Synthesis of some dithiocarbamate derivatives and their antimicrobial activity

Article abstract of DOI:10.1080/10426500490463664

Some new, 2-[(N-substituted aminothiocarbonylthio)acetyl]aminothiazole, N-substituted aminothiocarbonylthioacetylaminodiphenylmethane and 9-[(N-substituted aminothiocarbonylthio)acetyl]aminofluorene derivatives were synthesized by reacting 2-(chloroacetyl

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Phosphorus, Sulfur, and Silicon and the Related
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SYNTHESIS OF SOME DITHIOCARBAMATE DERIVATIVES
AND THEIR ANTIMICROBIAL ACTIVITY
Zafer Asim Kaplancıli a , Gülhan Turan-Zitouni a , Gilbert Revial b & Gökalp Işcan a
a Anadolu University, Eskisehir, Turkey
b CNRS, ESPCI, Paris, France
Available online: 16 Aug 2010
To cite this article: Zafer Asim Kaplancıli, Gülhan Turan-Zitouni, Gilbert Revial & Gökalp Işcan (2004): SYNTHESIS OF
SOME DITHIOCARBAMATE DERIVATIVES AND THEIR ANTIMICROBIAL ACTIVITY, Phosphorus, Sulfur, and Silicon and the Related
Elements, 179:7, 1449-1454
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Phosphorus, Sulfur, and Silicon, 179:1449–1454, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490463664
SYNTHESIS OF SOME DITHIOCARBAMATE
DERIVATIVES AND THEIR ANTIMICROBIAL
ACTIVITY
Zafer Asım Kaplancikli,a Gu¨lhan Turan-Zitouni,a
Gilbert Revial,b and Go¨kalp Is¸cana
Anadolu University, Eskisehir, Turkey;a and CNRS, ESPCI,
Paris, Franceb
(Received October 28, 2003; in final form November 25, 2003)
Some new, 2-[(N-substituted aminothiocarbonylthio)acetyl]aminothia-
zole, N-substituted aminothiocarbonylthioacetylaminodiphenylme-
thane and 9-[(N-substituted aminothiocarbonylthio)acetyl]aminofluo-
rene derivatives were synthesized by reacting 2-(chloroacetyl)
aminothiazole, chloroacetylaminodiphenylmethane, and 9-(chlo-
roacetyl)aminofluorene with secondary amine dithiocarbamate
derivatives in acetone respectively. The structure elucidation of the
compounds was performed by IR, 1H-NMR, and FAB+-MS spectral
data. The substances were tested for their antimicrobial activity.
Keywords: Antimicrobial activity; diphenylmethane; dithiocarbamate;
fluorene; thiazole
It is well known that, N-mono and N,N-di substituted dithiocarbamate
derivatives show antibacterial, antiviral and antifungal activities.1–7
The structure-activity relationship study revealed that the antibac-
terial activity on thiocarbonyl aromatic compounds was significantly
affected by the lipophilicity, that is obtained by thiocarbonyl moiety, es-
pecially the calculated log P value and the balance between hydrophilic
substituent and hydrophobic substituent on the aromatic compounds.2
Some thiocarbonyl aromatics that were synthesized inspired by the
above mentioned rationale were found to possess good in vitro antibac-
terial activity against gram-positive bacteria.2
In view of these observations, some aromatic compounds, i.e., 2-
(chloroacetyl)-aminothiazole, chloroacetylaminodiphenylmethane and
Address correspondence to Zafer Asım Kaplancikli, Anadolu University, Faculty of
Pharmacy, 26470 Eskisehir, Turkey. E-mail: zakaplan@anadolu.edu.tr
1449

1450
Z. A. Kaplancikli et al.
9-(chloroacetyl)aminofluorene were reacted with dithiocarbamates and
these compounds were tested for their antibacterial and antifungal
activities.
RESULTS AND DISCUSSION
Chemistry
The present report deals with the synthesis of 2-[(N-substituted
aminothiocarbonylthio)-acetyl]aminothiazole (5a–c), N-substituted
aminothiocarbonylthioacetylaminodiphenyl-methane
(6a–c)
and
9-[(N-substituted aminothiocarbonylthio)acetyl]aminofluorene (7a–d).
The 2-(chloroacetyl)aminothiazole (2), chloroacetylaminodiphenyl-
methane (3) 9-(chloroacetyl)aminofluorene (4) were prepared as start-
ing materials in accordance with the method described in the
literature.1,7
The reaction of chloroacetylamine (2, 3, 4) and appropriate sec-
ondary amine-dithiocarbamatepotassium (1) in acetone, gave the
2-[(N-substituted aminothiocarbonyl-thio)acetyl]aminothiazole (5a–c)
N-substituted aminothiocarbonylthioacetylaminodiphenyl-methane
(6a–c) 9-[(N-substituted aminothiocarbonylthio)acetyl]aminofluorene
(7a–d) (Table I, Scheme 1).
Analytical and spectral data (IR, 1H-NMR, FAB+-MS) confirmed the
structure of the compounds (see also Table I).
In the IR spectra, some significant stretching bands due to C O,
C S, N H were observed at 1640–1680 cm−1, 1225–1255 cm−1, 3270–
3080 cm−1 respectively.
1
In the H-NMR spectra, the signal due to COCH2 methylene pro-
tons, present in all compounds, appeared at 4.15–4.40 ppm, as singlets.
TABLE I Some Characterizations of the Compounds
Comp.
R
m.p. (◦C)
Yield (%)
Molecular formula Mol. weight
5a
5b
5c
6a
6b
6c
7a
7b
7c
7d
Pyrrolidine
Piperidine
Morpholine
Pyrrolidine
Piperidine
Morpholine
Pyrrolidine
Piperidine
Morpholine
Thiomorpholine
194
190
198
110
94
154
204
208
228
238
80
70
65
68
73
85
80
60
55
65
C10H13N3OS3
C11H15N3OS3
287
301
303
370
384
386
368
382
384
400
C
10H13N3O2S3
C20H22N2OS2
C21H24N2OS2
C
20H22N2O2S2
C20H20N2OS2
C21H22N2OS2
C
20H20N2O2S2
C20H20N2OS3

Dithiocarbamates
1451
SCHEME 1
Aliphatic protons of pyrrolidine, piperidine, morpholine and thiomor-
pholine were observed at the 1.50–4.50 ppm region. Aromatic protons
and NH proton were elucidated at expected regions.
Microbiology
All compounds were evaluated for their antimicrobial properties.
The compounds showed moderate inhibitor effects against human
pathogenic microorganisms. Especially E. coli, C. albicans were inhib-
ited by 7c, with a MIC values of 62.5 µg/ml which is equal to that of the
standard antifungal agent. 5c and 7d showed significant antibacterial
effects against S. aureus and S. typhimurium (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; MS: fast atom bombardment mass spectra (FAB+-MS) were
obtained by VG Quattro mass spectrometer.

1452
Z. A. Kaplancikli et al.
TABLE II Antimicrobial Activities of the Compounds
5a 5b 5c 6a 6b 6c 7a 7b
7c
7d
A
B
E.coli
S. aureus
500 250 125
250 250 62.5 125 250 125 250 250 125 500
500 250 500
250 125 250
250 250 250
250 250 125 250 250 62.5 500 31.25
3.9
250 500 125 500 500 250 250 62.5
250 250 250 250 250 250 250 62.5
250 125 250 125 250 125 125 15.6
500 250 250 250 125 250 62.5 31.25
.
.
.
.
.
.
P. aeruginosa
E. aerogenes
P. vulgaris
S. typhimurium 250 250 500
C. albicans 250 250 500
250 250 500 250 125 62.5 125
—
62.5
*MIC (µg/ml), A: Chloramphenicol, B: Ketoconazole.
General Procedure for Synthesis of the Compounds
2 - ( Chloroacetyl)aminothiazole ( 2), chloroacetylaminodiphenyl-
methane (3), 9-(chloroacetyl)aminofluorene (4). The amine (2-thiazolyl-
amine, diphenylmethylamine, and 9-fluorenylamine) (0.01 mmol) and
triethylamine (0.01 mmol) were dissolved in benzene (50 ml) with
constant stirring. Later, the mixture was cooled in an ice bath, and
chloroacetylchloride (0.01 mmol) was added dropwise with stirring.
The reaction mixture thus obtained was further agitated for 1 h at
room temperature. The precipitate was filtrated, the solvent was
evaporated to dryness under reduced pressure and the products were
recrystallized from ethanol.1,7
2-[(N-Substituted aminothiocarbonylthio)acetyl]aminothiazole (5a–
c) N-substituted aminothiocarbonylthioacetylaminodiphenylmethane
(6 a–c), 9-[(N-substituted aminothiocarbonylthio)acetyl]aminofluorene
(7a–d). A mixture of chloroacetylamine (2, 3, 4) (0.01 mmol) and ap-
propriate secondary amine dithiocarbamate potassium (1) (0.01 mmol)
was caused to react in acetone at room temperature for 4 h. The solvent
was evaporated, washed with water, and the residue recrystallized from
ethanol.
IR (KBr, cm−1): These compounds showed characteristic IR bands at
1640–1680 cm−1 (C O), 1225–1255 cm−1 (C S), and 3270–3080 cm−1
(N H).
1
5a: H-NMR (δ ppm) (DMSO-d6): 1,95–2,15 (4H, two p, C3 and C4
protons of pyrrolidine), 3,70 and 3,95 (4H, two t, C2 and C5 protons of
pyrrolidine), 4,35 (2H, s, COCH2), 6,95 (1H, d, C5 proton of thiazole),
7,50 (1H, d, C4 proton of thiazole), 12,45 (1H, br, NH)
MS (FAB+): m/z: 288 [M + 1]
1
5b: H-NMR (δ ppm)(DMSO-d6): 1,60–1,80 (6H, br, C3, C4 and C5
protons of piperidine), 3,90 and 4,30 (4H, two br s, C2 and C6 protons
of piperidine), 4,40 (2H, s, COCH2), 6,95 (1H, d, C5 proton of thiazole),
7,55 (1H, d, C4 proton of thiazole), 12,40 (1H, br, NH)

Dithiocarbamates
1453
MS (FAB+): m/z: 302 [M + 1]
1
6b: H-NMR (δ ppm)(DMSO-d6): 1,50–1,90 (6H, m, C3, C4 and C5
protons of piperidine), 3,85 and 4,25 (4H, two br s, C2 and C6 protons
of piperidine), 4,20 (2H, s, COCH2), 6,15 (1H, d, CH), 7,10–7,35 (10H,
m, aromatic protons), 9,10 (1H, d, NH)
MS (FAB+): m/z: 385 [M + 1]
1
6c: H-NMR (δ ppm)(DMSO-d6): 3,60 (4H, br, C3 and C5 protons of
morpholine), 3,90 (4H, br, C2 and C6 protons of morpholine), 4,15 (2H,
s, COCH2), 6,10 (1H, d, CH), 7,20–7,35 (10H, m, aromatic protons), 9,10
(1H, d, NH)
MS (FAB+): m/z: 387 [M + 1]
1
7a: H-NMR (δ ppm)(DMSO-d6): 1,85–2,15 (4H, two p, C3 and C4
protons of pyrrolidine), 3,65 and 3,75 (4H, two t, C2 and C5 protons of
pyrrolidine), 4,15 (2H, s, COCH2), 6,00 (1H, d, C9 proton of flourene),
7,20–7,45 (6H, m, aromatic protons), 7,85 (2H, d, C1 and C8 protons of
fluorene), 7,85 (1H, d, NH)
MS (FAB+): m/z: 369 [M + 1]
7b: 1H-NMR (δ ppm)(DMSO-d6): 1,55–1,75 (6H, br, C3, C4and C5
protons of piperidine), 3,90 and 4,30 (4H, two br, C2 and C6 protons of
piperidine), 4,25 (2H, s, COCH2), 6,05 (1H, d, C9 proton of flourene),
7,25–7,40 (6H, m, aromatic protons), 7,90 (2H, d, C1 and C8 protons of
fluorene), 8,80 (1H, d, NH)
MS (FAB+): m/z: 383 [M + 1]
1
7c: H-NMR (δ ppm)(DMSO-d6): 3,70 (4H, t, C3 and C5 protons of
morpholine), 4,00 (4H, br, C2 and C6 protons of morpholine), 4,25 (2H, s,
COCH2), 6,10 (1H, d, C9 proton of flourene), 7,30–7,60 (6H, m, aromatic
protons), 7,90 (2H, d, C1 and C8 protons of fluorene), 8,90 (1H, d, NH)
MS (FAB+): m/z: 385 [M + 1]
7d: 1H-NMR (δ ppm)(DMSO-d6): 2,70 (4H, t, C3 and C5 protons
of thiomorpholine), 4,30 and 4,50 (4H, two br, C2 and C6 protons
of thiomorpholine), 4,20 (2H, s, COCH2), 6,10 (1H, d, C9 proton of
flourene), 7,25–7,45 (6H, m, aromatic protons), 7,95 (2H, d, C1 and C8
protons of fluorene), 8,80 (1H, two d, NH)
MS (FAB+): m/z: 401 [M + 1]
Microbiology
Antibacterial activities of compounds were determined using the tube
dilution technique.8,9 MIC values were calculated as µg/ml. The follow-
ing were used as a test microorganisms; Esherichia coli (ATCC 25922),
Staphylococcus aureus (ATCC 6538), Pseudomonas aeruginosa (ATCC
27853), Proteus vulgaris (NRRL B-123), Enterobacter aerogenes (NRRL
3567), Salmonella typhimurium (NRRL B-4420), and Candida albicans
(University of Osmangazi, Faculty of Medicine, Eskis¸ehir).

1454
Z. A. Kaplancikli et al.
Microdilution broth susceptibility assay was used for the antimicro-
bial evaluation of the compounds. Stock solutions of the samples were
prepared in dimethylsulfoxide. Dilution series using sterile 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 bac-
terial and C. albicans suspensions in double-strength Mueller-Hinton
broth were standardised to 108 CFU/ml using McFarland No: 0.5 stan-
dard solution. 100 µl of each microorganism suspension was then added
into the wells. The last well-chain without microorganism was used as
a negative control. Sterile 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 minimal inhibitory con-
centration (MIC). Chloramphenicol was used as standard antibacterial
agent whereas ketoconazole was used as antifungal agent.
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