Synthesis and antimicrobial activity evaluation of new dithiocarbamate derivatives bearing thiazole/benzothiazole rings

Article abstract of DOI:10.1080/10426507.2016.1150277

The synthesis of 2-(substituted phenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A1-A24) derivatives and 2-(4-substituted thiazol-2-ylamino)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (B1-B14) derivatives was undertaken starting from the potassium salt of 4-(2-pyrimidinyl)piperazine dithiocarbamate. The structures of the obtained compounds were elucidated by¹H NMR,¹³C NMR, MS spectral data, and elemental analysis. The antimicrobial activity of the thirty eight newly synthesized compounds were tested against 12 microorganism strains using the microdilution technique. Compounds 2-(4-ethoxycarbonylthiazol-2-ylamino)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (B12), 2-(3-fluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A18) and 2-(3,4-difluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A21) were determined to possess high antimicrobial activity.

Full text of DOI:10.1080/10426507.2016.1150277

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and Antimicrobial Activity Evaluation
of New Dithiocarbamate Derivatives Bearing
Thiazole/Benzothiazole Rings
Leyla Yurttaş, Yusuf Özkay, Murat Duran, Gülhan Turan-Zitouni, Ahmet
Özdemir, Zerrin Cantürk, Kaan Küçükoğlu & Zafer Asım Kaplancıklı
To cite this article: Leyla Yurttaş, Yusuf Özkay, Murat Duran, Gülhan Turan-Zitouni, Ahmet
Özdemir, Zerrin Cantürk, Kaan Küçükoğlu & Zafer Asım Kaplancıklı (2016): Synthesis and
Antimicrobial Activity Evaluation of New Dithiocarbamate Derivatives Bearing Thiazole/
Benzothiazole Rings, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2016.1150277
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1150277
Accepted author version posted online: 22
Feb 2016.
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Date: 01 March 2016, At: 09:59

ACCEPTED MANUSCRIPT
SYNTHESIS AND ANTIMICROBIAL ACTIVITY EVALUATION OF NEW
DITHIOCARBAMATE DERIVATIVES BEARING THIAZOLE/BENZOTHIAZOLE RINGS
1
,*
1,2
3
1
1
Leyla Yurttaş , Yusuf Özkay , Murat Duran , Gülhan Turan-Zitouni , Ahmet Özdemir , Zerrin
4
5
1
Cantürk , Kaan Küçükoğlu , Zafer Asım Kaplancıklı
1
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu University, 26470,
Eskisehir, Turkey
2
Faculty of Pharmacy, Doping and Narcotic Compounds Analyses Laboratory, Anadolu
University, 26470, Eskisehir, Turkey
3
Faculty of Arts & Sciences, Department of Chemistry, Eskisehir Osmangazi University, 26480,
Eskisehir, Turkey
4
Faculty of Pharmacy, Department of Microbiology, Anadolu University, 26470, Eskisehir,
Turkey
5
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ataturk University, 25240,
Erzurum, Turkey
Email: lyurttas@anadolu.edu.tr
*
Corresponding author. Tel: +90-222-3350580/3776; Fax: +90-222-3350750 E-mail address:
lyurttas@anadolu.edu.tr
Abstract
The synthesis of 2-(substituted phenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-
carbodithiodate (A1-A24) derivatives and 2-(4-substituted thiazol-2-ylamino)-2-oxoethyl 4-
(pyrimidin-2-yl)piperazin-1-carbodithiodate (B1-B14) derivatives was undertaken starting from
the potassium salt of 4-(2-pyrimidinyl)piperazine dithiocarbamate. The structures of the obtained
1
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1
13
compounds were elucidated by H NMR, C NMR, MS spectral data and elemental analysis.
The antimicrobial activity of the thirty eight newly synthesized compounds were tested against
twelve microorganism strains using the microdilution technique. Compounds 2-(4-
ethoxycarbonylthiazol-2-ylamino)-2-oxoethyl
4-(pyrimidin-2-yl)piperazin-1-carbodithiodate
(B12), 2-(3-fluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A18) and
2
-(3,4-difluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A21) were
determined to possess high antimicrobial activity.
Keywords
dithiocarbamate, thiazole, benzothiazole, antimicrobial activity
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INTRODUCTION
In spite of rapid progress in the field of medicinal chemistry, the treatment of infectious
diseases still remains a serious health problem of concern to the scientific community, because of
an extensive range of factors leading to the emergence of these diseases and also the increased
1
-5
number of pathogenic microorganisms with resistance to current drugs.
Therefore, the
management of infectious diseases has become problematic and resulted in a clear need for novel
6
antimicrobial agents. In order to solve this severe medical problem, medicinal chemists have
7
carried our detailed investigations of new compounds.
Thiazole ring bearing compounds constitute an important class of heterocycles possessing
a wide variety of pharmacological activities and have a notable pharmaceutical value, because of
their potential chemo-therapeutic properties. The thiazole ring system is also an essential part of
8
,9
some of the penicillins, which have revolutionized the treatment of infectious diseases. The
importance of the antimicrobial activity of thiazoles is related to the inclusion of the -S-C = N
group in its molecular frame as toxophoric unit. Moreover, thiazoles have enhanced lipid
solubility with hydrophilicity and they are easily metabolized by routine biochemical reactions
1
0
and are non-carcinogenic in nature. In addition, benzothiazole has been reported in several
11-15
studies
because of its microbiological importance.
Dithiocarbamates generate another class of sulfur-containing compounds that have been
1
6-18
recognized as herbicides and fungicides.
After the report of the antifungal effect of 4-
1
9,20
dimethyl dithiocarbamate salt against several pathogenic fungi in human therapy,
the
dithiocarbamate moiety was combined with different heterocycles to examine their antifungal
activitities. These compounds became a promising group for new antifungal agent investigation.
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2
1
Tolciclate and brassinin are the well-known instances of dithiocarbamate fungicides. In
addition, rhodanine and its derivatives are the other dithiocarbamate-including molecules that
inhibit fungal protein mannosyl transferase 1 (PMT1), which is a key enzyme in the biosynthesis
2
2,23
of the fungal cell wall of Candida species.
In light of these observations, we synthesized 14 novel dithiocarbamate compounds including a
benzothiazole or thiazole ring systems. In order to compare impact of these rings on
antimicrobial activity, additional 24 compounds that do not include benzothiazole or thiazole
rings were synthesized (Scheme 1).
RESULTS AND DISCUSSION
Chemistry
In the synthetic procedure of the 2-(substituted phenyl)/2-((benzo)thiazol-2-ylamino)-2-
oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithioate derivatives, initially acetophenone
derivatives were brominated and 2-aminothiazole/benzothiazole derivatives were acetylated with
2
4
chloroacetyl chloride in conventional ways. These halogenated compounds were reacted with
4
-(2-pyrimidinyl)piperazine dithiocarbamate potassium salt in acetone in the presence of
potassium carbonate. The final synthesized compounds can be evaluated in two different groups
although they have similar molecular frameworks. The structures of 2-(substituted phenyl) 4-
(pyrimidin-2-yl)piperazin-1-carbodithioate (A1-A24) and 2-[(benzo)thiazol-2-ylamino]-2-
oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithioate derivatives (B1-B14) were elucidated by
1
13
1
using spectroscopic methods H NMR, C NMR, MASS and elemental analysis results. The H
NMR spectra of two group of compounds were assigned similarly. When the spectra of these two
groups were evaluated commonly, piperazine protons were seen between 3.85-4.30 ppm as three
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broad singlet peaks. It is known that in cyclic compounds conformational mobility is greatly
restricted, so that less rotational averaging of various chemical shift anisotropic effects occurs.
Thus, the chemical shift values of the axial and equatorial hydrogens of the piperazine ring were
2
5
seen at different regions as different 2H, 2H and 4H peaks in agreement with the literature. -
CH -protons bonded to the sulfur atom were found between 4.39-5.03 ppm and aromatic protons
2
were observed in the range of 6.67-8.41 ppm. The peaks belonging to amine proton were
observed as singlets and in the range of 10.37-13.43 ppm in the B coded compounds spectra.
1
3
According to the C NMR data of the compounds, peaks belonging to piperazine carbons, other
aliphatic carbons (ethyl, methyl) and aromatic protons were detected at estimated areas. Peaks
between 196.9-191.8, 195.5-165.3 and 43.3-42.4 ppm were assigned to carbon atoms of C = S, C
=
O and C-S groups, respectively. Also, the carbon atoms of piperazine ring were observed in the
usual aliphatic region at about 52.5-43.1 ppm. Also, the mass spectral data of the compounds
demonstrated that the data were compatible with of the molecular weight of the compounds and
the calculated values of elemental analysis were determined in the range of  0.4%.
Antimicrobial activity
Thirty-eight newly synthesized compounds were screened for their antimicrobial activity
against eight bacteria and four Candida species. Ketoconazole and chloramphenicol were used as
standard drugs and the concentration of the compounds to inhibite microorganisms was defined
as minimum inhibitory concentration which was determined by using microbroth dilution
2
6
method and the results (MIC values) were shown in Table S 1 (Supplemental Materials). Many
of the compounds showed high activity against to the identified microorganisms compared with
standard drugs. L. monocytogenes (ATCC 1911); K. pneumoniae (ATCC 700603), P. aeruginosa
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(ATCC 27853); E. coli (ATCC 35218); E. coli (ATCC 25922); C. albicans (ATCC 90028); C.
glabrata (ATCC 90030) were determined as the most susceptible species.
CONCLUSION
In summary, new thirty-eight compounds were synthesized and screened for their
antibacterial and antifungal activity. Among 2-(substituted phenyl) 4-(pyrimidin-2-yl)piperazin-
1
-carbodithioate (A1-A24) derivatives and 2-[(benzo)thiazol-2-ylamino]-2-oxoethyl 4-
(pyrimidin-2-yl)piperazin-1-carbodithioate derivatives (B1-B14), compound A21 bearing 3,4-
difluorophenyl moiety and B12 bearing 4-ethoxycarbonylthiazole were found as the most active
compounds.
EXPERIMENTAL
Material and Methods
All chemicals were purchased from Sigma-Aldrich Chemical Co (Sigma-Aldrich Corp.,
St. Louis, MO, USA) and Merck (Darmstadt, Germany). All melting points (m.p.) were
determined by Electrothermal 9300 digital melting point apparatus (Electrothermal, Essex, UK)
and were uncorrected. All the reactions were monitored by thin-layer chromatography (TLC)
using Silica Gel 60 F254 TLC plates (Merck KGaA, Darmstadt, Germany). Spectroscopic data
1
13
were recorded with the following instruments: H NMR and C NMR, Bruker DPX 400 MHz
spectrometer (Bruker Bioscience, Billerica, MA, USA); M+1 peaks were determined by Agilent
MS Trap SL mass spectrometer (Agilent technologies, Palo Alto, CA, USA) and Bruker
Daltonics Microtof II (Bruker Bioscience, Billerica, MA, USA). Elemental analyses were
performed on a Thermo Finnigan EA1112 series Flash elemental analyzer (Thermo Finnigan,
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1
13
Milano, Italy). The Supplemental Materials contains sample H and C NMR spectra for the
novel compounds (Figures S 1 -- S 42)
General procedure to obtain α-bromoacetophenone derivatives
Acetophenone derivative (10 mmol) was solved in acetic acid (50 mL) and hydrobromic
acid (0.5 mL) mixture. Bromine (10 mmol, 0.52 mL) was added dropwise to this mixture at 0-5

C temperature and the mixture was stirred for 6-7 h. After this period, the mixture was poured
into ice-water, collapsed portion was filtrated and after dryness it was crystallized from ethanol.
2
-Chloro-N-(thiazol-2-yl/benzothiazol-2-yl)acetamide derivatives
Thiazole/benzothiazole derivative (10 mmol) was solved in THF (200 mL). After
triethylamine (12 mmol, 1.67 mL) was added to the solution, chloroacetyl chloride (12 mmol,
.96 mL) was added dropwise at 0-5 C and the mixture was stirred for 3-5 h. After the reaction
0
completed, the mixture was poured into ice-water and the collapsed raw product was filtered and
dried.
4
-(2-Pyrimidinyl)piperazine Dithiocarbamate Potassium Salt
-(2-Pyrimidinyl)piperazine (100 mmol) was dissolved in ethanol (100 mL) in a reaction
1
flask which was placed on an ice-water bath. Potassium hydroxide solution (10 N, 20 mL) was
added to this flask and the mixture was homogenized. Carbon disulfide (500 mL) was added
dropwise and the mixture was stirred for 1 h. The precipitated dithiocarbamate salt was filtered
and washed with excess ethanol.
General procedure to obtain 2-(substituted phenyl)/2-[(benzo/thiazol-2-yl)amino]-2-
oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithioate derivatives (A1-A24, B1-B14)
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A mixture of 4-(2-pyrimidinyl)piperazine dithiocarbamate potassium salt (10 mmol), a α-
bromoacetophenone derivative or a 2-chloro-N-(thiazol/benzothiazol-2-yl)acetamide derivate (10
mmol) was stirred in acetone at room temperature with the presence of potassium carbonate (10
mmol). After TLC, the reaction mixture was poured into ice-water and the precipitated portion
was filtered and crystallised from ethanol to gain the final products.
2
1
4
7
-Phenyl-2-oxo-ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A1) Yield 94%. m.p. 122-
1
24 C. H NMR (400 MHz, DMSO-d ppm) δ 3.85 (brs, 4H, pip CH ), 4.08 (brs, 2H, pip CH ),
6
,
2
2
.26 (brs, 2H, pip CH ), 4.80 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 7.40 (m, 3H, Ar-H),
2
2
1
3
.85 (d, 2H, J:8.0 Hz, Ar-H), 8.39 (d, 2H, J:4.4 Hz, Ar-H). C NMR (100 MHz, DMSO-d ppm)
6
,
δ 43.0 (S-CH ), 44.1 (piperazine C C ), 50.0 (piperazine C C ), 111.3, 127.3, 127.5, 127.7,
2
3,
5
2,
6
1
28.0, 132.4, 135.6, 156.7, 158.7, 161.5 (pyrimidine C ), 192.9 (C = O), 195.4 (C = S).
2
C H N OS calculated: (%) C 56.96, H 5.06, N 15.63; found: (%)C 56.69, H 5.30, N 15.73.
17
18
4
2
+
MS [M+1] : m/z 359.
2
-Oxo-2-o-tolylethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A2) Yield 84%. m.p. 141-
1
1
43 C. H NMR (400 MHz, DMSO-d ppm) δ 2.43 (s, 3H, CH ), 3.86 (brs, 4H, pip CH ), 4.09
6
,
3
2
(
brs, 2H, pip CH ), 4.27 (brs, 2H, pip CH ), 4.82 (s, 2H, CH ), 6.67 (t, 1H, J:4.8 Hz, Ar-H), 7.28-
2 2 2
1
3
7
.45 (m, 3H, Ar-H), 7.91 (d, 1H, J:7.6 Hz, Ar-H), 8.38 (d, 2H, J:4.4 Hz, Ar-H). C NMR (100
MHz, DMSO-d ppm) δ 21.1 (CH ), 43.2 (S-CH ), 46.5 (piperazine C C ), 50.9 (piperazine C
2,
6
,
3
2
3,
5
C ), 111.3, 126.5, 129.2, 132.1, 132.3, 137.9, 138.0, 158.7, 158.9, 161.5 (pyrimidine C ), 195.5
6
2
(
C = O), 196.9 (C = S). C H N OS calculated: (%) C 58.04, H 5.41, N 15.04; found: (%) C
18 20 4 2
+
5
7.76, H 5.34, N 14.89. MS [M+1] : m/z 373.
8
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2
-Oxo-2-m-tolylethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A3) Yield 75%. m.p. 97-99
1

C. H NMR (400 MHz, DMSO-d ppm) δ 2.40 (s, 3H, CH ), 3.89 (brs, 4H, pip CH ), 4.14 (brs
6
,
3
2
2
H, pip CH ), 4.30 (brs, 2H, pip CH ), 4.99 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 7.43-7.50
2 2 2
(m, 2H, Ar-H), 7.80 (s, 1H, Ar-H), 7.86 (d, 1H, J:7.0 Hz, Ar-H), 8.41 (d, 2H, J:4.8 Hz, Ar-H).
1
3
C NMR (100 MHz, DMSO-d ppm) δ 21.1 (CH ), 43.1 (S-CH ), 44.0 (piperazine C C ), 50.1
6
,
3
2
3,
5
(
piperazine C C ), 111.3, 126.4, 128.5, 129.3, 134.2, 137.6, 139.4, 158.7, 158.8, 161.5
2, 6
(
pyrimidine C ), 192.1 (C = O), 195.9 (C = S). C H N OS calculated: (%) C 58.04, H 5.41, N
2 18 20 4 2
+
1
2
1
5.04; found: (%) C 57.69, H 5.08, N 14.93. MS [M+1] : m/z 373.
-Oxo-2-p-tolylethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A4) Yield 77%. m.p. 123-
1
25 C. H NMR (400 MHz, DMSO-d ppm) δ 2.36 (s, 3H, CH ), 3.85 (brs, 4H, pip CH ), 4.09
6
,
3
2
(
(
(
(
brs, 2H, pip CH ), 4.26 (brs, 2H, pip CH ), 4.93 (s, 2H, CH ), 6.61 (t, 1H, J:4.8 Hz, Ar-H), 7.33
2 2 2
1
3
d, 2H, J:8.0 Hz, Ar-H), 7.92 (d, 2H, J:8.0 Hz, Ar-H), 8.37 (d, 2H, J:4.8 Hz, Ar-H). C NMR
100 MHz, DMSO-d ppm) δ 21.2 (CH ), 43.3 (S-CH ), 44.0 (piperazine C C ), 50.2
6
,
3
2
3,
5
piperazine C C ), 111.3, 127.8, 128.2, 133.2, 143.3, 158.6, 161.5 (pyrimidine C ), 191.1 (C =
2
,
6
2
O), 196.3 (C = S). C H N OS calculated: (%) C 58.04, H 5.41, N 15.04; found: (%) C 57.98,
1
8
20
4
2
+
H 5.27, N 14.92. MS [M+1] : m/z 373.
2
-Oxo-2-(2,4-dimethylphenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A5) Yield
1
7
8%. m.p. 117-119 C. H NMR (400 MHz, DMSO-d ppm) δ 2.36 (s, 3H, CH ), 2.42 (s, 3H,
6
,
3
CH ), 3.91 (brs, 4H, pip CH ), 4.14 (brs, 2H, pip CH ), 4.30 (brs, 2H, pip CH ), 4.85 (s, 2H,
3
2
2
2
CH ), 6.68 (t, 1H, J:4.4 Hz, Ar-H), 7.10 (s, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 7.65 (d, 1H, J:8.1 Hz,
2
1
3
Ar-H), 8.38 (d, 2H, J:4.4 Hz, Ar-H). C NMR (100 MHz, DMSO-d ppm) δ 21.9 (CH ), 22.2
6
,
3
(
CH ), 43.0 (S-CH ), 44.1 (piperazine C C ), 50.1 (piperazine C C ), 111.3, 128.7, 129.6,
3 2 3, 5 2, 6
9
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1
31.2, 133.6, 138.2, 139.5, 158.7, 161.2 (pyrimidine C ), 191.9 (C = O), 197.0 (C = S).
2
C H N OS calculated: (%) C 59.04, H 5.74, N 14.49; found: (%) C 58.98, H 5.66, N 14.40.
19
22
4
2
+
MS [M+1] : m/z 387.
2
-Oxo-2-(2-methoxyphenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A6) Yield 87%.
1
m.p. 110-112 C. H NMR (400 MHz, DMSO-d ppm) δ 3.82 (s, 3H, OCH ), 3.87 (brs, 4H, pip
6
,
3
CH ), 4.09 (brs, 2H, pip CH ), 4.26 (brs, 2H, pip CH ), 4.93 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz,
2
2
2
2
1
3
Ar-H), 7.15-7.32 (m, 3H, Ar-H), 7.80 (d, 1H, J:7.6 Hz, Ar-H), 8.37 (d, 2H, J:4.8 Hz, Ar-H). C
NMR (100 MHz, DMSO-d ppm) δ 43.1 (S-CH ), 44.1 (piperazine C C ), 50.5 (piperazine C
6
,
2
3,
5
2,
C ), 56.5 (OCH ), 111.3, 112.5, 121.3, 121.5, 129.5, 135.2, 158.2, 159.2, 164.3 (pyrimidine C ),
6
3
2
1
92.6 (C = O), 195.2 (C = S). C H N O S calculated: (%) C 55.65, H 5.19, N 14.42; found:
18 20 4 2 2
+
(
%) C 55.36, H 5.20, N 14.21. MS [M+1] : m/z 389.
2
-Oxo-2-(3-methoxyphenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A7) Yield 92%.
1
m.p. 122-124 C. H NMR (400 MHz, DMSO-d ppm) δ 3.86 (brs, 4H, pip CH ), 3.91 (s, 3H,
6
,
2
OCH ), 4.10 (brs, 2H, pip CH ), 4.28 (brs, 2H, pip CH ), 4.95 (s, 2H, CH ), 6.69 (t, 1H, J:4.4 Hz
3
2
2
2
Ar-H), 7.25 (d, 1H, J:8.0 Hz, Ar-H), 7.47-7.53 (m, 2H, Ar-H), 7.74 (t, 1H, J:8.1 Hz, Ar-H), 8.39
1
3
(
d, 2H, J:5.2 Hz, Ar-H). C NMR (100 MHz, DMSO-d ppm) δ 43.1 (S-CH ), 44.1 (piperazine
6, 2
C C ), 50.3 (piperazine C C ), 56.1 (OCH ), 111.2, 118.8, 121.2, 122.3, 129.9, 138.0, 159.8,
3
,
5
2,
6
3
1
5
2
61.4, 164.3 (pyrimidine C ), 191.6 (C = O), 195.6 (C = S). C H N O S calculated: (%) C
2 18 20 4 2 2
+
5.65, H 5.19, N 14.42; found: (%) C 55.35, H 5.01, N 14.27. MS [M+1] : m/z 389.
-Oxo-2-(4-methoxyphenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A8) Yield 86%.
1
m.p. 172-174 C. H NMR (400 MHz, DMSO-d ppm) δ 3.84 (s, 3H, OCH ), 3.86 (brs, 4H, pip
6
,
3
CH ), 4.01 (brs, 2H, pip CH ), 4.27 (brs, 2H, pip CH ), 4.94 (s, 2H, CH ), 6.68 (t, 1H, J:4.4 Hz,
2
2
2
2
10
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Ar-H), 7.09 (d, 2H, J:8.8 Hz, Ar-H), 8.04 (d, 2H, J:9.2 Hz, Ar-H), 8.39 (d, 2H, J:4.4 Hz, Ar-H).
1
3
C NMR (100 MHz, DMSO-d ppm) δ 42.9 (S-CH ), 43.1 (piperazine C C ), 51.1 (piperazine
6
,
2
3,
5
C C ), 56.3 (OCH ), 111.3, 114.9, 127.9, 131.6, 158.7, 161.4, 164.3 (pyrimidine C ), 188.8 (C =
2
,
6
3
2
O), 191.8 (C = S). C H N O S calculated: (%) C 55.65, H 5.19, N 14.42; found: (%) C 55.35,
1
8
20
4
2 2
+
H 5.01, N 14.27. MS [M+1] : m/z 389.
2
-Oxo-2-(2,5-dimethoxyphenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A9) Yield
1
8
1%. m.p. 150-152 C. H NMR (400 MHz, DMSO-d ppm) δ 3.84 (s, 3H, OCH ), 3.91 (m, 7H,
6
,
3
OCH , pip CH ) 4.13 (brs, 2H, pip CH ), 4.29 (brs, 2H, pip CH ), 4.92 (s, 2H, CH ), 6.68 (t, 1H,
3
2
2
2
2
1
3
J:4.4 Hz, Ar-H), 7.01-7.08 (m, 2H, Ar-H), 7.42 (s, 1H, Ar-H), 8.40 (d, 2H, J:5.2 Hz, Ar-H). C
NMR (100 MHz, DMSO-d ppm) δ 43.1 (S-CH ), 44.2 (piperazine C C ), 51.2 (piperazine C
6
,
2
3,
5
2,
C ), 56.1 (OCH ), 56.2 (OCH ), 111.3, 113.3, 114.3, 120.5, 122.1, 155.2, 158.7, 161.6, 164.5
6
3
3
(
pyrimidine C ), 193.1 (C = O), 195.9 (C = S). C H N O S calculated: (%) C 54.52, H 5.30, N
2 19 22 4 3 2
+
1
2
8
3.39; found: (%) C 54.51, H 5.25, N 13.27. MS [M+1] : m/z 419.
-Oxo-2-(3,4-dimethoxyphenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A10) Yield
1
0%. m.p. 116-118 C. H NMR (400 MHz, DMSO-d ppm) δ 3.83 (s, 3H, OCH ), 3.87 (m, 7H,
6
,
3
OCH , pip CH ), 4.14 (brs, 2H, pip CH ), 4.31 (brs, 2H, pip CH ), 4.98 (s, 2H, CH ), 6.70 (t, 1H,
3
2
2
2
2
J:4.8 Hz, Ar-H), 7.11 (d, 1H, J:8.4 Hz, Ar-H), 7.50 (s, 1H, Ar-H), 7.78 (q, 1H, J:8.4 Hz, Ar-H),
1
3
8
.41 (d, 2H, J:5.2 Hz, Ar-H). C NMR (100 MHz, DMSO-d ppm) δ 43.2 (S-CH ), 44.1
6, 2
(
piperazine C C ), 51.0 (piperazine C C ), 56.3 (OCH ), 56.5 (OCH ), 111.1, 123.9, 129.2,
3, 5 2, 6 3 3
1
29.6, 149.3, 154.0, 161.7, 164.5 (pyrimidine C ), 191.8 (C = O), 195.5 (C = S). C H N O S
2 19 22 4 3 2
+
calculated: (%) C 54.52, H 5.30, N 13.39; found: (%) C 54.31, H 5.03, N 13.07. MS [M+1] : m/z
4
19.
11
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2
-Oxo-2-(2-chlorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A11) Yield 81%.
1
m.p. 80-82 C. H NMR (400 MHz, DMSO-d ppm) δ 3.86 (br, s, 4H), 4.08 (brs, 2H, pip CH ),
6,
2
4
.27 (brs, 2H, pip CH ), 4.83 (s, 2H, CH ), 6.68 (t, 1H, J:4.4 Hz, Ar-H), 7.45-7.57 (m, 3H, Ar-
2 2
1
3
H), 7.77-7.35 (m, 1H, Ar-H), 8.39 (d, 2H, J:4.8 Hz, Ar-H). C NMR (100 MHz, DMSO-d ppm)
6
,
δ 43.1 (S-CH ), 44.1 (piperazine C C ), 50.8 (piperazine C C ), 111.3, 127.7, 127.8, 130.9,
2
3,
5
2,
6
1
32.3, 135.5, 139.8, 158.7, 160.9, 163.5 (pyrimidine C ), 192.0 (C = O), 195.9 (C = S).
2
C H ClN OS calculated: (%) C 51.96, H 4.36, N 14.26; found: (%) C 51.58, H 4.16, N 14.27.
17
17
4
2
+
MS [M+1] : m/z 393.
2
-Oxo-2-(3-chlorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A12) Yield 91%.
1
m.p. 118-120 C. H NMR (400 MHz, DMSO-d ppm) δ 3.86 (brs, 4H, pip CH ), 4.09 (brs, 2H,
6
,
2
pip CH ), 4.28 (brs, 2H, pip CH ), 4.90 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 7.49 (t, 1H,
2
2
2
J:8.2 Hz, Ar-H), 7.65 (d, 1H, J:8.0 Hz, Ar-H), 7.80-7.84 (m, 2H, Ar-H), 8.40 (d, 2H, J:5.2 Hz,
1
3
Ar-H). C NMR (100 MHz, DMSO-d ppm) δ 43.2 (S-CH ), 44.2 (piperazine C C ), 50.5
6
,
2
3,
5
(piperazine C C ), 111.3, 128.2, 129.8, 131.0, 134.8, 135.9, 139.1, 158.7, 161.4, 163.5
2, 6
(
pyrimidine C ), 193.8 (C = O), 196.1 (C = S). C H ClN OS calculated: (%) C 51.96, H 4.36,
2
17 17
4
2
+
N 14.26; found: (%) C 51.77, H 4.06, N 14.23. MS [M+1] : m/z 393.
2
-Oxo-2-(4-chlorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A13) Yield 82%.
1
m.p. 175-177 C. H NMR (400 MHz, DMSO-d ppm) δ 3.87 (brs, 4H, pip CH ), 4.12 (brs, 2H,
6
,
2
pip CH ), 4.27 (brs, 2H, pip CH ), 4.95 (s, 2H, CH ), 6.68 (t, 1H, J:4.4 Hz, Ar-H), 7.62 (d, 2H,
2
2
2
1
3
J:8.8 Hz, Ar-H), 8.06 (d, 2H, J:8.4 Hz, Ar-H), 8.39 (d, 2H, J:4.8 Hz, Ar-H). C NMR (100
MHz, DMSO-d ppm) δ 43.2 (S-CH ), 44.2 (piperazine C C ), 50.9 (piperazine C C ), 111.4,
6
,
2
3,
5
2,
6
1
29.6, 130.8, 135.7, 139.0, 158.7, 161.5 (pyrimidine C ), 192.7 (C = O), 195.3 (C = S).
2
12
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C H ClN OS calculated: (%) C 51.96, H 4.36, N 14.26; found: (%) C 51.71, H 4.23, N 13.96.
17
17
4
2
+
MS [M+1] : m/z 393.
2
-Oxo-2-(2,4-dichlorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A14) Yield
1
7
6%. m.p. 142-144 C. H NMR (400 MHz, DMSO-d ppm) δ 3.88 (brs, 4H, pip CH ), 4.09
6
,
2
(brs, 2H, pip CH ), 4.29 (brs, 2H, pip CH ), 4.83 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 7.61
2 2 2
(d, 1H, J:6.4 Hz, Ar-H), 7.67, (s, 1H, Ar-H), 7.88 (d, 1H, J:8.8 Hz, Ar-H), 8.41 (d, 2H, J:4.8 Hz,
1
3
Ar-H). C NMR (100 MHz, DMSO-d ppm) δ 43.2 (S-CH ), 44.0 (piperazine C C ), 50.4
6
,
2
3,
5
(
piperazine C C ), 111.3, 129.8, 130.8, 131.5, 132.7, 137.4, 137.5, 158.7, 161.5 (pyrimidine C ),
2
,
6
2
1
92.5 (C = O), 195.7 (C = S). C H Cl N OS calculated: (%) C 47.78, H 3.77, N 13.11; found:
17 16 2 4 2
+
(
%) C 47.62, H 3.53, N 12.72. MS [M+1] : m/z 428.
2
-Oxo-2-(2,5-dichlorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A15) Yield
1
8
2%. m.p. 119-122 C. H NMR (400 MHz, DMSO-d ppm) δ 3.88 (brs, 4H, pip CH ), 4.09
6
,
2
(brs, 2H, pip CH ), 4.29 (brs, 2H, pip CH ), 4.84 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 7.63
2 2 2
1
3
(
m, 2H, Ar-H), 7.90 (dd, 1H, J:6.4 Hz, Ar-H), 8.41 (d, 2H, J:4.8 Hz, Ar-H). C NMR (100 MHz,
DMSO-d ppm) δ 43.1 (S-CH ), 44.1 (piperazine C C ), 50.7 (piperazine C C ), 111.3, 130.6,
6
,
2
3,
5
2,
6
1
31.1, 131.6, 133.6, 133.8, 140.9, 158.7, 161.6 (pyrimidine C ), 193.3 (C = O), 196.6 (C = S).
2
C H Cl N OS calculated: (%) C 47.78, H 3.77, N 13.11; found: (%) C 47.76, H 3.95, N 13.47.
17
16
2
4
2
+
MS [M+1] : m/z 428.
2
-Oxo-2-(3,4-dichlorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A16) Yield
1
7
7%. m.p. 132-134 C. H NMR (400 MHz, DMSO-d ppm) δ 3.87 (brs, 4H, pip CH ), 4.10
6
,
2
(brs, 2H, pip CH ), 4.27 (brs, 2H, pip CH ), 4.85 (s, 2H, CH ), 6.71 (t, 1H, J:4.8 Hz, Ar-H), 7.65
2 2 2
(d, 1H, J:8.2 Hz, Ar-H), 7.75 (d, 1H, J:8.1 Hz, Ar-H), 7.80 (s, 1H, Ar-H), 8.40 (d, 2H, J:5.2 Hz,
13
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1
3
Ar-H). C NMR (100 MHz, DMSO-d ppm) δ 43.2 (S-CH ), 44.1 (piperazine C C ), 50.6
6
,
2
3,
5
(
piperazine C C ), 111.4, 129.6, 131.1, 131.2, 134.8, 137.3, 138.9, 158.7, 161.5 (pyrimidine C ),
2
,
6
2
1
92.2 (C = O), 195.6 (C = S). C H Cl N OS calculated: (%) C 47.78, H 3.77, N 13.11; found:
17 16 2 4 2
+
(
%) C 47.51, H 3.54, N 12.93. MS [M+1] : m/z 428.
2
-Oxo-2-(2-fluorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A17) Yield 85%.
1
m.p. 116-118 C. H NMR (400 MHz, DMSO-d ppm) δ 3.87 (brs, 4H, pip CH ), 4.10 (brs, 2H,
6
,
2
pip CH ), 4.25 (brs, 2H, pip CH ), 4.96 (s, 2H, CH ), 6.71 (t, 1H, J:4.8 Hz, Ar-H), 7.30 (m, 3H,
2
2
2
1
3
Ar-H), 7.95 (m, 1H, Ar-H), 8.40 (d, 2H, J:5.2 Hz, Ar-H). C NMR (100 MHz, DMSO-d ppm) δ
6
,
4
1
3.2 (S-CH ), 44.2 (piperazine C C ), 50.1 (piperazine C C ), 111.1, 116.5, 126.6, 128.2,
2 3, 5 2, 6
28.8, 135.9, 158.2, 161.43, 164.3 (pyrimidine C ), 193.8 (C = O), 196.5 (C = S). C H FN OS
2
2
17 17
4
+
calculated: (%) C 54.24, H 4.55, N 14.88; found: (%) C 54.09, H 4.47, N 14.90. MS [M+1] : m/z
3
77.
2
-Oxo-2-(3-fluorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A18) Yield 79%.
1
m.p. 106-108 C. H NMR (400 MHz, DMSO-d ppm) δ 3.91 (brs, 4H, pip CH ), 4.14 (brs, 2H,
6
,
2
pip CH ), 4.29 (brs, 2H, pip CH ), 4.88 (s, 2H, CH ), 6.69 (t, 1H, J:4.8 Hz, Ar-H), 7.46-7.50 (m,
2
2
2
1
3
2
H, Ar-H), 7.55 (m, 1H, Ar-H), 7.77 (m, 1H, Ar-H), 8.41 (d, 2H, J:4.8 Hz, Ar-H). C NMR (100
MHz, DMSO-d ppm) δ 43.2 (S-CH ), 44.1 (piperazine C C ), 50.5 (piperazine C C ), 111.2,
6
,
2
3,
5
2,
6
1
14.8, 120.9, 125.5, 131.3, 139.1, 158.2, 161.5, 164.4 (pyrimidine C ), 192.4 (C = O), 195.3 (C =
2
S). C H FN OS calculated: (%) C 54.24, H 4.55, N 14.88; found: (%) C 54.52, H 4.74, N
17
17
4
2
+
1
4.80. MS [M+1] : m/z 377.
2
-Oxo-2-(4-fluorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A19) Yield 74%.
1
m.p. 144-146 C. H NMR (400 MHz, DMSO-d ppm) δ 3.88 (brs, 4H, pip CH ), 4.12 (brs, 2H,
6
,
2
14
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pip CH ), 4.28 (brs, 2H, pip CH ), 4.96 (s, 2H, CH ), 6.68 (t, 1H, J:4.4 Hz, Ar-H), 7.38 (m, 2H,
2
2
2
1
3
Ar-H), 8.13 (m, 2H, Ar-H), 8.39 (d, 2H, J:5.2 Hz, Ar-H). C NMR (100 MHz, DMSO-d ppm) δ
6
,
4
1
3.0 (S-CH ), 44.1 (piperazine C C ), 50.4 (piperazine C C ), 111.3, 116.5, 131.8, 132.3,
2 3, 5 2, 6
58.5, 161.5, 168.9 (pyrimidine C ), 193.9 (C = O), 196.8 (C = S). C H FN OS calculated:
2
17 17
4
2
+
(
%) C 54.24, H 4.55, N 14.88; found: (%) C 54.00, H 4.90, N 15.01. MS [M+1] : m/z 377.
2
-Oxo-2-(2,4-difluorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A20) Yield
1
8
8%. m.p. 100-103 C. H NMR (400 MHz, DMSO-d ppm) δ 3.89 (brs, 4H, pip CH ), 4.12
6
,
2
(
brs, 2H, pip CH ), 4.29 (brs, 2H, pip CH ), 4.87 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H),
2 2 2
1
3
7
.27(m, 1H, Ar-H), 7.47 (m, 1H, Ar-H), 7.97 (m, 1H, Ar-H), 8.41 (d, 2H, J:4.8 Hz, Ar-H). C
NMR (100 MHz, DMSO-d ppm) δ 43.3 (S-CH ), 44.1 (piperazine C C ), 50.7 (piperazine C
2,
6
,
2
3,
5
C ), 111.4, 112.2, 113.2, 122.2, 133.0, 158.5, 161.5, 161.8, 166.9 (pyrimidine C ), 192.7 (C =
6
2
O), 195.3 (C = S). C H F N OS calculated: (%) C 51.76, H 4.09, N 14.20; found: (%) C
1
7
16
2
4
2
+
5
2
8
2
1
1.76, H 4.01, N 14.17. MS [M+1] : m/z 395.
-Oxo-2-(3,4-difluorophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A21) Yield
1
0%. m.p. 97-99 C. H NMR (400 MHz, DMSO-d ppm) δ 3.88 (brs, 4H, pip CH ), 4.11 (brs,
6
,
2
H, pip CH ), 4.27 (brs, 2H, pip CH ), 4.86 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 7.15 (m,
2
2
2
1
3
H, Ar-H), 7.75 (m, 1H, Ar-H), 7.82 (m, 1H, Ar-H), 8.41 (d, 2H, J:4.8 Hz, Ar-H). C NMR (100
MHz, DMSO-d ppm) δ 43.0 (S-CH ), 44.1 (piperazine C C ), 50.8 (piperazine C C ), 111.3,
6
,
2
3,
5
2,
6
1
16.5, 126.8, 127.1, 134.9, 150.1, 154.8, 158.5, 161.5 (pyrimidine C ), 192.4 (C = O), 195.5 (C =
2
S). C H F N OS calculated: (%) C 51.76, H 4.09, N 14.20; found: (%) C 51.44, H 3.89, N
17
16
2
4
2
+
1
4.13. MS [M+1] : m/z 395.
15
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2
-Oxo-2-(2-nitrophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A22) Yield 88%.
1
m.p. 117-119 C. H NMR (400 MHz, DMSO-d ppm) δ 3.89 (brs, 4H, pip CH ), 4.12 (brs, 2H,
6
,
2
pip CH ), 4.28 (brs, 2H, pip CH ), 5.03 (s, 2H, CH ), 6.72 (t, 1H, J:4.8 Hz, Ar-H), 7.80 (t, 1H,
2
2
2
J:9.0 Hz, Ar-H), 8.20 (t, 1H, J:9.2 Hz, Ar-H), 8.25 (s, 1H, Ar-H), 8.30 (m, 1H, Ar-H), 8.40 (d,
1
3
2
H, J:5.2 Hz, Ar-H). C NMR (100 MHz, DMSO-d ppm) δ 43.1 (S-CH ), 44.0 (piperazine C
6, 2 3,
C ), 50.5 (piperazine C C ), 111.2, 124.7, 127.2, 135.1, 135.9, 136.6, 145.7, 158.5, 161.2
5
2,
6
(
pyrimidine C ), 192.6 (C = O), 195.9 (C = S). C H N O S calculated: (%) C 50.61, H 4.25, N
2 17 17 5 3 2
+
1
2
7.36; found: (%) C 50.47, H 4.08, N 17.29. MS [M+1] : m/z 404.
-Oxo-2-(3-nitrophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A23) Yield 72%.
1
m.p. 189-191 C. H NMR (400 MHz, DMSO-d ppm) δ 3.90 (brs, 4H, pip CH ), 4.14 (brs, 2H,
6
,
2
pip CH ), 4.29 (brs, 2H, pip CH ), 5.05 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 7.89 (m, 1H,
2
2
2
1
3
Ar-H), 8.51 (m, 2H, Ar-H), 8.73 (m, 1H, Ar-H), 8.41 (d, 2H, J:4.8 Hz, Ar-H). C NMR (100
MHz, DMSO-d ppm) δ 43.2 (S-CH ), 44.2 (piperazine C C ), 51.0 (piperazine C C ), 111.4,
6
,
2
3,
5
2,
6
1
23.1, 128.2, 131.4, 135.1, 138.3, 148.7, 158.7, 161.5 (pyrimidine C ), 192.5 (C = O), 195.1 (C =
2
S). C H N O S calculated: (%) C 50.61, H 4.25, N 17.36; found: (%) C 50.58, H 4.58, N
1
7
17
5
3 2
+
1
7.72. MS [M+1] : m/z 404.
2
-Oxo-2-(4-nitrophenyl)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (A24) Yield 79%.
1
m.p. 207-209 C. H NMR (400 MHz, DMSO-d ppm) δ 3.89 (brs, 4H, pip CH ), 4.13 (brs, 2H,
6
,
2
pip CH ), 4.29 (brs, 2H, pip CH ), 5.02 (s, 2H, CH ), 6.71 (t, 1H, J:4.8 Hz, Ar-H), 8.28 (d, 2H,
2
2
2
1
3
J:9.2 Hz, Ar-H), 8.38 (d, 2H, J:9.2 Hz, Ar-H), 8.41 (d, 2H, J:4.8 Hz, Ar-H). C NMR (100
MHz, DMSO-d ppm) δ 43.3 (S-CH ), 44.2 (piperazine C C ), 50.4 (piperazine C C ), 111.3,
6
,
2
3,
5
2,
6
1
26.1, 129.3, 138.1, 148.5, 158.8, 162.0 (pyrimidine C ), 193.3 (C = O), 196.5 (C = S).
2
16
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C H N O S calculated: (%) C 50.61, H 4.25, N 17.36; found: (%) C 50.35, H 4.57, N 17.61.
17
17
5
3 2
+
MS [M+1] : m/z 404.
2
-Oxo-2-(thiazol-2-ylamino)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (B1) Yield
1
8
9%. m.p. 228-230 C. H NMR (400 MHz, DMSO-d ppm) δ 3.88 (brs, 4H, pip-CH ), 4.07
6
,
2
(
brs, 2H, pip-CH ), 4.29 (brs, 2H, pip-CH ), 4.39 (s, 2H, CH ), 6.68 (t, 1H, J:4.4 Hz, Ar-H), 7.19
2 2 2
(d, 1H, J:3.6 Hz, thiazole), 7.45 (d, 1H, J:3.6 Hz, thiazole), 8.39 (d, 2H, J:4.4 Hz, Ar-H), 12.39
1
3
(
brs, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ 43.2 (S-CH ), 50.0 (piperazine C C ),
6, 2 3, 5
5
1.5 (piperazine C C ), 111.3, 114.2, 138.4, 157.0, 158.7, 161.5, 166.4 (C = O), 195.1 (C = S).
2, 6
C H N OS calculated: (%) C 44.19, H 4.24, N 22.09; found: (%) C 43.80, H 4.22, N 22.02.
14
16
6
3
+
MS [M+1] : m/z 381.
2
-Oxo-2-[(5-nitrothiazol-2-yl)amino]ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (B2)
1
Yield 85%. m.p. 208-210 C. H NMR (400 MHz, DMSO-d ppm) δ 3.90 (brs, 4H, pip-CH ),
6
,
2
4
8
.10 (brs, 2H, pip-CH ), 4.30 (brs, 2H, pip-CH ), 4.48 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H),
2 2 2
1
3
.41 (d, 2H, J:4.8 Hz, Ar-H), 8.64 (s, 1H, thiazole), 13.43 (brs, 1H, NH). C NMR (100 MHz,
DMSO-d ppm) δ 43.1 (S-CH ), 50.1 (piperazine C C ), 51.5 (piperazine C C ), 111.3, 142.5,
6
,
2
3,
5
2,
6
1
3
2
43.4, 158.7, 161.5, 162.4, 168.6 (C = O), 194.7 (C = S). For C H N O S calculated: (%) C
1
4
15
7
3 3
+
9.52, H 3.55, N 23.04; found: (%) C 39.39, H 3.71, N 22.70. MS [M+1] : m/z 426.
-Oxo-2-(benzothiazol-2-ylamino)ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate (B3)
1
Yield 86%. m.p. 191-193 C. H NMR (400 MHz, DMSO-d ppm) δ 3.91 (brs, 4H, pip-CH ),
6
,
2
4
7
1
.11 (brs, 2H, pip-CH ), 4.32 (brs, 2H, pip-CH ), 4.48 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H),
2 2 2
.31 (t, 1H, J:7.2 Hz, Ar-H), 7.45 (t, 1H, J:6.8 Hz, Ar-H), 7.76 (d, 1H, J:8.0 Hz, Ar-H), 7.97 (d,
1
3
H, J:7.6 Hz, Ar-H), 8.42 (d, 2H, J:4.8 Hz, Ar-H), 12.70 (brs, 1H, NH). C NMR (100 MHz,
17
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DMSO-d ppm) δ 43.1 (S-CH ), 50.1 (piperazine C C ), 51.5 (piperazine C C ), 111.3, 121.2,
6
,
2
3,
5
2,
6
1
22.4, 124.2, 126.8, 132.1, 149.2, 158.58, 158.7, 161.5, 167.6 (C = O), 195.0 (C = S).
C H N OS calculated: (%) C 50.21, H 4.21, N 19.52; found: (%) C 49.87, H 4.05, N 19.35.
18
18
6
3
+
MS [M+1] : m/z 431.
2
-Oxo-2-[(6-methylbenzothiazol-2-yl)amino]ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate
1
(
B4) Yield 87%. m.p. 221-223 C. H NMR (400 MHz, DMSO-d ppm) δ 2.41 (s, 3H, -CH ),
6,
3
3
6
1
.91 (brs, 4H, pip-CH ), 4.11 (brs, 2H, pip-CH ), 4.32 (brs, 2H, pip-CH ), 4.47 (s, 2H, CH ),
2 2 2 2
.70 (t, 1H, J:4.8 Hz, Ar-H), 7.25 (d, 1H, J:8.4 Hz, Ar-H), 7.65 (d, 1H, J:8.0 Hz, Ar-H), 7.75 (s,
1
3
H, Ar-H), 8.42 (d, 2H, J:4.8 Hz, Ar-H), 12.60 (brs, 1H, NH). C NMR (100 MHz, DMSO-d
6,
ppm) δ 21.7 (CH ), 43.1 (S-CH ), 50.2 (piperazine C C ), 51.5 (piperazine C C ), 111.3, 120.9,
3
2
3,
5
2,
6
1
21.9, 128.1, 132.3, 133.7, 147.2, 157.7, 158.7, 161.5, 167.39 (C = O), 195.1 (C = S).
C H N OS calculated: (%) C 51.33, H 4.53, N 18.90; found: (%) C 50.94, H 4.19, N 18.55.
19
20
6
3
+
MS [M+1] : m/z 445.
2
-Oxo-2-[(6-methoxybenzothiazol-2-yl)amino]ethyl
4-(pyrimidin-2-yl)piperazine-1-
1
carbodithioate (B5) Yield 84%. m.p. 219-221 C. H NMR (400 MHz, DMSO-d ppm) δ 3.77
6
,
(s, 3H, -OCH ), 3.87 (brs, 4H, pip-CH ), 4.07 (brs, 2H, pip-CH ), 4.28 (brs, 2H, pip-CH ), 4.42
3 2 2 2
(
s, 2H, CH ), 6.67 (t, 1H, J:4.8 Hz, Ar-H), 7.00 (dd, 1H, J:4.6 Hz, Ar-H), 7.53 (d, 1H, J:1.2 Hz,
2
1
3
Ar-H), 7.62 (d, 1H, J:9.2 Hz, Ar-H), 8.38 (d, 2H, J:4.4 Hz, Ar-H), 12.55 (brs, 1H, NH). C
NMR (100 MHz, DMSO-d ppm) δ 43.1 (S-CH ), 50.1 (piperazine C C ), 51.4 (piperazine C
6
,
2
3,
5
2,
C ), 56.3 (OCH ), 105.4, 111.3, 115.6, 121.8, 133.4, 143.3, 156.5, 156.8, 158.7, 161.5, 167.2 (C
6
3
=
O), 195.1 (C = S). C H N O S calculated: (%) C 49.55, H 4.38, N 18.25; found: (%) C
19 20 6 2 3
+
4
9.46, H 4.08, N 18.16. MS [M+1] : m/z 461.
18
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2
-Oxo-2-[(6-ethoxybenzothiazol-2-yl)amino]ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate
1
(
B6) Yield 82%. m.p. 206-208 C. H NMR (400 MHz, DMSO-d ppm) δ 1.44 (t, 3H, J:7.2 Hz),
6
,
4
1
.02 (m, 6H, pip CH ), 4.08 (q, 2H, J:7.2 Hz), 4.41 (s, 2H, CH ), 4.45 (brs, 2H, pip CH ), 6.59 (t,
2 2 2
H, J:4.8 Hz, Ar-H), 7.02 (dd, 1H, J:4.4 Hz, Ar-H), 7.26 (d, 1H, J:2.4 Hz, Ar-H), 7.67 (d, 1H,
1
3
J:9.2 Hz, Ar-H), 8.35 (d, 2H, J:4.4 Hz, Ar-H), 10.37 (brs, 1H, NH). C NMR (100 MHz,
DMSO-d ppm) δ 15.1 (CH ), 43.1 (S-CH ), 50.3 (piperazine C C ), 52.5 (piperazine C C ),
6
,
3
2
3,
5
2,
6
6
1
4
2
4.3 (OCH ), 105.2, 111.2, 115.9, 121.9, 133.8, 142.9, 155.4, 156.4, 158.1, 161.4, 166.9 (C = O),
2
95.2 (C = S). C H N O S calculated: (%) C 50.61, H 4.67, N 17.71; found: (%) C 50.61, H
2
0
22
6
2 3
+
.51, N 17.38. MS [M+1] : m/z 475.
-Oxo-2-[(6-chlorobenzothiazol-2-yl)amino]ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate
1
(
B7) Yield 80%. m.p. 246-248 C. H NMR (400 MHz, DMSO-d ppm) δ 3.91 (brs, 4H, pip
6
,
CH ), 4.11 (brs, 2H, pip CH ), 4.31 (brs, 2H, pip CH ), 4.48 (s, 2H, CH ), 6.70 (t, 1H, J:5.2 Hz,
2
2
2
2
Ar-H), 7.46 (dd, 1H, J:2.4 Hz, Ar-H), 7.76 (d, 1H, J:8.8 Hz, Ar-H), 8.12 (d, 1H, J:2.0 Hz, Ar-H),
1
3
8
.42 (d, 2H, J:4.8 Hz, Ar-H), 12.73 (brs, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ 43.1
6,
(
S-CH ), 50.1 (piperazine C C ), 51.6 (piperazine C C ), 111.3, 122.1, 122.4, 127.2, 128.3,
2 3, 5 2, 6
1
33.8, 148.1, 158.7, 159.4, 161.5, 167.8 (C = O), 194.9 (C = S). C H ClN OS calculated: (%)
18 17 6 3
+
C 46.49, H 3.68, N 18.07; found: (%) C 46.22, H 3.60, N 17.99. MS [M+1] : m/z 466.
2
-Oxo-2-[(6-fluorobenzothiazol-2-yl)amino]ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate
1
(
B8) Yield 75%. m.p. 237-239 C. H NMR (400 MHz, DMSO-d ppm) δ 3.91 (brs, 4H, pip
6
,
CH ), 4.11 (brs, 2H, pip CH ), 4.31 (brs, 2H, pip CH ), 4.47 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz,
2
2
2
2
Ar-H), 7.29 (td, 1H, J:2.6 Hz, Ar-H), 7.77 (q, 1H, J:4.8 Hz, Ar-H), 7.89 (dd, 1H, J:4.2 Hz, Ar-
1
3
H), 8.42 (d, 2H, J:4.8 Hz, Ar-H), 12.69 (brs, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ
6
,
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1
3.1 (S-CH ), 50.1 (piperazine C C ), 51.5 (piperazine C C ), 108.8, 111.3, 114.9, 122.3,
2 3, 5 2, 6
33.3, 145.9, 158.1, 158.7, 160.5, 161.5, 167.7 (C = O), 195.0 (C = S). C H FN OS
3
1
8
17
6
+
calculated: (%) C 48.20, H 3.82, N 18.74; found: (%) C 48.07, H 3.57, N 18.71. MS [M+1] : m/z
4
49.
2
-Oxo-2-[(6-nitrobenzothiazol-2-yl)amino]ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate
1
(
B9) Yield 79%. m.p. 239-241 C. H NMR (400 MHz, DMSO-d ppm) δ 3.86 (brs, 4H, pip
6
,
CH ), 4.06 (brs, 2H, pip CH ), 4.26 (brs, 2H, pip CH ), 4.47 (s, 2H, CH ), 6.66 (t, 1H, J:4.8 Hz,
2
2
2
2
Ar-H), 7.87 (d, 1H, J:9.2 Hz, Ar-H), 8.24 (d, 1H, J:8.8 Hz, Ar-H), 8.37 (d, 2H, J:4.4 Hz, Ar-H),
1
3
9
5
1
3
2
.02 (s, 1H, Ar-H), 13.06 (brs, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ 43.2 (S-CH ),
6, 2
0.1 (piperazine C C ), 51.5 (piperazine C C ), 111.3, 119.7, 121.3, 122.5, 132.8, 143.7, 154.2,
3
,
5
2,
6
58.7, 161.5, 164.1, 168.4 (C = O), 194.9 (C = S). C H N O S calculated: (%) C 45.46, H
1
8
17
7
3 3
+
.60, N 20.62; found: (%) C 45.21, H 3.45, N 20.55. MS [M+1] : m/z 476.
-Oxo-2-[(4-methylthiazol-2-yl)amino]ethyl
4-(pyrimidin-2-yl)piperazine-1-carbodithioate
1
(
B10) Yield 82%. m.p. 170-172 C. H NMR (400 MHz, DMSO-d ppm) δ 2.26 (s, 3H, thiazole-
6
,
CH ), 3.89 (brs, 4H, pip CH ), 4.09 (brs, 2H, pip CH ), 4.31 (brs, 2H, pip CH ), 4.39 (s, 2H,
3
2
2
2
CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 6.75 (s, 1H, thiazole), 8.41 (d, 2H, J:4.8 Hz, Ar-H), 12.34
2
1
3
(
brs, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ 16.8 (CH ), 42.4 (S-CH ), 49.2
6, 3 2
(
piperazine C C ), 50.7 (piperazine C C ), 107.6, 110.5, 146.6, 157.1, 157.9, 160.7, 165.5 (C =
3
,
5
2,
6
O), 194.3 (C = S). C H N OS calculated: (%) C 45.66, H 4.60, N 21.30; found: (%) C 45.62,
1
5
18
6
3
+
H 4.58, N 21.30. MS [M+1] : m/z 395.
2
-Oxo-2-[(4,5-dimethylthiazol-2-yl)amino]ethyl 4-(pyrimidin-2-yl)piperazine-1-carbodithioate
1
(
B11) Yield 81%. m.p. 187-189 C. H NMR (400 MHz, DMSO-d ppm) δ 2.15 (br,s, 3H,
6
,
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thiazole-CH ), 2.22 (brs, 3H, thiazole-CH ), 3.89 (brs, 4H, pip CH ), 4.09 (brs, 2H, pip CH ),
3
3
2
2
4
.30 (brs, 2H, pip CH ), 4.34 (s, 2H, CH ), 6.70 (t, 1H, J:4.8 Hz, Ar-H), 8.41 (d, 2H, J:4.8 Hz,
2 2
1
3
Ar-H), 12.11 (br, s, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ 14.6 (CH ), 16.7 (CH ),
6
,
3
3
4
1
2
2
2.6 (S-CH ), 50.1 (piperazine C C ), 51.6 (piperazine C C ), 111.3, 117.5, 145.3, 158.1,
2 3, 5 2, 6
58.6, 161.5, 167.6 (C = O), 194.6 (C = S). C H N OS calculated: (%) C 47.04, H 4.93, N
1
6
20
6
3
+
0.57; found: (%) C 46.90, H 4.86, N 20.40. MS [M+1] : m/z 409.
-Oxo-2-[(4-ethoxycarbonylthiazol-2-yl)amino]ethyl
4-(pyrimidin-2-yl)piperazine-1-
1
carbodithioate (B12) Yield 87%. m.p. 136-138 C. H NMR (400 MHz, DMSO-d ppm) δ 1.19
6
,
(
t, 3H, J:7.2 Hz), 3.89 (brs, 4H, pip CH ), 4.09 (q, 4H, J:6.8 Hz, pip CH ve CH ), 4.31 (brs, 2H,
2 2 2
pip CH ), 4.37 (s, 2H, CH ), 6.69 (t, 1H, J:4.8 Hz, Ar-H), 6.98 (s, 1H, thiazole), 8.41 (d, 2H,
2
2
1
3
J:4.8 Hz, Ar-H), 12.45 (brs, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ 14.8 (CH ), 43.2
6
,
3
(
S-CH ), 50.0 (piperazine C C ), 51.4 (piperazine C C ), 61.0 (OCH ), 111.3, 111.6, 144.4,
2 3, 5 2, 6 2
1
58.3, 158.7, 161.5, 166.5, 170.7 (C = O), 195.1 (C = S). C H N O S calculated: (%) C 45.12,
17 20 6 3 3
+
H 4.45, N 18.57; found: (%) C 44.99, H 4.35, N 18.57. MS [M+1] : m/z 453.
2
-Oxo-2-[(4-methyl-5-ethoxycarbonylthiazol-2-yl)amino]ethyl
4-(pyrimidin-2-yl)piperazin-1-
1
carbodithiodate (B13) Yield 80%. m.p. 219-221 C. H NMR (400 MHz, DMSO-d ppm) δ 1.28
6
,
(
t, 3H, J:7.2 Hz), 2.56 (s, 3H, thiazole-CH ), 3.90 (brs, 4H, pip CH ), 4.10 (brs, 2H, pip CH ),
3 2 2
4
8
.27 (q, 2H, J:7.2 Hz), 4.30 (brs, 2H, pip CH ), 4.44 (s, 2H, CH ), 6.71 (t, 1H, J:4.8 Hz, Ar-H),
2 2
1
3
.42 (d, 2H, J:4.8 Hz, Ar-H), 12.88 (brs, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ 14.7
6
,
(
CH ), 17.7 (CH ), 43.1 (S-CH ), 50.1 (piperazine C C ), 51.5 (piperazine C C ), 61.2 (OCH ),
3 3 2 3, 5 2, 6 2
1
11.3, 114.7, 156.9, 158.7, 160.2, 161.5, 162.7, 167.5 (C = O), 194.9 (C = S). C H N O S
18 22 6 3 3
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+
calculated: (%) C 46.33, H 4.75, N 18.01; found: (%) C 46.10, H 4.70, N 17.95. MS [M+1] : m/z
4
67.
2
-Oxo-2-[(4,5,6,7-tetrahydrobenzothiazol-2-yl)amino]ethyl
4-(pyrimidin-2-yl)piperazine-1-
1
carbodithioate (B14) Yield 84%. m.p. 174-176 C. H NMR (400 MHz, DMSO-d ppm) δ 1.76
6
,
(
(
(
(
(
brs, 4H, -CH -CH -), 2.56 (brs, 2H, -CH -), 2.62 (brs, 2H, -CH -), 3.89 (brs, 4H, pip CH ), 4.09
2 2 2 2 2
brs, 2H, pip CH ), 4.30 (brs, 2H, pip CH ), 4.37 (s, 2H, CH ), 6.70 (t, 1H, J:5.2 Hz, Ar-H), 8.41
2
2
2
1
3
d, 2H, J:4.8 Hz, Ar-H), 12.18 (brs, 1H, NH). C NMR (100 MHz, DMSO-d ppm) δ 22.1
6
,
CH ), 22.5 (CH ), 22.8 (CH ), 25.9 (CH ), 42.4 (S-CH ), 49.2 (piperazine C C ), 50.7
2
2
2
2
2
3,
5
piperazine C C ), 110.5, 121.2, 143.9, 154.5, 157.9, 160.7, 165.3 (C = O), 194.38 (C = S).
2
,
6
C H N OS calculated: (%) C 49.74, H 5.10, N 19.34; found: (%) C 49.57, H 4.96, N 19.30.
18
22
6
3
+
MS [M+1] : m/z 435.
Antimicrobial activity
Antimicrobial activity of the final compounds was evaluated by the broth microdilution
method according to the modified NCCLS M27-A2 standard procedure as indicated in the
2
6
literature. Tested microorganism strains and origins were as follows : Staphylococcus aureus
ATCC 25923); Enterococcus faecalis (ATCC 29212); Enterococcus faecalis (ATCC 51922);
(
Listeria monocytogenes (ATCC 1911); Klebsiella pneumoniae (ATCC 700603); Pseudomonas
aeruginosa (ATCC 27853); Escherichia coli (ATCC 35218); Escherichia coli (ATCC 25922);
Candida albicans (ATCC 90028); Candida glabrata (ATCC 90030); Candida krusei (ATCC
6
258); Candida parapsilopsis (ATCC 22019). Ketoconazole and chloramphenicol were used as
positive control and the results (MIC values) are shown in Table S 1 and S 2 (Supplemental
Materials)
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ACKNOWLEDGMENTS
This study was supported within the Anadolu University Scientific Research Project (No:
1
305S102), Eskişehir, Turkey. The authors are thankful to the university for the financial
support.
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Scheme 1. Synthesis of the compounds. Reactants/reagents and conditions. i: CS , KOH,
2
EtOH; ii: α-Bromoacetophenones, K CO , acetone, r.t., 5-6 h; iii: 2-Chloro-N-(thiazol-2-
2
3
yl/benzothiazol-2-yl)acetamides
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