Synthesis and antimicrobial activity of some 5-aryl-2-[(N,N-disubstituted thiocarbamoylthio)acylamino]-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/S0014-827X(98)00063-9

In this study, a number of novel 5-aryl-2-[(N,N-disubstituted thiocarbamoylthio)acylamino]-1,3,4-oxadiazole derivatives were synthesized by the reaction of potassium salts of N,N-disubstituted dithiocarbamoic acids with 2-[(α-chloro-α-phenylacetyl/α-bromo

Full text of DOI:10.1016/S0014-827X(98)00063-9

Il Farmaco 53 (1998) 541±544
Synthesis and antimicrobial activity of some 5-aryl-2-[(N,N-disubstituted
thiocarbamoylthio)acylamino]-1,3,4-oxadiazoles
a,
a
Oznur AtesË , AysËe Kocabalkanli , Nesrin Cesur , GuÈlten OtuÈk
a
b
È
È
*
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Istanbul, 34452 Beyazõt, Istanbul, Turkey
bDepartment of Microbiology, Faculty of Pharmacy, University of Istanbul, 34452 Beyazõt, Istanbul, Turkey
Received 22 April 1998; accepted 27 July 1998
Abstract
In this study, a number of novel 5-aryl-2-[(N,N-disubstituted thiocarbamoylthio)acylamino]-1,3,4-oxadiazole derivatives were synthe-
sized by the reaction of potassium salts of N,N-disubstituted dithiocarbamoic acids with 2-[(a-chloro-a-phenylacetyl/a-bromopropionyl)-
1
amino]-5-aryl-1,3,4-oxadiazoles. Structures of the compounds were con®rmed by the spectral data (IR, H NMR, EIMS) and elemental
analyses. Most of the compounds were tested against various microorganisms and four of them were found to be weakly active against
Staphylococcus aureus and Staphylococcus epidermidis. q 1998 Elsevier Science S.A. All rights reserved.
Keywords: Antibacterial drugs; 5-Aryl-2-[(N,N-disubstituted thiocarbamoylthio)acylamino]-1,3,4-oxadiazole; Microbiology; Synthesis
1. Introduction
The structure of the compounds was elucidated by
1
elemental analyses and IR, H NMR and EI mass spectral
Both dithiocarbamates and 2-amino-1,3,4-oxadiazoles
are known to possess antimicrobial activity [1±10], along
with other activities. In this study, potassium salts of N,N-
disubstituted dithiocarbamoic acids were reacted with
2-[(a-chloro-a-phenylacetyl/a-bromopropionyl)amino]-5-
aryl-1,3,4-oxadiazoles to obtain a series of new compounds
which were expected to be antimicrobial agents. As a result
of microbiological research, four of the compounds were
found to be weakly active against Staphylococcus aureus
and Staphylococcus epidermidis.
data. The IR spectra of the compounds showed bands at
3466±3158, 1741±1697 and 1248±1150 cm21 indicating
1
N±H, CyO and CyS stretchings, respectively. H NMR
spectral data of compounds were also consistent with the
assigned structures. The EI mass spectra of compounds 5a
and 5k showed molecular ions which con®rmed their mole-
cular weights. The major fragmentation pathway involved
the cleavage of the C±S bonds or bonds adjacent to the
carbonyl group, which was in accordance with the literature
[10,13]. The proposed fragmentation route of compounds 5a
and 5k is shown in Scheme 2.
2. Chemistry
3. Experimental
Aromatic aldehyde semicarbazones (1a,b) [11] sus-
pended in glacial acetic acid were stirred with bromine
and anhydrous sodium acetate to give 5-aryl-2-amino-1,3,4-
oxadiazoles (2a,b) [12]. Reaction of these with a-chloro-
a-phenylacetyl chloride or a-bromopropionyl bromide
yielded 5-aryl-2-[(a-chloro-a-phenylacetyl/a-bromopro-
pionyl)amino]-1,3,4-oxadiazoles (3a±d) [6]. Compounds
3a±d were reacted with potassium salts of N,N-disubstituted
dithiocarbamoic acids (4a±e) [7±10] and 5-aryl-2-[(N,N-
disubstituted thiocarbamoylthio)acylamino]-1,3,4-oxadia-
zoles (5a±n) were obtained (Scheme 1, Table 1).
Melting points were measured on a BuÈchi 530 melting
point apparatus (Flawil, Switzerland) in open capillaries and
are uncorrected. The compounds were checked for purity by
TLC on Silicagel HF254. IR Spectra (KBr) were recorded on
1
a Perkin Elmer Model 1600 FT-IR spectrophotometer. H
NMR spectra were obtained in DMSO-d6 on Bruker AC 200
(200 MHz) and Bruker DPX 400 (400 MHz) NMR spectro-
photometers using TMS as the internal standard. EIMS was
recorded on a VG Zab Spec (70 eV) mass spectrometer.
Elemental analyses were performed on a Carlo Erba 1106
elemental analyzer. Starting materials were purchased from
E. Merck (Darmstadt, Germany).
* Corresponding author; e-mail: gulcapan@superonline.com
0014-827X/98/$ - see front matter q 1998 Elsevier Science S.A. All rights reserved.
PII S0014-827X(98)00063-9

542
O. AtesË et al. / Il Farmaco 53 (1998) 541±544
bamoic acid in 30 ml of ethanol were re¯uxed on a water
bath for 1 h. Crystals were ®ltered off and recrystallized
from ethanol. Physical data of compounds 5a±n are reported
in Table 1.
1
IR, H NMR and EI mass spectral data of some novel
compounds chosen as prototypes are as follows.
3.2. 5-Phenyl-2-[(N,N-dimethylthiocarbamoylthio)-
phenylacetylamino]-1,3,4-oxadiazole (5a)
IR [n, cm21, KBr]: 3447 (N±H), 3034 (arom. C±H), 2927
(aliph. C±H), 1704 (CyO), 1580, 1547, 1489 (arom. CyC),
1448 (CO±CH), 1381 (C±N, ter. amine), 1252 (N±H and
C±N), 1150 (CyS), 1021, 986 (oxadiazole C±O±C).
1H NMR [400 MHz, d ppm, DMSO-d6]: 3.40 (s, 3H,
CH3), 3.49 (s, 3H, CH3), 5.91 (s, 1H, CH±S), 7.33±7.97
(m, 10H, Harom.), 12.19 (s, 1H, NH).
Scheme 1.
Aromatic aldehyde semicarbazones [11], 5-aryl-2-amino-
1,3,4-oxadiazoles [12], 5-aryl-2-acylamino-1,3,4-oxadia-
zoles [6] and potassium salts of N,N-disubstituted dithiocar-
bamoic acids [7±10] were prepared as previously described.
3.1. 5-Aryl-2-[(N,N-disubstituted thiocarbamoylthio)-
acylamino]-1,3,4-oxadiazoles (5a±n)
MS: m/z (%): 398 (2), 310 (40), 279 (22), 237 (95), 210
(4), 209 (22), 188 (39), 161 (45), 145 (35), 122 (17), 120
(47), 118 (75), 117 (3), 105 (50), 103 (21), 90 (45), 88 (100),
78 (11), 77 (57), 57 (1), 56 (6).
2-[(a-Chloro-a-phenylacetyl/a-bromopropionyl)amino]-
5-phenyl/p-chlorophenyl-1,3,4-oxadiazole (0.005 mol) and
0.005 mol of potassium salt of N,N-disubstituted dithiocar-
3.3. 5-Phenyl-2-[2-(N,N-dimethylthiocarbamoylthio)-
propionylamino]-1,3,4-oxadiazole (5f)
Table 1
Physical constants of compounds 5a±n
IR [n, cm21, KBr]: 3158 (N±H), 3070 (arom. C±H), 2978
(aliph. C±H), 1697 (CyO), 1614, 1584, 1508, 1488 (arom.
CyC), 1450 (CO±CH), 1379 (C±N, ter. amine), 1248
(CyS), 1213 (N±H and C±N), 1038, 968 (oxadiazole
C±O±C).
1H NMR [400 MHz, d ppm, DMSO-d6]: 1.52 (d, J ˆ
7:29 Hz, 3H, CH±CH3), 3.31 (s, 3H, N±CH3), 3.37 (s, 3H,
N±CH3), 4.68 (q, 1H, CH±S) 7.13±7.87 (m, 5H, Harom.),
12.06 (s, 1H, NH).
3.4. 5-(p-Chlorophenyl)-2-[(N,N-diethylthiocarbamoyl-
thio)phenylacetylamino]-1,3,4-oxadiazole (5h)
IR [n, cm21, KBr]: 3436 (N±H), 3056 (arom. C±H), 2973,
2932 (aliph. CH), 1727 (CyO), 1607, 1576, 1546, 1485
(arom. CyC), 1452 (CO±CH), 1355 (C±N, ter. amine),
1273 (N±H and C±N), 1206 (CyS), 1047, 983 (oxadiazole
C±O±C).
1H NMR [200 MHz, d ppm, DMSO-d6]: 1.17 (t, 3H,
CH3), 1.23 (t, 3H, CH3), 3.74 (q, 2H, CH2), 3.93 (q, 2H,
CH2), 5.91 (s, 1H, CH±S), 7.38±7.51 (m, 5H, Harom.), 7.65
(d, J ˆ 8:40 Hz, 2H, C3,5±H of phenyl bonded to oxadia-
zole), 7.90 (d, J ˆ 8:48 Hz, 2H, C2,6±H of phenyl bonded to
oxadiazole), 12.41 (s, 1H, NH).
3.5. 5-(p-Chlorophenyl)-2-[2-(N,N-dimethylthiocarbamoyl-
thio)propionylamino]-1,3,4-oxadiazole (5k)
IR [n, cm21, KBr]: 3463 (N±H), 3139 (arom. C±H), 2870
(aliph. C±H), 1741 (CyO), 1606, 1576, 1499, 1482 (arom.

O. AtesË et al. / Il Farmaco 53 (1998) 541±544
543
Scheme 2.
CyC), 1450 (CO±CH), 1383 (C±N, ter. amine), 1260 (N±H
and C±N), 1157 (CyS), 1048, 992 (oxadiazole C±O±C).
1H NMR [200 MHz, d ppm, DMSO-d6]: 1.58 (d, J ˆ
7:27 Hz, 3H, CH±CH3), 3.37 (s, 3H, N±CH3), 3.43 (s, 3H,
N±CH3), 4.74 (q, J ˆ 7:21 Hz, 1H, CH±S), 7.66 (d, J ˆ
8:52 Hz, 2H, C3,5±H of phenyl bonded to oxadiazole),
7.92 (d, J ˆ 8:62 Hz, 2H, C2,6±H of phenyl bonded to
oxadiazole), 12.15 (s, 1H, NH).
MS (m/z): 372 (3), 370 (6), 284 (32), 282 (62), 253 (2),
251 (4), 224 (3), 222 (9), 197 (11), 195 (26), 181 (5), 179
(16), 176 (70), 175 (60), 154 (8), 152 (14), 148 (3), 147 (22),
141 (12), 139 (32), 137 (13), 127 (1.5), 126 (1), 125 (5), 124
(2), 120 (34), 114 (1.5), 113 (11), 112 (3), 111 (26), 90 (21),
88 (100), 60 (8.5), 57 (3), 56 (13).
20 ml, and left on a ¯at surface to solidify and the surface of
the medium was dried at 378C. Then, cultures of each
bacteria and yeast strain, after being kept in Mueller-Hinton
broth (DIFCO) at 378C for 18±24 h and diluted with Muel-
ler±Hinton broth to 105 cfu/ml, were pipetted into the Muel-
ler±Hinton agar plate prepared as described above. The
surface of the medium was allowed to dry. The 8000 mg/
ml (in DMSO) compound impregnated discs were applied to
the surface of inoculated plates. The petri plates were placed
in an incubator at 378C. After 18±24 h of incubation, the
petri plates were examined and it was found that compounds
5f, 5l, 5m and 5n were active against S. aureus and S.
epidermidis.
The minimum inhibitory concentrations (MIC) of the
compounds were determined by the microbroth dilution
technique using Mueller±Hinton broth (Difco Laboratories,
Detroit, MI). Serial two-fold dilutions ranged from 2500 to
2.4 mg/l for compounds. The inoculum was prepared in
broth which had been kept overnight at 378C and which
had been diluted with Mueller±Hinton broth to give a ®nal
concentration of 105 cfu/ml in the test tray. The trays were
covered and placed in plastic bags to prevent drying. After
4. Microbiology
Derivatives 5a±n except 5g, 5h and 5k were tested in
vitro for antibacterial activity against S. aureus ATCC
6538, S. epidermidis ATCC 12228, Escherichia coli
ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudo-
monas aeruginosa ATCC 1539, Salmonella typhi, Shigella
¯exneri, Proteus mirabilis and for antifungal activity against
Candida albicans ATCC 10231.
Table 2
MIC values of compounds 5f, 5l, 5m and 5n
Compound
MIC (mg/ml)
4.1. Microbiological experimental
S. aureus ATCC 6538
S. epidermidis ATCC 12228
The disc diffusion method was used for antimicrobial
activity where each disc contained 160 mg of the tested
compound. For this method, Mueller±Hinton agar
(DIFCO) was melted at 1008C and after cooling to 568C,
was poured into petri plates of 9 cm diameter in quantities of
5f
78
1250
1250
1250
78
625
5l
5m
5n
1250
1250

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O. AtesË et al. / Il Farmaco 53 (1998) 541±544
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The antibacterial and antifungal activities were evaluated
by the disc diffusion method against eight representative
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epidermidis and their MIC were determined by dilution
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È
È
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This work was supported by Istanbul University Research
È
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