Synthesis, structure, and tuberculostatic activity of dimethyl benzoylcarbonohydrazonodithioates

Article abstract of DOI:10.1007/s00706-011-0572-9

New dimethyl benzoylcarbonohydrazonodithioates were obtained by CS ₂ addition to arylcarboxylic acid hydrazides and methylation of the formed adduct. The new derivatives were tested for their activity against Mycobacterium tuberculosis. Some co

Full text of DOI:10.1007/s00706-011-0572-9

Monatsh Chem (2011) 142:1137–1142
DOI 10.1007/s00706-011-0572-9
ORIGINAL PAPER
Synthesis, structure, and tuberculostatic activity of dimethyl
benzoylcarbonohydrazonodithioates
•
Katarzyna Gobis Henryk Foks Zofia Zwolska
•
•
•
Ewa Augustynowicz-Kopec Marek L. Głowka
•
´
Andrzej Olczak Michał Sabisz
´
•
Received: 23 September 2010 / Accepted: 12 July 2011 / Published online: 16 August 2011
Ó The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract New dimethyl benzoylcarbonohydrazonodi-
thioates were obtained by CS2 addition to arylcarboxylic
acid hydrazides and methylation of the formed adduct. The
new derivatives were tested for their activity against
Mycobacterium tuberculosis. Some compounds exhibited
high activity toward sensitive and resistant strains.
for HIV-infected individuals, because of increased risk of
the infection progressing to active disease [3]. Thus complex
chemotherapy protocols with a combination of different
drugs are required. The World Health Organization (WHO)
and other organizations including the European Commission
(EC) therefore create new directly observed treatment short-
course (DOTS)-type therapeutic strategies [4]. A different
solution to the global problem of tuberculosis consists in
farther searching for new targets for tuberculostatic thera-
peutics and new chemical structures able to overcome
M. tuberculosis infections. During the last few years new
targets for tuberculostatics have been identified, among
others fatty acid biosynthesis, amino acid biosynthesis, and
DNA synthesis [5].
Keywords Benzohydrazides Á Crystal structure Á
Hydrogen bonds Á Tuberculostatic activity Á
Structure–activity relationship
Introduction
Tuberculosis (TB) is one of the most deadly infectious
diseases with almost 2 million fatalities a year [1]. Myco-
bacterium tuberculosis strains are known to express
multidrug resistance toward a number of chemotherapeu-
tics and antibiotics (MDR and XDR-TB) [2]. This
phenomenon is associated with higher mortality, especially
The most widely used drug in antituberculosis regimens
is isoniazid (INH). Unfortunately mycobacteria become
resistant to that drug very quickly, and INH causes serious
side effects. These problems are being addressed by vari-
ous research groups [6, 7]. For example new potentially
active structures have been found among hydrazones [8, 9]
and arylhydrazones [10]. Some of them exhibit promising
tuberculostatic activity [11].
In our previous papers we demonstrated that some INH
analogs such as pyridine- and pyrazinecarboxamidrazones
exhibit high activity against tuberculosis [12]. Crystal
structures of representatives from these classes of com-
pounds have been determined. We have found that all of
them are in dipolar form, and intramolecular hydrogen
bonds maintain the planar arrangement of atoms of the
amidrazone functional group [13–15]. Continuing that
research program we have synthesized a series of dimethyl
benzoylcarbonohydrazonodithioates. In this work we
present the synthesis, promising results of tuberculostatic
activity tests in vitro, and crystal structures of two isomeric
nitrophenyl derivatives.
K. Gobis (&) Á H. Foks
Department of Organic Chemistry,
Medical University of Gdansk, Gdansk, Poland
e-mail: kgobis@gumed.edu.pl
´
Z. Zwolska Á E. Augustynowicz-Kopec
Department of Microbiology, Institute of Tuberculosis
and Pulmonary Diseases, Warsaw, Poland
´
M. L. Głowka Á A. Olczak
Institute of General and Ecological Chemistry,
´ ´ ´ ´
Technical University of Łodz, Łodz, Poland
M. Sabisz
Department of Pharmaceutical Technology and Biochemistry,
Gdansk University of Technology, Gdansk, Poland
123

1138
K. Gobis et al.
Results and discussion
Synthesis
The starting benzohydrazides were obtained from methyl
esters in a typical reaction with 100% hydrazine hydrate.
Hydrazides upon treatment with carbon disulfide and a
double excess of methyl iodide in a basic environment of
KOH or triethylamine were transformed into the corre-
sponding dimethyl benzoylcarbonohydrazonodithioates
1–14 (Scheme 1).
Reactions were performed in ethanol–water solution at
room temperature and occurred with good yields. The
structures of the obtained compounds were confirmed by
elemental analysis, IR, 1H and 13C NMR spectroscopy, and
mass spectrometry (compounds 1 and 2); compounds 6 and
7 were also unequivocally determined by X-ray diffraction
(Fig. 1).
1H NMR spectra and X-ray diffraction provided inter-
esting information about the new compounds. Unexpectedly
in some products the two thiomethyl groups are not detected
in the 1H NMR spectrum as a singlet of six protons but rather
as two singlets of three protons, which indicates the magnetic
inequivalence of both groups. Aromatic ring substituents
that are able to exert a strong negative inductive effect
(NO2, Cl), especially in the 2-position, probably interact
with SCH3 groups through space. This interaction (or lack
of it) is well illustrated in the monocrystal structure of
2-nitrobenzoylcarbonohydrazonodithioate (6) and 4-nitro-
benzoylcarbonohydrazonodithioate (7) (Fig. 1). Crystal data
of compound 6 indicate double bond character of bonds
C1–N2 and N2–N3. This results in restriction of internal
rotation and changes the electron density around protons of
only one of the SCH3 groups, resulting in the magnetic
inequivalence of both groups. Lack of a substituent or
insertion of a substituent exerting a weak negative induc-
tive effect (OH, OCH3) does not cause the aforementioned
interaction, and the thiomethyl groups of those compounds
Fig. 1 ORTEP views of molecules 6 and 7 in their crystals. The
ellipsoids are drawn at 50% probability level [16]. Crystal data:
monoclinic, P21/c, Z = 4; with a = 8.138(1), b = 18.920(1),
˚
c = 9.270(1) A, b = 111.77(1)°, R1 = 0.053 (wR2 = 0.177) for
2,044 observed reflections for 6; and a = 7.437(1), b = 23.140(1),
˚
c = 8.874(1) A, b = 121.36(1)°, R1 = 0.043 (wR2 = 0.112) for
2,374 observed reflections for 7. The distances C1–N2 and N2–N3
˚
˚
are 1.272(3) and 1.390(3) A for 6, and 1.276(3) and 1.401(2) A and 7,
indicating double bond character of the former bond. The dihedral
angle between the phenyl ring and the carbonyl group is 58.0° for 6
and 33.6° for 7
are present in the spectrum mainly as a singlet of six
protons.
Reaction yields and the physical constants of the newly
synthesized compounds are given in Table 1.
O
HN
1 - 14
Microbiology
O
HN NH2
2 Et3N or 2 KOH
r.t.
R
S
S
CH3
CH3
R
+ CS2 + 2 CH3I
N
The newly synthesized dimethylesters were examined in
vitro for their tuberculostatic activity against M. tuberculosis
H37Rv strain and two wild-type strains isolated from patients
with tuberculosis: one (sp. 210) resistant to p-aminosalicylic
acid (PAS), isonicotinic acid hydrazide (INH), ethambutol
(ETB), and rifampicin (RFP) and the other (sp. 192) fully
sensitive to the administered tuberculostatics (Table 2).
Investigations were performed by a classical test-tube
method of successive dilution in Youmans’ modification of
Proskauer and Beck’s medium containing 10% of bovine
No R
No R
1
2
3
4
5
6
7
Ph
8
9
2-HO-Ph
3-HO-Ph
2-Cl-Ph
4-Cl-Ph
2,4-Cl2-Ph
3,4-Cl2-Ph
2-NO2-Ph
4-NO2-Ph
10 4-HO-Ph
11 4-CH3O-Ph
12 3,4,5-(CH3O)3-Ph
13 3,4-(CH3O)2-Ph-CH2
14 Pyrazin-2-yl
Scheme 1
123

Synthesis, structure, and tuberculostatic activity of dimethyl benzoylcarbonohydrazonodithioates
1139
that obtained for the reference drug isoniazid (INH).
Derivative 7, which has a nitro group in the 4-position of the
benzene ring, was the most active compound toward H37Rv
and 192 strains (MICs 3.1 lg cm-3). Its activity toward the
resistant 210 strain was lower (MIC 25 lg cm-3). Deriva-
tive 5, which has two chlorine atoms in the 3- and 4-position,
was the most active against resistant strain 210 (MIC
12.5 lg cm-3). It was also very active toward H37Rv and
192 strains (MIC 6.2 and 3.1 lg cm-3). Similar results were
obtained for compound 10, which has a hydroxy group in the
4-position of the aromatic ring. It inhibited the growth of M.
tuberculosis strains at concentrations of 3.1 lg cm-3
(H37Rv), 6.2 lg cm-3 (192), and 25 lg cm-3 (210).
Derivatives 3 (4-Cl), 4 (2,4-di-Cl), 8 (2-OH), and 9
(3-OH) generally exhibited average activity against all of
the tested strains (MIC 6.2–25 lg cm-3). Other compounds
such as derivatives 2 (2-Cl), 6 (2-NO2), 11 (4-OCH3),
12 (3,4,5-tri-OCH3), and 13, which has a 3,4-dimethoxy-
phenyl substituent separated from the carbonyl by a
methylene group, have the lowest tuberculostatic activity
(MIC 25–50 lg cm-3).
Table 1 Characteristics of the newly synthesized dimethyl ben-
zoylcarbonohydrazonodithioates 2–14
No.
Yield/%
M.p./°C
Solvent
2
95
97
93
90
74
87
46
87
75
54
81
67
95
73–75
EtOH
3
83–85
EtOH/H2O
EtOH
4
113–115
131–133
141–144
154–146
173–175
153–155
160–163
70–72
5
MeOH
EtOH
6
7
EtOH
8
Toluene
Chloroform
EtOH
9
10
11
12
13
14
Cyclohexane
EtOH
158–160
97–99
EtOH
150–152
MeOH
Table 2 Tuberculostatic activity of the tested compounds
No.
MIC/lg cm-3
On the basis of the above results we conclude that
electronegative substituents (NO2, Cl, OH) in the 4-posi-
tion of the aromatic ring caused higher tuberculostatic
activity, whereas derivatives with substituents in the
2-position exhibit moderate or low activity. Similar results
were obtained for compounds with one or more methoxy
groups as a substituent. It is very significant that derivative
6, which has an NO2 group in the 2-position, possesses
structural factors allowing it to form intramolecular
hydrogen bonds and to adopt a planar structure (Fig. 1) and
exhibit lower tuberculostatic activity. Compound 7, which
cannot adopt a planar structure, shows the highest activity
among the tested derivatives.
H37Rv
210 resistant
192 sensitive
2
25
50
25
50
12.5
50
25
25
25
25
25
50
50
1.1
25
3
6.2
6.2
6.2
25
12.5
6.2
3.1
50
4
5
6
7
3.1
12.5
6.2
3.1
25
3.1
25
8
9
6.2
6.2
25
10
11
12
13
INH
25
50
The most active compounds 3–5, 7, 9, and 10 were
screened in widened tuberculostatic tests using ten acid-
resistant strains of Mycobacterium genus (Table 3) and they
exhibited activity against only a few strain types: H37Rv,
An5, Wells, Kirchberg, and Kansasii. In those tests deriva-
tives 5 (3,4-di-Cl), 7 (4-NO2), and 10 (4-OH) generally
exhibited the highest activity (MIC 6.2–25 lg cm-3). All
compounds exhibited rather weak activity toward Scrofula-
ceum, Intracellularum, Fortuitum, Smegmatis, and Phlei
strains. However, their activity against Kirchberg and
Kansasii strains was higher than that exhibited by isoniazid
(INH).
25
50
0.5
0.5
serum [17, 18]. Bacterial suspensions were prepared
from 14-day-old cultures of slowly growing strains and
from 48-h-old cultures of saprophytic strains [19, 20].
Solutions of compounds in ethylene glycol were tested.
Stock solutions contained 10 mg of compounds per cm3.
Dilutions (in geometric progression) were prepared in
Youmans’ medium. The medium containing no investi-
gated substances and containing isoniazid (INH) as
reference drug were used for comparison. Incubation was
performed at a temperature of 37 °C. The MIC values were
determined as minimum concentration inhibiting the
growth of tested tuberculous strains in relation to the probe
with no tested compound.
Cytotoxicity
Compounds 5, 7, and 10, the most active toward
M. tuberculosis strains, were tested for cytotoxicity against
human non-small lung cancer cell line A549 and human
colon cancer cell line HCT116. Both lines were maintained
All tested compounds exhibited average or high tuber-
culostatic activity. However, their activity was lower than
123

1140
K. Gobis et al.
Table 3 Widened tuberculostatic tests for chosen dimethylesters
Bacteria strain
MIC/lg cm-3
3
4
5
7
9
10
INH
H37Rv
12.5 6.2
12.5 6.2
6.2
6.2
6.2
6.2
6.2
50
6.2
6.2
0.5
1.1
An5
12.5 6.2
6.2
12.5 50
Wells
12.5 12.5 6.2
12.5 0.5
Kirchberg
Kansasii
Scrofulaceum
25
100
25
50
156
39
78
78
78
39
39
25
6.2
25
25
12.5 25
100
25
100 25
100 25
100 25
50
Intracellularum 50
100
100
100
100
100
100
100
100
100
100
100
100
Fortuitum
Smegmatis
Phlei
100
100
100
50
50
100 100
in RPMI1640 or McCoy’s 5A medium, respectively,
supplemented with 10% fetal bovine serum, 2 mM
L-glutamine, and antibiotics (100 units/cm3 of penicillin
and 100 mg cm-3 of streptomycin) at 37 °C in a 5% CO2/
air atmosphere [21]. Cells were screened routinely for
mycoplasma by the PCR method with a Mycoplasma Plus
PCR Primer Set (Stratagene, La Jolla, CA, USA) [22]. The
cytotoxicity of the tested compounds was determined by
the MTT viability assay with exponentially growing cells
and continuous drug exposure (120 h). After drug treat-
ment cells were exposed to the MTT, a tetrazolium salt, for
4 h at 37 °C, and the formation of formazan was measured
3
by a VICTOR V microplate reader (Wallac Perkin). The
concentrations required to inhibit cell growth by 50%
compared to untreated controls were determined from the
curves plotting survival as a function of dose using the
SlideWrite program (Fig. 2). All values are means of at
least two independent experiments, each done in duplicate
(Table 4). Cisplatin (Cis-Pt) and doxotubicin (Dox) were
used as control cytostatic drugs. IC50 values determined in
the A549 cell line were 0.63 0.018 lM (Cis-Pt) and
0.008 0.0011 lM (Dox).
Fig. 2 Effect of compounds 5, 7, and 10 on A549 (a) and HCT116
human cell lines (b)
Tested compounds exhibited rather low cytotoxic
activity. Derivatives 7 and 10 inhibited the growth of the
both cell lines by 50% at concentrations greater than
100 lM. Lower values of IC50 were obtained for com-
pound 5: 69 lM (A549) and 28 lM (HCT116). However,
IC50 values (ca. 100 lM) are ten times higher than MICs
(3.1 lg cm-3) for compounds 7 and 10 and three times
Table 4 Cytotoxicity of compounds 5, 7, and 10
No.
IC50/mM
A549
HCT116
5
69 23
28 11
7
[100
ꢀ100
ꢀ100 (ca. 380)
higher for compound
5
(IC50 ca. 30 lM, MIC
10
[100 (ca. 126)
3.1 lg cm-3). Therefore the tuberculostatic activity of
those derivatives does not seem to be caused by their
cytotoxicity.
The structure of the most active compound 7 has no ability
to form hydrogen bonds or to adopt a planar structure.
Therefore, its activity has to be associated with other
structural factors. Taking into consideration the structural
In summary, the synthesized and tested compounds
exhibit promising tuberculostatic activity. Unexpectedly we
have found no correlation between the rather planar structure
of compound 6 and its activity toward M. tuberculosis.
123

Synthesis, structure, and tuberculostatic activity of dimethyl benzoylcarbonohydrazonodithioates
1141
Ph), 9.19 (brs, 1H, NH) ppm;13C NMR (DMSO-d6):
d = 14.7, 15.0, 127.2, 128.7, 129.8, 130.6, 131.3, 135.7,
160.9, 162.1 ppm; MS (?): m/z = 571 (27%,
[2M ? Na - 2H]?), 297 (100%, [M ? Na]?); MS (-):
m/z = 569 (100%, [2M ? Na - 4H]-), 273 (30%,
[M - 2H]-).
similarity of compound 7 and INH, the substituent in the
4-position could be that factor, and susceptibility to acti-
vation by catalase-peroxidase KatG could limit the
tuberculostatic activity of all the synthesized derivatives.
Experimental
Dimethyl 4-chlorobenzoylcarbonohydrazonodithioate
(3, C10H11ClN2OS2)
IR (KBr):v = 3,264; 1,664; 1,492; 1,360; 1,083; 1,003;
All materials and solvents were of analytical reagent grade.
Thin-layer chromatography was performed on Merck
Kieselgel 60F254 plates and visualized with UV. The results
of elemental analyses (% C, H, N) for all compounds
obtained were in good agreement with calculated values
within 0.3%. 1H and 13C NMR spectra in CDCl3 or
DMSO-d6 were recorded on Varian Gemini (200 MHz)
instruments. IR spectra were determined as KBr pellets of
the solids on a Satellite FT-IR spectrophotometer. Elec-
trospray MS analyses for compounds 2 and 3 were
performed on an HCT Ultra Bruker Daltonics spectrometer
operating in positive- and negative-ion modes (sheath gas
N2, temperature 300 °C, flow 7 dm3/min, pressure 10 psi
(689.48 hPa); capillary voltage in positive ion mode
?4 kV, in negative ion mode -4 kV). Compounds sam-
ples were prepared in a chloroform/methanol (1:1) mixture.
Melting points were determined on a BOETIUS apparatus.
Benzohydrazides were prepared according to known pro-
cedures, and yields and melting points were found to be
identical with those described in the literature [23–32].
1
656 cm-1; H NMR (DMSO-d6): d = 2.53 (s, 3H, SCH3),
2.78 (s, 3H, SCH3), 7.55 (d, 2H, Ph, J = 8.1 Hz), 7.83 (d,
2H, Ph, J = 8.4 Hz), 10.86 (brs, 1H, NH) ppm; 13C NMR
(DMSO-d6): d = 14.6, 15.1, 128.7, 129.7, 132.6, 136.4,
161.8, 163.7 ppm.
Dimethyl 2,4-dichlorobenzoylcarbonohydrazonodithioate
(4, C10H10Cl2N2OS2)
IR (KBr):v = 3,160; 1,643; 1,520; 1,296; 1,056;
832 cm-1
;
1H NMR (DMSO-d6): d = 2.49 (s, 3H,
SCH3), 2.53 (s, 3H, SCH3), 7.43–7.51 (m, 2H, Ph), 7.66–
7.71 (m, 1H, Ph), 10.90 (brs, 1H, NH) ppm; 13C NMR
(DMSO-d6): d = 14.7, 15.1, 127.5, 129.4, 129.9, 131.0,
132.0, 135.1, 161.3, 167.5 ppm.
Dimethyl 3,4-dichlorobenzoylcarbonohydrazonodithioate
(5, C10H10Cl2N2OS2)
IR (KBr):v = 3,148; 1,632; 1,536; 1,472; 1,296; 1,056;
1
720 cm-1; H NMR (DMSO-d6): d = 2.53 (s, 3H, SCH3),
2.54 (s, 3H, SCH3), 7.78 (d, 2H, Ph, J = 1.5 Hz), 8.03 (s,
1H, Ph), 11.0 (brs, 1H, NH) ppm; 13C NMR (DMSO-d6):
d = 14.6, 15.1, 128.0, 129.6, 131.1, 131.5, 134.2, 134.4,
160.6, 164.6 ppm.
General procedure for the preparation of dimethyl
benzoylcarbonohydrazonodithioates 1–14
Dimethyl 2-nitrobenzoylcarbonohydrazonodithioate
(6, C10H11N3O3S2)
To a suspension of the appropriate benzohydrazide
(0.03 mol) in 10 cm3 of ethanol, 2 cm3 of carbon disulfide
(0.03 mol) was added in a few portions. Then a solution of
3.7 g of potassium hydroxide (0.06 mol) in 5 cm3 of water
was added. After 15 min of stirring 4 cm3 of methyl iodide
(0.06 mol) was added dropwise. The solution was cooled
and the precipitate of potassium iodide was filtered off. The
filtrate was diluted with 50 cm3 of ice-cold water and
extracted with chloroform. Chloroform extracts were col-
lected, dried with magnesium sulfate, and evaporated. The
crude oily product was washed with dry diethyl ether, fil-
tered, and recrystallized from an appropriate solvent
(Table 1).
1
IR (KBr):v = 3,160; 1,652; 1,520; 1,376; 944 cm-1; H
NMR (CDCl3): d = 1.94 (s, 3H, SCH3), 2.50 (s, 3H,
SCH3), 7.55–7.80 (m, 3H, Ph), 8.10–8.18 (m, 1H, Ph), 9.19
(brs, 1H, NH) ppm; 13C NMR (DMSO-d6): d = 14.8, 15.1,
123.6, 129.2, 130.5, 134.1, 134.8, 148.9, 161.8, 168.1 ppm.
Dimethyl 4-benzoylcarbonohydrazonodithioate
(7, C10H11N3O3S2)
IR (KBr):v = 3,176; 3,000; 1,643; 1,600; 1,523; 1,344;
1,280; 860; 720 cm-1; 1H NMR (CDCl3): d = 2.59 (s, 6H,
2SCH3), 7.94–8.05 (m, 2H, Ph), 8.21–8.40 (m, 2H, Ph),
9.35–9.58 (brs, 1H, NH) ppm; 13C NMR (DMSO-d6):
d = 14.5, 15.1, 123.9, 129.2, 139.6, 149.3, 161.1,
164.9 ppm.
Dimethyl benzoylcarbonohydrazonodithioate (1)
Yield 90%, m.p.: 85–86 °C (Ref. [33] 85–86 °C).
Dimethyl 2-hydroxybenzoylcarbonohydrazonodithioate
(8, C10H12N2O2S2)
IR (KBr):v = 3,056; 1,632; 1,543; 1,456; 1,312; 1,232;
Dimethyl 2-chlorobenzoylcarbonohydrazonodithioate
(2, C10H11ClN2OS2)
IR (KBr):v = 3,144; 1,643; 1,552; 1,424; 1,636; 763;
;
603 cm-1 1H NMR (CDCl3): d = 2.43 (s, 3H, SCH3),
1
896; 752 cm-1; H NMR (DMSO-d6): d = 2.56 (s, 6H,
2SCH3), 6.73–7.80 (m, 4H, Ph), 9.80–10.20 (brs, 1H, NH)
2.70 (s, 3H, SCH3), 7.28–7.53 and 7.68–7.95 (2 m, 4H,
123

1142
K. Gobis et al.
ppm; 13C NMR (DMSO-d6): d = 15.0, 117.1, 117.7, 120.0,
130.9, 133.6, 151.7, 156.5, 161.0 ppm.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
Dimethyl 3-hydroxybenzoylcarbonohydrazonodithioate
(9, C10H12N2O2S2)
IR (KBr):v = 3,152; 1,643; 1,600; 1,483; 1,456; 1,296;
1,232; 832; 736 cm-1; 1H NMR (CDCl3): d = 2.55 (s, 3H,
SCH3), 2.57 (s, 3H, SCH3), 7.02–7.38 (2 m, 4H, Ph), 7.57
(s, 1H, OH), 9.46-9.61 (brs, 1H, NH) ppm; 13C NMR
(DMSO-d6): d = 14.7, 15.0, 114.6, 118.2, 118.6, 129.7,
135.2, 155.3, 157.6, 163.9 ppm.
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IR (KBr):v = 3,136; 1,643; 1,592; 1,483; 1,440; 1,280;
1
1,232; 896; 752 cm-1; H NMR (DMSO-d6): d = 2.00 (s,
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¨
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45:1898
1
1,024 cm-1; H NMR (CDCl3): d = 2.50 (s, 6H, 2SCH3),
3.80 (s, 3H, OCH3), 6.70–7.06 and 7.60–7.93 (2 m, 4H,
Ph), 9.20–9.56 (brs, 1H, NH) ppm; 13C NMR (DMSO-d6):
d = 14.7, 15.0, 55.7, 113.7, 125.9, 129.6, 162.0,
162.6 ppm.
12. Orlewska C, Foks H, Janowiec M, Zwolska Z (1995) Pharmazie
50:563
´
13. Orlewska C, Foks H, Sowinski P, Martynowski D, Olczak A,
´
Dimethyl 3,4,5-trimethoxybenzoylcarbonohydrazonodithioate
(12, C13H18N2O4S2)
IR (KBr):v = 3,176; 3,000; 1,640; 1,584; 1,532; 1,340;
Głowka ML (2001) Polish J Chem 75:1237
´
14. Głowka ML, Martynowski D, Olczak A, Orlewska C, Foks H,
Bojarska J, Szczesio M, Gołka J (2005) J Chem Cryst 35:477
1
1,232; 1,120 cm-1; H NMR (CDCl3): d = 2.58 (s, 6H,
´
15. Olczak A, Głowka ML, Gołka J, Szczesio M, Bojarska J,
Kozłowska K, Foks H, Orlewska C (2007) J Mol Struct 830:171
16. Spek AL (2003) J Appl Cryst 36:7
17. Youmans GP (1947) Am Rev Tuberc 56:376
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19. Atlas RM, Singler JW (1995) Media for clinical microbiology.
CRC, Boca Raton, p 313
20. Foks H, Buraczewska M, Manowska W, Sawlewicz J (1971)
Dissert Pharm Pharmacol 23:49
21. Greer JP, Wintrobe MM (2009) Wintrobe’s clinical hematology.
Lippincott Williams & Wilkins, Philadelphia, p 52
22. Welti M, Jaton K, Altweg M, Sahli R, Wenger A, Bille J (2003)
Diagn Microbiol Infect Dis 45:85
23. Curtius T, Struve G (1894) J Prakt Chem 50:295
24. Sah PPT (1940) Recl Trav Chim Pays-Bas 59:1029
25. Kahl R (1904) Chem Zentralbl 11:1493
2SCH3), 3.88–3.96 (m, 9H, 3OCH3), 7.07 (s, 2H, Ph), 9.36
(s, 1H, NH) ppm; 13C NMR (DMSO-d6): d = 14.6, 15.1,
56.28, 60.4, 105.2, 128.9, 140.6, 152.9, 162.0 ppm.
Dimethyl 2-(3,4-dimethoxyphenyl)acetylcarbono-
hydrazonodithioate (13, C13H18N2O3S2)
IR (KBr):v = 3,152; 1,664; 1,520; 1,264; 1,216; 1,136;
1
1,024 cm-1; H NMR (CDCl3): d = 2.47 (s, 6H, 2SCH3),
3.43–4.10 (m, 8H, 2OCH3 and CH2), 6.80 (s, 3H, Ph),
8.63–9.07 (brs, 1H, NH) ppm; 13C NMR (DMSO-d6):
d = 14.8, 15.0, 39.6, 55.8, 112.0, 113.2, 121.4, 128.6,
147.8, 148.7, 154.7, 172.5 ppm.
26. Yale HL, Losee K, Martins J, Holsing M, Perry FM, Bernstein J
(1953) J Am Chem Soc 75:1933
27. Curtius T, Trachmann R (1895) J Prakt Chem 51:168
28. Curtius T, Struve A, Radenhausen R (1895) J Prakt Chem 52:234
29. Curtius T, Melsbach H (1910) J Prakt Chem 81:536
30. Pepe R (1930) J Prakt Chem 126:241
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32. Foks H, Sawlewicz J (1964) Acta Polon Pharm 21:458
33. Ru¨fenacht K (1974) Helv Chim Acta 57:23
Dimethyl pyrazine-2-carbonylcarbonohydrazonodithioate
(14, C8H10N4OS2)
IR (KBr):v = 3,243; 1,700; 1,508; 1,392; 1,156;
1,072 cm-1
;
1H NMR (CDCl3): d = 2.55 (s, 6H,
2SCH3), 8.00, 8.57, and 9.48 (3 s, 3H, pyrazine), 10.95
(s, 1H, NH) ppm; 13C NMR (DMSO-d6): d = 15.0, 15.3,
143.9, 144.2, 148.4, 157.1, 157.7 ppm.
123