 7.45 Hz],
C3, C5 protons of O-phenyl), 7.40–7.55 (5H, m, protons of
N-phenyl), 8.10 (1H, s, C5 protons of thiazole), 12.90 (1H, s,
N–H).
IR (KBr) tmaks (cm–1): 3260–3201 (N–H), 1598–1434
(C=C and C=N), 1373 (C=S), 1236–1170 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.45 (3H, d
[J:6.48 Hz], CH–CH3), 5.25 (1H, q [J = 6.44 Hz], CH–CH3),
6.75 (2H, d [J = 6.78 Hz], C2, C6 protons of O-phenyl), 7.10–
7.45 (5H, m, protons of N-phenyl), 7.25 (2H, d [J = 6.79 Hz],
C3, C5 protons of O-phenyl).
Anal. Calc. for C16H14ClN3OS: C, 57.92; H, 4.25; N,
12.66. Found: C, 57.82; H, 4.30; N, 12.41.
MS (FAB) [M + 1]: m/z 510.
IVc:
Anal. Calc. for C24H23N5O4S2: C, 56.57; H, 4.55; N, 13.74.
Found: C, 56.75; H, 4.50; N, 13.60.
IR (KBr) tmaks (cm–1): 3421–3099 (N–H), 1610–1419
(C=C and C=N), 1382 (C=S), 1240–1080 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.50 (3H, d
[J = 6.45 Hz], CH–CH3), 2.20 (3H, s, phenyl-CH3), 5.30 (1H,
q [J = 6.41 Hz], CH–CH3), 6.60 (2H, d [J = 8.54 Hz], C2, C6
protons of O-phenyl), 7.05 (2H, d [J = 8.36 Hz], C3, C5 pro-
tons of O-phenyl), 7.35–7.50 (5H, m, protons of N-phenyl),
14.05 (1H, s, N–H).
Vc:
IR (KBr) tmaks (cm–1): 3163–3105 (NH), 1731 (ester C=O),
1676 (amide C=O), 1585–1454 (C=C and C=N), 1255–1080
(C–O).
Anal. Calc. for C25H25N5O4S2: C, 57.34; H, 4.81; N, 13.37.
Found: C, 57.34; H, 4.91; N, 13.55.
Vd:
MS (FAB) [M + 1]: m/z 312.
Anal. Calc. for C17H17N3OS: C, 65.57; H, 5.50; N, 13.49.
Found: C, 65.30; H, 5.30; N, 13.49.
IR (KBr) tmaks (cm–1): 3179 (NH), 1684 (amide C=O),
1595–1488 (C=C, C=N), 1228–1080 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.55 (3H, d
[J = 6.44 Hz], CH–CH3), 4.20 (2H, s, S–CH2), 5.50 (1H, q
[J = 6.45 Hz], CH–CH3), 6.70 (2H, d [J = 9.20 Hz], C2, C6
protons of O-phenyl), 7.15–755 (9H, m, aromatic protons),
12.45 (1H, s, N–H).
IVd:
IR (KBr) tmaks (cm–1): 3088 (N–H), 1600–1446 (C=C and
C=N), 1399 (C=S), 1228–1083 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 0.85–1.75
(10H, m, protons of cyclohexyl), 1.55 (3H, d [J = 6.33 Hz],
CH–CH3), 4.15 (1H, br, proton of cyclohexyl), 5.75 (1H, q
[J = 6.34 Hz], CH–CH3), 6.90–7.05 (3H, m, C2, C4,C6 pro-
tons of O-phenyl), 7.25–7.35 (2H, t [J = 7.44 Hz], C3, C5
protons of O-phenyl), 13.70 (1H, s, N–H).
MS (FAB) [M + 1]: m/z 472.
Anal. Calc. for C21H18ClN5O2S2: C, 53.55; H, 3.84; N,
14.84. Found: C, 53.35; H, 3.90; N, 14.60.
Ve:
IR (KBr) tmaks (cm–1): 3169 (NH), 1737 (ester C=O), 1701
(amide C=O), 1562–1461 (C=C, C=N), 1235–1091 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.30 (3H, t
[J = 7.11 Hz], COO–CH2–CH3), 1.55 (3H, d [J = 6.46 Hz],
CH–CH3), 4.05 (2H, s, S–CH2), 4.20 (2H, q [J = 7.13 Hz],
COO–CH2–CH3), 5.50 (1H, q [J = 6.49 Hz], CH–CH3), 6.80
(2H, d [J = 9.02 Hz], C2, C6 protons of O-phenyl), 7.25 (2H,
d [J = 8.97 Hz], C3, C5 protons of O-phenyl), 7.40–7.60 (5H,
m, protons of N-phenyl), 7.65 (1H, s, C5 proton of thiazole).
Anal. Calc. for C24H22ClN5O4S2: C, 52.99; H, 4.08; N,
12.87. Found: C, 53.25; H, 4.20; N, 12.60.
Vf:
MS (FAB) [M + 1]: m/z 312.
Anal. Calc. for C16H21N3OS: C, 63.34; H, 6.98; N, 13.85.
Found: C, 63.34; H, 7.18; N, 13.80.
IVe:
IR (KBr) tmaks (cm–1): 3240–3095 (N–H), 1614–1456
(C=C and C=N), 1375 (C=S), 1255–1072 (C–O).
Anal. Calc. for C17H23N3OS: C, 64.32; H, 7.30; N, 13.24.
Found: C, 64.32; H, 7.55; N, 13.60.
Va:
IR (KBr) tmaks (cm–1): 3185 (NH), 1685 (C=O), 1575–
1443 (C=C and C=N), 1223–1072 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.60 (3H, d
[J = 6.46 Hz], CH–CH3), 4.25 (2H, s, S–CH2), 5.50 (1H, q
[J = 6.46 Hz], CH–CH3), 6.70 (2H, d [J = 7.86 Hz], C2, C6
protons of O-phenyl), 6.90 (1H, t [J = 7.29], C4 proton of
O-phenyl), 7.20 (2H, t [J = 8.48 Hz] C3, C5 protons of
IR (KBr) tmaks (cm–1): 3164 (NH), 1735 (ester C=O), 1671
(amide C=O), 1582–1455 (C=C, C=N), 1259–1077 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.20 (3H, t
[J = 7.09 Hz], COO–CH2–CH3), 1.55 (3H, d [J = 6.44 Hz],
CH–CH3), 3.70 (2H, s, CH2–COO–C2H5), 4.10 (2H, q

612
G. Turan-Zitouni et al. / European Journal of Medicinal Chemistry 40 (2005) 607–613
[J = 7.10 Hz], COO–CH2–CH3), 4.20 (2H, s, S–CH2), 5.50
(1H, q [J = 6.46 Hz], CH–CH3), 6.70 (2H, d [J = 8.97 Hz],
C2, C6 protons of O-phenyl), 7.00 (1H, s, C5 proton of thiaz-
ole), 7.25 (2H, d [J = 8.95 Hz], C3, C5 protons of O-phenyl),
7.35–7.55 (5H, m, protons of N-phenyl), 12.50 (1H, s, N–H).
MS (FAB) [M + 1]: m/z 558.
q [J = 6.50 Hz], CH–CH3), 6.90–7.55 (7H, m, aromatic pro-
tons), 12.45 (1H, s, N–H).
MS (FAB) [M + 1]: m/z 444.
Anal. Calc. for C21H25N5O2S2: C, 56.86; H, 5.68; N, 15.79.
Found: C, 56.66; H, 5.70; N, 15.30.
Vk:
IR (KBr) tmaks (cm–1): 3122 (NH), 1723 (ester C=O), 1663
(amide C=O), 1579–1460 (C=C, C=N), 1230–1097 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 0.90–1.20 (3H,
m, protons of cyclohexyl), 1.25 (3H, t [J = 7.11 Hz], COO–
CH2–CH3), 1.50–2.05 (7H, m, protons of cyclohexyl), 1.65
(3H, d [J = 6.41 Hz], CH–CH3), 4.00–4.15 (1H, m, C1 proton
of cyclohexyl), 4.20–4.30 (4H, m, S–CH2 ve COO–CH2–
CH3), 5.85 (1H, q [J = 6.46 Hz], CH–CH3), 6.90–7.00 (3H,
m, C2, C4, C6 protons of O-phenyl), 7.25 (2H, t [J = 7.52 Hz],
C3, C5 protons of O-phenyl), 8.05 (1H, s, C5 protons of thia-
zole), 12.85 (1H, s, N–H).
Anal. Calc. for C25H24ClN5O4S2: C, 53.81; H, 4.33; N,
12.55. Found: C, 53.81; H, 4.43; N, 1280.
Vg:
IR (KBr) tmaks (cm–1): 3180 (NH), 1686 (amide C=O),
1575–1435 (C=C, C=N), 1225, 1068 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.55 (3H, d
[J = 6.46 Hz], CH–CH3), 2.20 (3H, s, phenyl-CH3), 4.25 (2H,
s, S–CH2), 5.45 (1H, q [J = 6.47 Hz], CH–CH3), 6.60 (2H, d
[J = 8.53 Hz], C2, C6 protons of O-phenyl), 7.00 (2H, d
[J = 8.45 Hz], C3, C5 protons of O-phenyl), 7.25–760 (7H, m,
aromatic protons), 12.45 (1H, s, N–H).
MS (FAB) [M + 1]: m/z 516.
Anal. Calc. for C24H29N5O4S2: C, 55.90; H, 5.67; N, 13.58.
Found: C, 55.90; H, 5.60; N, 13.58.
MS (FAB) [M + 1]: m/z 452.
Anal. Calc. for C22H21N5O2S2: C, 58.52; H, 4.69; N, 15.51.
Found: C, 58.65; H, 4.80; N, 15.40.
Vl:
Vh:
IR (KBr) tmaks (cm–1): 3166 (NH), 1736 (ester C=O), 1672
(amid C=O), 1576–1449 (C=C, C=N), 1223–1086 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 0.90–1.30 (3H,
m, protons of cyclohexyl), 1.15 (3H, t [J = 7.14 Hz], COO–
CH2–CH3), 1.45–1.80 (5H, m, protons of cyclohexyl), 1.65
(3H, d [J = 6.41 Hz], CH–CH3), 1.90–2.05 (2H, m, protons
of cyclohexyl), 3.60 (2H, s, CH2–COO–C2H5), 3.95–4.10
(3H, m, COO–CH2–CH3 and proton of cyclohexyl), 4.15 (2H,
s, S–CH2), 5.85 (1H, q [J = 6.91 Hz], CH–CH3), 6.70 (1H, s,
C5 protons of thiazole), 6.90–7.05 (3H, m, C2, C4, C6 protons
of O-phenyl), 7.30 (2H, t [J = 7.35 Hz], C3, C5 protons of
O-phenyl).
IR (KBr) tmaks (cm–1): 3123 (NH), 1725 (ester C=O), 1663
(amide C=O), 1575–1463 (C=C, C=N), 1232–1096 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.25 (3H, t
[J = 7.09 Hz], COO–CH2–CH3), 1.50 (3H, d [J = 6.46 Hz],
CH–CH3), 2.15 (3H, s, phenyl-CH3), 4.15 (2H, s, S–CH2),
4.25 (2H, q [J = 7.08 Hz], COO–CH2–CH3), 5.40 (1H, q
[J = 6.45 Hz], CH–CH3), 6.55 (2H, d [J = 8.54 Hz], C2, C6
protons of O-phenyl), 6.90 (2H, d [J = 8.43 Hz], C3, C5 pro-
tons of O-phenyl), 7.30–7.50 (5H, m, protons of N-phenyl),
8.05 (1H, s, C5 proton of thiazole), 12.70 (1H, s, N–H).
MS (FAB) [M + 1]: m/z 524.
Anal. Calc. for C25H25N5O4S2: C, 57.34; H, 4.81; N, 13.37.
Found: C, 57.65; H, 4.70; N, 13.40.
MS (FAB) [M + 1]: m/z 530.
Anal. Calc. for C25H31N5O4S2: C, 56.69; H, 5.90; N, 13.22.
Found: C, 56.60; H, 5.95; N, 13.20.
Vi:
IR (KBr) tmaks (cm–1): 3164, 3105 (NH), 1745 (ester C=O),
1668 (amide C=O), 1580–1450 (C=C, C=N), 1255–1081
(C–O).
Vm:
IR (KBr) tmaks (cm–1): 3166 (NH), 1671 (amide C=O),
1574–1454 (C=C, C=N), 1225–1080 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.00–1.30 (3H,
m, protons of cyclohexyl), 1.60–1.85 (5H, m, protons of cyclo-
hexyl), 1.65 (3H, d [J = 6.41 Hz], CH–CH3), 1.90–2.05 (2H,
m, protons of cyclohexyl), 2.20 (3H, s, phenyl-CH3), 4.05–
4.25 (1H, m, C1 proton of cyclohexyl), 4.30 (2H, s, S–CH2),
5.80 (1H, q [J = 6.51 Hz], CH–CH3), 6.90 (2H, d
[J = 8.57 Hz], C2, C6 protons of O-phenyl), 7.05 (2H, d
[J = 8.39 Hz], C3, C5 protons of O-phenyl), 7.25 (1H, d
[J = 3.53 Hz], C4 proton of thiazole), 7.50 (1H, d [J = 3.54 Hz],
C5 proton of thiazole), 12.45 (1H, s, N–H).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.15 (3H, t
[J = 7.09 Hz], COO–CH2–CH3), 1.50 (3H, d [J = 6.46 Hz],
CH–CH3), 2.15 (3H, s, phenyl-CH3), 3.65 (2H, s, CH2–COO–
C2H5), 4.05 (2H, q [J = 7.11 Hz], COO–CH2–CH3), 4.15 (2H,
s, S–CH2), 5.35 (1H, q [J = 6.47 Hz], CH–CH3), 6.55 (2H, d
[J = 8.51 Hz], C2, C6 protons of O-phenyl), 6.90–7.00 (3H,
m, aromatic protons), 7.30–7.55 (5H, m, aromatic protons),
12.45 (1H, s, N–H).
MS (FAB) [M + 1]: m/z 538.
Anal. Calc. for C26H27N5O4S2: C, 58.08; H, 5.06; N, 13.03.
Found: C, 58.18; H, 5.20; N, 13.32.
MS (FAB) [M + 1]: m/z 458.
Vj:
Anal. Calc. for C22H27N5O2S2: C, 57.74; H, 5.95; N, 15.30.
Found: C, 57.64; H, 6.20; N, 15.37.
IR (KBr) tmaks (cm–1): 3165 (NH), 1682 (amid C=O),
1585–1447 (C=C, C=N), 1218–1072 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 0.95–1.35 (3H,
m, protons of cyclohexyl), 1.50–2.10 (7H, m, protons of cyclo-
hexyl), 1.70 (3H, d (J = 6.38 Hz), CH–CH3), 4.05–4.20 (1H,
m, C1 proton of cyclohexyl), 4.30 (2H, s, S–CH2), 5.90 (1H,
Vn:
IR (KBr) tmaks (cm–1): 3132 (NH), 1715 (ester C=O), 1679
(amide C=O), 1578–1451 (C=C, C=N), 1226–1075 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.00–1.20 (3H,
m, protons of cyclohexyl), 1.25 (3H, t [J = 7.11 Hz], COO–

G. Turan-Zitouni et al. / European Journal of Medicinal Chemistry 40 (2005) 607–613
613
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CH2–CH3), 1.55–1.70 (5H, m, protons of cyclohexyl), 1.60
(3H, d [J = 6.44 Hz], CH–CH3), 1.85–2.05 (2H, m, protons
of cyclohexyl), 2.20 (3H, s, phenyl-CH3), 4.05–4.15 (1H, m,
C1 proton of cyclohexyl), 4.20–4.30 (4H, m, S–CH2 ve COO–
CH2–CH3), 5.80 (1H, q [J = 6.51 Hz], CH–CH3), 6.85 (2H, d
[J = 8.59 Hz], C2, C6 protons of O-phenyl), 7.10 (2H, d
[J = 8.38 Hz], C3, C5 protons of O-phenyl), 8.05 (1H, s, C5
proton of thiazole), 12.85 (1H, s, N–H).
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MS (FAB) [M + 1]: m/z 530.
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Anal. Calc. for C25H31N5O4S2: C, 56.69; H, 5.90; N, 13.22.
Found: C, 56.80; H, 6.25; N, 13.55.
Vo:
IR (KBr) tmaks (cm–1): 3158 (NH), 1741 (ester C=O), 1673
(amide C=O), 1571–1451 (C=C, C=N), 1228–1074 (C–O).
1H-NMR (250 MHz) (DMSO-d6) d (ppm): 1.00–1.10 (3H,
m, protons of cyclohexyl), 1.15 (3H, t [J = 7.11 Hz], COO–
CH2–CH3), 1.50–1.80 (5H, m, protons of cyclohexyl), 1.65
(3H, d [J = 6.28 Hz], CH–CH3), 1.85–2.10 (2H, m, protons
of cyclohexyl), 2.20 (3H, s, phenyl-CH3), 3.65 (2H, s, CH2–
COO–C2H5), 4.10 (1H, q [J = 7.10 Hz], COO–CH2–CH3),
4.10–4.20 (1H, m, C1 proton of cyclohexyl), 4.25 (2H, s,
S–CH2), 5.80 (1H, q [J = 6.49 Hz], CH–CH3), 6.85 (2H, d
[J = 8.54 Hz], C2, C6 protons of O-phenyl), 7.00 (1H, s, C5
proton of thiazole), 7.05 (2H, d [J = 8.47 Hz], C3, C5 protons
of O-phenyl), 12.45 (1H, s, N–H).
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Anal. Calc. for C26H33N5O4S2: C, 57.44; H, 6.12; N, 12.88.
Found: C, 57.68; H, 6.53; N, 12.71.
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5.2. Biology
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fungal susceptibility of the fungus yeasts were examined
according to NCCLS reference method for broth dilution anti-
fungal susceptibility testing of yeasts [40]. Chloramphenicol
was used as standard antibacterial agent and ketoconazole
was used as antifungal agent. And both are prepared as
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