Synthesis of some 2-[(benzazole-2-yl)Thio]-diphenylmethylacetamide derivatives and their antimicrobial activity

Article abstract of DOI:10.1080/10426500490474851

Some 2-[(benzazole-2-yl)thio]diphenylmethylacetamide derivatives were synthesized by reacting 2-chloroacethylaminodiphenylmethane with benzazole-2-thions. The structure elucidation of the compounds was performed by IR, ¹H NMR, and MS-FAB spectral data. Antimicrobial activity of the compounds was examined. Some of the compounds have shown similar antifungal activities against C. albicans when compared with ketoconazole. It was also observed that some of these compounds have moderate antimicrobial activity when compared with chloramphenicole.

Full text of DOI:10.1080/10426500490474851

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SYNTHESIS OF SOME 2-
[(BENZAZOLE-2-YL)THIO]-
DIPHENYLMETHYLACETAMIDE
DERIVATIVES AND THEIR
ANTIMICROBIAL ACTIVITY
G. Turan-Zitouni a , Z. A. Kaplancikli , Ü. Uçucu a ,
A. Özdemir a , P. Chevallet b & Y. Tunali c
a Anadolu University, Faculty of Pharmacy,
Department of Pharmaceutical Chemistry , Eskisehir,
Turkey
b Montpellier University, Faculty of Pharmacy,
Department of Pharmaceutical Chemistry ,
Montpellier, France
c Anadolu University, Faculty of Pharmacy,
Department of Microbiology , Eskisehir, Turkey
Published online: 16 Aug 2010.
To cite this article: G. Turan-Zitouni , Z. A. Kaplancikli , Ü. Uçucu , A. Özdemir ,
P. Chevallet & Y. Tunali (2004) SYNTHESIS OF SOME 2-[(BENZAZOLE-2-YL)THIO]-
DIPHENYLMETHYLACETAMIDE DERIVATIVES AND THEIR ANTIMICROBIAL ACTIVITY,
Phosphorus, Sulfur, and Silicon and the Related Elements, 179:11, 2183-2188, DOI:
10.1080/10426500490474851
To link to this article: http://dx.doi.org/10.1080/10426500490474851
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Phosphorus, Sulfur, and Silicon, 179:2183–2188, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490474851
SYNTHESIS OF SOME 2-[(BENZAZOLE-2-YL)THIO]-
DIPHENYLMETHYLACETAMIDE DERIVATIVES
AND THEIR ANTIMICROBIAL ACTIVITY
a
a
a
a
¨
¨
G. Turan-Zitouni, Z. A. Kaplancıklı, U. Uc¸ucu, A. Ozdemir,
P. Chevallet,b and Y. Tunalıc
Anadolu University, Faculty of Pharmacy, Department of
Pharmaceutical Chemistry, Eskisehir, Turkey;a Montpellier
University, Faculty of Pharmacy, Department of Pharmaceutical
Chemistry, Montpellier, France;b and Anadolu University,
Faculty of Pharmacy, Department of Microbiology,
Eskisehir, Turkeyc
(Received March 16, 2004; accepted March 18, 2004)
Some 2-[(benzazole-2-yl)thio]diphenylmethylacetamide derivatives
were synthesized by reacting 2-chloroacethylaminodiphenylmethane
with benzazole-2-thions. The structure elucidation of the compounds
was performed by IR, 1H NMR, and MS-FAB spectral data.
Antimicrobial activity of the compounds was examined. Some
of the compounds have shown similar antifungal activities against
C. albicans when compared with ketoconazole. It was also observed that
some of these compounds have moderate antimicrobial activity when
compared with chloramphenicole.
Keywords: Antimicrobial activity; benzimidazole; benzothiazole;
benzoxazole
INTRODUCTION
The number of cases of multidrug-resistant bacterial infections are in-
creasing at a significant rate. Clinicians have become reliant on antibi-
otics for serious infections that are resistant to traditional agents,1 so
there is a need for new classes of antibacterial agents.
The benzothiazole ring is present in various marine or terrestrial
natural compounds that have useful biological activities.2–5 Benzothia-
zole and its bioisosteres, benzoxazole and benzimidazole, were studied
Address correspondence to G. Turan-Zitouni, Anadolu University, Faculty of Phar-
macy, 26470 Eskisehir, Turkey. E-mail: gturan@anadolu.edu.tr
2183

2184
G. Turan-Zitouni et al.
for their antitumor, antiviral, and antimicrobial activities.6–10 In the
last few years, it was reported that the 2- and 5-substituted benzoth-
iazole, benzoxazole, and benzimidazole derivatives have antimicrobial
activities against some Gram-positive and Gram-negative bacteria and
yeast, and these compounds provided a wide variety of in vitro an-
timicrobial effects, especially against the enterobacter Pseudomonas
aeruginosa and the yeast Candida albicans.11–17
In view of these observations, we synthesized new 2-[(benzazole-2-
yl)thio]-diphenylmethylacetamide derivatives and tested them for an-
tibacterial and antifungal activities.
RESULTS AND DISCUSSION
Chemistry
In the present work, 2-(chloroacetylamino)diphenylmethane (1) was
prepared by reacting diphenylmethylamine with chloroacetyl chloride
in accordance with the method described in the literature.18–20
2-[(Benzazole-2-yl)thio]diphenylmethylacetamide derivatives (3a–
h) were synthesized by reacting 1 and benzazol-2-thiol derivatives (2)
(Scheme 1 and Table I).
1
Analytical and spectral data (IR, H NMR, MS (FAB+)) confirmed
the structures of 3a–h.
The structures of the obtained compounds were elucidated by spec-
tral data. In the IR spectra some significant stretching bands due N H
and C O were at 3270–3080 and 1670–1640 cm−1, respectively.
In the 1H NMR spectra, the signal due to COCH2 methylene protons,
present in all compounds, appeared at 4.2–4.3 ppm as singlets. The
signals due to CH proton appeared at 6.1 ppm as doublets. The aromatic
protons were observed at 6.8–7.6 ppm as multiplets. The NH proton was
observed at 9.3–9.4 ppm as a doublet.
TABLE I Some Characterizations of the Compounds
Compound
R
X
m.p.(◦C)
Yield (%)
Molecular formula
M.W.
3a
3b
3c
3d
3e
3f
H
Cl
CH3
NO2
H
Cl
CH3
H
NH
NH
NH
NH
O
O
O
S
207
227
202
231
172
130
156
201
72
75
78
72
69
71
70
70
C22H19N3OS
373
407.5
387
418
374
408.5
388
390
C
22H18ClN3OS
C23H21N3OS
C22H18N4O3S
C22H18N2O2S
C
22H17ClN2O2S
C23H20N2O2S
22H18N2OS2
3g
3h
C

Benzothiazole
2185
SCHEME 1
Microbiology
All compounds were evaluated for their antimicrobial properties. Min-
imal inhibitory concentrations (MICs) were recorded as the minimum
concentration of compound, which inhibits the growth of tested microor-
ganisms. Compounds 3b and 3e showed similar antifungal activities
against C. albicans, when compared with ketoconazole. It was also ob-
served that all of the compounds have changing antimicrobial activity

2186
G. Turan-Zitouni et al.
TABLE II Antimicrobial Activities of the Compounds
Microorganism
3b
3c
3e
3f
3g
A
B
E. coli
S. aureus
>250
>250
125
>250
500
62.5
250
125
125
125
>250
>250
125
125
>250
>250
>250
125
>250
125
>250
>250
125
31.25
3.9
—
—
—
—
—
62.5
>250
125
125
31.25
62.5
P. aeruginosa
E. aerogenes
P. vulgaris
S. typhimurium
C. albicans
62.5
62.5
15.6
31.25
—
250
62.5
250
>250
62.5
125
—
62.5
MIC (as µg /ml), Control compounds; A, Chloramphenicole; B, Ketoconazole.
ranges against all tested bacteria when compared with chlorampheni-
cole (Table II).
EXPERIMENTAL
Chemistry
Melting points were determined by using a Gallenkamp apparatus.
Spectroscopic data were recorded by the following instruments: IR,
Shimadzu IR-435 spectrophotometer; 1H NMR, Bruker 250 MHz spek-
trometer; and MS, fast atom bombardment mass spectra (FAB+-MS)
were obtained by VG Quattro mass spectrometer.
General Procedure for Synthesis of the Compounds
2-Chloroacetylaminodiphenylmethane (1)
Chloroacetyl chloride (0.02 mol) and triethylamine (0.03 mol) were
dissolved in anhydrous benzene (30 ml) with constant stirring. The mix-
ture was cooled in an ice bath, and chloroacetyl chloride (0.02 mol) was
added dropwise with stirring. The reaction mixture thus obtained was
further agitated for 1 h at room temperature. The precipitate was fil-
trated, the solvent was evaporated to dryness under reduced pressure,
and the products were recrystallized from ethanol.
2-[(Benzazole-2-yl)thio]diphenylmethylacetamide
Derivatives (3a–h)
A mixture of 2-chloroacetylaminodiphenylmethane (1) (0.01 mol),
benzazol-2-thiol (2) (0.01 mol), and K2CO3 (0.01 mol) were treated in
acetone (50 ml) at room temperature for 8 h. The solvent was evaporated
until dryness. The residue was washed with water and recrystallized
from ethanol.

Benzothiazole
2187
3a–h: IR (KBr) νmax(cm−1): 3220 (NH), 1645 (C O), 1570 (C N), 1530
(C C), 1210 (C O C).
3b: 1H NMR (250 MHz) (DMSO-d6) δ (ppm): 4.2 (2H, s, COCH2), 6.1 (1H,
d, CH ), 7.1–7.5 (13H, m, aromatic protons), 9.4 (1H, d, NHCO).
MS (FAB+): m/z: 408 (M + 1).
1
3c: H NMR (250 MHz) (DMSO-d6) δ (ppm): 2.4 (3H, s, CH3), 4.1 (2H,
s, COCH2), 6.1 (1H, d, CH ), 6.9–7.4 (13H, m, aromatic protons),
9.4 (1H, d, NHCO). MS (FAB+): m/z: 388 (M + 1).
3e: 1H NMR (250 MHz) (DMSO-d6) δ (ppm): 4.3 (2H, s, COCH2), 6.1 (1H,
d, CH ), 7.2–7.6 (14H, m, aromatic protons), 9.3 (1H, d, NHCO).
MS (FAB+): m/z: 375 (M + 1).
3f: 1H NMR (250 MHz) (DMSO-d6) δ (ppm): 4.3 (2H, s, COCH2), 6.2 (1H,
d, CH ), 7.1–7.5 (13H, m, aromatic protons), 9.4 (1H, d, NHCO).
MS (FAB+): m/z: 409 (M + 1).
3g: 1H NMR (250 MHz) (DMSO-d6) δ (ppm): 2.4 (3H, s, CH3), 4.3 (2H,
s, COCH2), 6.2 (1H, d, CH ), 7.1–7.4 (13H, m, aromatic protons),
9.3 (1H, d, NHCO). MS (FAB+): m/z: 389 (M + 1).
Microbiology
Antimicrobial activities of the compounds were determined using the
tube dilution technique.21 MIC values were calculated as µg/ml. Stan-
dard bacteria strain used were Esherichia coli (ATCC 25922), Staphy-
lococcus aureus (ATCC 6538), Pseudomonas aeruginosa (ATCC 27853),
Proteus vulgaris (NRRL B-123), Enterobacter aerogenes (NRRL 3567),
Salmonella typhimurium (NRRL B-4420), and Candida albicans (Uni-
versity of Osmangazi, Faculty of Medicine, Eskisehir).
Microdilution broth susceptibility assay was used for the antimi-
crobial evaluation of the compounds. Stock solutions of the samples
were prepared in dimethylsulfoxide (DMSO). Dilution series using ster-
ile distilled water were prepared from 4 mg/ml to 0.007 mg/ml in
micro-test tubes that were transferred to 96-well microtiter plates.
Overnight-grown bacterial and C. albicans suspensions in double-
strength Mueller-Hinton broth were standardized to 108 CFU/ml us-
ing McFarland No: 0.5 standard solution. One hundred microliters of
each microorganism suspension was then added into the wells. The last
well-chain without microorganism was used as a negative control. Ster-
ile distilled water and the medium served as a positive growth control.
After incubation at 37◦C for 18–24 h, the first well without turbidity
was determined as the MIC. Chloramphenicol was used as standard an-
tibacterial agent, whereas ketoconazole was used as antifungal agent.

2188
G. Turan-Zitouni et al.
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