New carbodithioate derivatives: Synthesis, characterization, and in vitro antibacterial, antifungal, antitubercular, and antimalarial activity

Article abstract of DOI:10.1007/s00044-013-0472-0

A series of structurally new, 2-(5-substituted-2,3-dioxoindolin-1-yl)ethyl/ propyl 4-(3,4-dichlorophenyl)piperazine-1-carbodithioate derivatives 5a-j were designed and synthesized by conventional technique as well as ultrasound irradiation. All the new co

Full text of DOI:10.1007/s00044-013-0472-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4700–4707
DOI 10.1007/s00044-013-0472-0
ORIGINAL RESEARCH
New carbodithioate derivatives: synthesis, characterization,
and in vitro antibacterial, antifungal, antitubercular,
and antimalarial activity
•
Tarunkumar Nanjibhai Akhaja Jignesh Priyakant Raval
Received: 16 July 2012 / Accepted: 6 January 2013 / Published online: 19 January 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of structurally new, 2-(5-substituted-
2,3-dioxoindolin-1-yl)ethyl/propyl 4-(3,4-dichlorophenyl)
piperazine-1-carbodithioate derivatives 5a–j were designed
and synthesized by conventional technique as well as
ultrasound irradiation. All the new compounds were char-
acterized by spectral and elemental analyses. Furthermore,
they were evaluated for their in vitro antibacterial, anti-
fungal, antitubercular, and antimalarial activities. The
results indicated that some of the synthesized compounds
posses promising antimicrobial activity against some gram-
positive and gram-negative bacteria. Compounds 5b, 5d,
and 5e displayed the highest inhibition (99 %) in the range
of 3.10–6.25 lg/ml against Mycobacterium tuberculosis
H37 Rv, while compounds 5b–g displayed promising anti-
malarial activity in the range of 0.043–0.092 lg/mL against
Plasmodium falciparum 3D7. Thus, these molecules can
provide prospective leads in chemotherapy against tuber-
culosis and malaria.
Introduction
Sulfur-containing heterocycles are undoubtedly one of the
most important targets in organic as well as medicinal
chemistry. They are not only widely distributed in natural
products but also found to be useful as pharmaceutical
agents. Structurally, dithiocarbamates (DTC) (Thorn and
Ludwig, 1962) are examples of such heterocyclic system
which is found to have interesting chemistry and wide
utility. They have received considerable interest because
they are ubiquitously found in a variety of biologically
active compounds (Erian and Sherif, 1999; Wood and
Gardner, 1941; Bowden and Chana, 1990; Beji et al., 1999;
Goel et al., 2002). They are proved to be important for its
applications in pesticides, fungicides, vulcanization of
rubber (Marinovich et al., 2001; Weissmahr et al., 1998;
Len et al., 1996; Bergendorff and Hansson, 2002;
Halimehjani et al., 2010), as linkers in solid-phase organic
synthesis (Morf et al., 2006; Mcclain and Hsieh, 2004;
Dunn, 1989), radical precursors (Crich and Quintero, 1989;
Zard, 1997; Barton, 1992), ionic liquids (Zhang et al.,
2005), and quantam dots (Wang et al., 2008). Besides
antibacterial (Ates et al., 1995; Gu¨nay et al., 1999;
Farghaly et al., 1999; Xu et al., 2002; Ozkirimli et al.,
2005) and antifungal activity (Gu¨nay et al., 1999; Scho-
nenberger et al, 1972; Capan, 1993; Chourasia and
Devendra, 1999; Imamura et al., 2001), some of its
derivatives are found to display promising anticancer
(brassinin) (Mehta et al., 1995; Cao et al., 2005; Gu¨zel and
Salman, 2006; Sauna et al., 2005), antimycobacterial
activity (OCT-313) (Horita et al., 2009), also has strong
inhibiting ability for replication of human rhinoviruses,
coxsackievirus myocarditis (Cvek and Dvorak, 2007; Chen
and Dou, 2008; Huang et al., 2009) Inhibitor of nuclear
factor kB in the tumor tissue and induce apoptosis in
Keywords Isatin Á 2,3-Dioxoindoline Á Carbodithioate Á
Ultrasound Á Antitubercular Á Antimalarial activities
T. N. Akhaja (&) Á J. P. Raval
Department of Pharmaceutical Chemistry, Ashok & Rita Patel
Institute of Integrated Study and Research in Biotechnology
and Allied Sciences (ARIBAS), New Vallabh
Vidyanagar 388121, Gujarat, India
e-mail: tarun.pch@gmail.com
J. P. Raval
e-mail: drjpraval@gmail.com
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Med Chem Res (2013) 22:4700–4707
4701
T-Cells (PDTC) (Cvek and Dvorak, 2007; Chen and Dou,
2008; Huang et al., 2009; Fernandez et al., 1999).
Green aspect over the organic synthesis is a noticeable
approach in the current situation and ultrasound is one of
the favorable aspect and technique to overcome onerous
condition of classical and conventional methods (Cravotto
and Cintas, 2006). Various tedious and useful synthesis of
heterocyclic compounds are synthesized an effortlessly
way using ultrasound with more yield and less time (Fu and
Shao, 2011; Liu et al., 2011; Bejan et al., 2009; Pizzuti
et al., 2010).
here in our synthetic protocol to obtain high yield and less
reaction time and very trace amount of undesired product
formation and studied data are mentioned in Table 1.
All Reaction progresses were monitored by TLC. The
structure of all the synthesized compounds was established
by IR, (1H and 13C) NMR, elemental analysis, and Mass
spectral analysis. For example, 1H-NMR spectra of 5a
exhibits characteristic multiplet for aromatic protons at
7.12–7.79 d ppm along with aliphatic multiplet at 2.15–
3.89 d ppm which was to be in agreement with proposed
structure. The 13C-NMR of 5a showed desired aromatic
and aliphatic carbons including peaks at 162.43, 171.90
(C=O), and 191.51 (C=S) d ppm. Elemental analysis and
molecular ion peck at 481.6 gives the conformation of
molecular formula and successfully proves the structure of
5a.
As part of a continuing program (Akhaja and Raval,
2011; Akhaja and Raval, 2012b; Akhaja and Raval, 2012a)
on the development of new chemical entity (NCE) for
treatment of tuberculosis and malaria, we have synthesized
and evaluated novel dithiocarbamate derivatives to obtain a
new and more potent antituberculosis and antimalarial
agent.
Biologic activity
Antibacterial and antifungal activity
Results and discussion
The antibacterial screening results are summarized in
Table 2. The MICs of synthesized compounds were carried
out by broth Microdilution method (Rattan, 2000). DMSO
was used as diluents to get desired concentration of drugs
to test upon standard bacterial strains. Serial dilutions were
prepared in primary and secondary screening. The MIC of
the control organism was read to check the accuracy of the
drug concentrations. The lowest concentration inhibiting
growth of the organism was recorded as MIC. Each syn-
thesized drug was diluted obtaining 2000 lg/ml concen-
tration, as a stock solution. In primary screening 500, 250,
and 125 lg/ml concentrations of the synthesized drugs
were taken. The active synthesized drugs found in this
primary screening were further tested in a second set of
dilution against all microorganisms. The drugs found active
in primary screening were similarly diluted to obtain 100,
50, 25, 12.5, 6.250, 3.125, and 1.5625 lg/ml concentra-
tions. The highest dilution showing at least 99 % inhibition
is taken as MIC (Table 2). From in vitro antibacterial and
antifungal activity data, it is confirmed that compounds 5b,
5d, 5e, and 6 exhibited excellent activity against all tested
microbial and fungal strains, while compounds 5g, 5i, and
5j displayed comparable activity as compared to Ampi-
cillin. Antimicrobial effect may be due to reaction with
HS-groups of physiologically important enzymes by
transferring the alkyl group of the dithioester to the HS-
function of the enzyme (Schonenberger et al., 1972).
Chemistry
Detailed synthetic pathways to title compounds 5a–j are
depicted in Scheme 1. 1-(2-3-Dichlorophenyl)piperizine 1
on treatment with sodium hydroxide and carbon disulfide
according to the reported procedure (Feng et al., 2010)
gives sodium 4-(3,4-dichlorophenyl)piperazine-1-carbo-
dithioate 2 in a good yield. Thereafter, alkylation of
5-substituted isatins 3a–e in the presence of dry K2CO3
using 1,2-dibromoethane/1,3-dibromopropane in dimethyl
formamide was carried out to give 5-substituted-N-
(2-bromoethyl/propyl)isatin 4a–j in a yield of 55–76 %
according to reported procedure (Nath et al., 2009). And
finally, condensation of 4a–j and 2 was done using ethanol
as solvent at reflux temperature to get target compounds
5a–j (Gu¨rsoy et al., 1996). Fortunately, we also observed
the formation of dimer of 2, that is, compound 6 in trace
amount along with each final product, it was separated and
characterized. All spectroscopic and analytical data is
given in experimental part.
To improve the yield and the reaction time of conven-
tional procedure, acoustic cavitation in liquid solution
plays lead role via sonication in heterogeneous/homo-
geneous system reported in many literatures (Mason and
Peters, 2002). Under sonication study, we found some
interesting results, compound 5a (entry 1; Table 1) which
was yielded 83 %, 7 h in conventional method while son-
ication improved condensation rate of 4a and 2 in 128 min
and yield 94 % and undesired product formation was
decreased and very trace amount of 6 obtained in each final
step under sonication. Thus, sonication technique applied
Antitubercular activity
From literature survey (Ates et al., 1995; Gu¨nay et al.,
1999; Farghaly et al., 1999; Xu et al., 2002; Ozkirimli
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Med Chem Res (2013) 22:4700–4707
Scheme 1 General method for synthesis of new carbodithioates
the screening of antitubercular activity. Thus, all the newly
synthesized compounds were evaluated in vitro, to study its
activity against Mycobacterium tuberculosis H37 Rv. The
primary screening was conducted at concentration 6.25 lg/
mL in BACTEC MGIT system (Anargyros et al., 1990).
Compounds demonstrating 99 % inhibition in the primary
screen were described as most potent compounds. The
preliminary results observed, indicated that compounds 5b,
5d, 5e, 5g, 5i, 5j, and 6 showed highest inhibition (99 %) at
a constant concentration level (6.25 lg/ml). This primary
bioassay results have driven us to examine the real potency
(MIC) of the title compounds against M. tuberculosis H37
Rv. Thus, secondary biologic screening was performed by
Lowenstein-Jensen MIC method (Isenberg, 1992; Akhaja
and Raval, 2012a) and it is worthwhile to note that com-
pound 5b, 5d, and 5e displayed inhibition completely
(99 %) at the MIC of (3.10–6.25 lg/ml). All the remain-
ing compounds displayed moderate to good activity within
87–98 % inhibition at the concentration of (100–250 lg/ml).
Also, dimer (compound 6) formed during the reaction as
Table 1 Studied data of synthesis 5a–j
Entry Conventional yielda Time (h) Sonication yielda Time (min)
5a
5b
5c
5d
5e
5f
5g
5h
5i
83
77
86
80
76
81
78
79
76
87
6.1
6.4
7.5
6.5
7.3
8.2
6.4
7.3
8.0
7.5
94
89
92
91
88
90
86
92
84
93
128
137
112
141
133
129
121
125
120
116
5j
a
Yield after purification, mole ratio is same in conventional and
sonication method
et al., 2005; Chen and Dou, 2008; Huang et al., 2009;
Fernandez et al., 1999) and the encouraging results from
the antibacterial, antifungal studies, impelled us to go for
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Table 2 In vitro antibacterial and antifungal activity of compounds, 5a–j and 6
Entry
N
R
Minimal inhibition concentration (MICs, lg/mL)
Antibacterial activity
Antifungal activity
Gram -ve organism
Gram ?ve organism
E.c.
P.a
Kl.pn
S.a.
S.py.
B.s.
C.a
A.n
A.c
5a
2
2
2
2
2
3
3
3
3
3
–
H
500
62.5
500
100
100
500
250
200
200
100
100
100
B25
B10
–
100
100
250
62.5
62.5
200
250
250
100
200
100
100
B25
B10
–
500
62.5
250
250
100
500
100
500
250
100
62.5
100
B25
B10
–
250
100
500
250
62.5
500
500
500
200
500
200
250
B25
B10
–
100
62.5
250
62.5
100
500
250
500
100
250
62.5
100
B50
B10
–
200
200
100
250
100
100
500
500
250
250
100
100
B50
B10
–
[1000
100
[1000
200
100
[1000
500
500
250
500
200
–
500
100
[1000
200
100
500
200
[1000
100
250
100
–
500
100
500
500
100
[1000
250
[1000
500
200
100
–
5b
F
5c
Cl
Br
NO2
H
5d
5e
5f
5g
F
5h
Cl
Br
NO2
–
5i
5j
6
Ampicillin
Ciprofloxacin
Norfloxacin
Nystatin
–
–
–
–
–
–
100
500
100
100
100
100
Greseofulvin
–
–
–
–
–
–
E.c. E. coli (MTCC-443), P.a. P. aeruginosa (MTCC-1688), Kl.pn. Kl. pneumoniae (MTCC-109), S.a. S. aureus (MTCC-96), S.py. S. pyogenus
(MTCC-442), B.s. B. subtilis (MTCC-441), C.a. C. Albicans (MTCC 227), A.n. A. Niger (MTCC 282), A.c. A. Clavatus (MTCC 1323)
Table 3 In vitro antitubercular activity of compounds, 5a–j and 6
byproduct displayed inhibition up to 98 % (6.25 lg/ml).
The observed MICs of compounds are presented in
against M. tuberculosis H37Rv (MTCC-200)
Entry
BACTEC MGIT method L.J. MIC method
Table 3. Isoniazid, Refampin, Ethambutol, and Pyrazina-
mide were used as the reference drug. Concurrent with the
determination of MICs, compounds were also tested for
cytotoxicity (IC50) in VERO at concentration equal to and
greater than the MIC for M. tuberculosis H37Rv after 72 h
of exposure, viability is assessed on the basis of cellular
conversion of MTT into a formazan product by the Pro-
mega Cell Titer 96 Non-radioactive Cell proliferation assay
(Gundersen et al., 2002). All the active compounds were
found to be non-toxic.
MIC values
(lg/mL)
%
MIC values
%
inhibition
inhibition (lg/mL)
5a
[6.25
6.25
92
99
98
99
99
96
99
91
99
99
99
99
99
99
99
250
3.10
100
6.15
6.25
200
6.25
250
100
100
6.25
ND
ND
ND
ND
87
5b
99
5c
[6.25
6.25
96
5d
99
5e
6.25
99
5f
[6.25
6.25
97
5g
98
5h
[6.25
6.25
92
Antimalarial activity
5i
94
5j
6.25
96
All the synthesized compounds were also evaluated in vitro
for antimalarial assay against Plasmodium falciparum 3D7
chloroquine-sensitive strain (Microcare laboratory and
TRC, Surat, Gujarat, India), in 96-well microtitre plates
according to the microassay protocol of Rieckmann and co-
workers with minor modifications (Rieckmann et al., 1978;
Desjardins, 1984; Trager and Jensen, 1976; Lambros and
Vanderberg, 1979). The test concentration which inhibited
the complete maturation into schizonts was recorded as the
minimum inhibitory concentrations (MIC). Chloroquine
was used as the reference drug. Observations of the in vitro
6
6.25
98
Isoniazid
Refampicin
Ethambutol
0.20
ND
ND
ND
ND
0.25
3.12
Pyrazinamide 6.25
ND not determined
antimalarial screening are presented in the Table 4.
Compounds 5b–g have remarkable improvement in
antimalarial potency with MIC value in the range of
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Activity Relationships (SAR), Multi-drug resistant (MDR)
TB, and in vivo antimalarial activity are in progress in our
laboratory.
Table 4 In vitro antimalarial activity of compounds, 5a–j and 6
against Plasmodium falciparum 3D7 chloroquine-sensitive strain
Entry
aMIC (lg/mL)
bLog P
5a
0.250
0.043
0.061
0.052
0.072
0.089
0.092
0.200
0.250
0.500
0.250
0.125
4.13 0.64
4.38 0.70
4.93 0.65
5.10 0.70
4.04 0.65
4.35 0.63
4.60 0.68
5.14 0.64
5.32 0.69
4.26 0.64
7.28 0.60
4.69 0.32
5b
Experimental section
5c
5d
General
5e
5f
The sonication reaction was carried out in Apl Digital
Ultrasound Cleaner CD-4820 (frequency 60 Hz and output
power 170 W, with digital timer, heater, and tank size
340 9 255 9 225 mm, capacity 4500 ml). All the melting
points were taken in scientific melting point apparatus and
are uncorrected. Silica gel-G coated aluminums plates
(Merck) were used to check purity and completion of the
reaction and spots were visualized by exposing the dry
plates in iodine vapors. Mass spectra of intermediates and
final products were scanned on a Shimadzu LCMS 2010
5g
5h
5i
5j
6
Chloroquine
a
MIC minimum inhibiting concentration for the development of ring
stage parasite into the schizont stage during 40-h incubation
b
Theoretic values of log P were calculated by commercially avail-
able ChemDraw program
1
spectrometer. H and 13C NMR spectra on a Bruker’s WM
400 FT MHz NMR instrument using DMSO-d6 as solvent
and TMS as internal reference (chemical shifts in d ppm).
The elemental analysis (C, H, and N) of compounds was
performed on Carlo Erba—1108 elemental analyzer.
0.043–0.092 lg/mL. The presence of flouro (5c,
MIC = 0.043 lg/mL) and the presence of bromo (5d,
MIC = 0.052 lg/mL) displayed excellent antimalarial
potency. Also, the increment in alkyl chain, i.e., com-
pounds 5a–e (where n = 2) to compounds 5f–j (where
n = 3), it was found that compounds 5a–e are found to be
more active and potent compared to compound 5f–j, and the
order of activity with respect to substituents can be given as
F [ Br [ NO2 C Cl [ H. Reason behind this is not well
understood, but we can say that the presence of these electron
withdrawing groups may have effect on variety of properties,
viz., binding interactions, steric, electronic, metabolic sta-
bility, etc. (Wermuth, 2003; Hagmann, 2008). Also, hydro-
gen bonding capacity with desired lipophilicity or with
favorable stearic hinderance plays important role for its
Synthesis of sodium 4-(3,4-dichlorophenyl)piperazine-1-
carbodithioate 2
Solution of sodium hydroxide (0.05 mol) in water
(15 ml) was added to the 1-(2-3-dichlorophenyl)piperizine
1 (0.04 mol) and allowed to stir for 30 min. Carbon
disulfide (0.47 mol) was added dropwise. After the for-
mation of solid mass, ethanol (50 ml) was added to dis-
solve solid mass and stirred more for 5h. Progress of
reaction was monitored by TLC. After completion of the
reaction, excess ethanol was distilled off, dried, poured on
water, filtered, dried, and purification was done by crys-
tallization in ethyl acetate to obtain pure product sodium
4-(3,4-dichlorophenyl)piperazine-1-carbodithioate 2, white
crystalline solid, yield 75 %.
¨ ¨
pharmacological activity (Malkia et al., 2004).
Conclusion
2-(5-Substituted-2,3-dioxoindolin-1-yl)alkyl-4-(3,4-dichlo-
rophenyl)piperazine-1-carbodithioate derivatives were syn-
thesized and characterized for their structure elucidation.
Various chemical and spectral data supported the structures
of newly synthesized compounds. Also, some of the
compounds showed significant antibacterial, antifungal,
antitubercular, and antimalarial activity. Thus, considering
the promising pharmacological profile of the newly syn-
thesized compounds, this present library model can be used
to design the new ligand of this class for their antituber-
cular, antimalarial, and antimicrobial activity. Further
studies to acquire more information about Structure
General procedure of synthesis of 5-substituted-N-(2-
bromoethyl/propyl)isatin 4a–j
Appropriate isatin derivatives 3a–e (0.05 mol) is dissolved
in DMF (20 ml) and dibromoethane (0.05 mol)/dibromo-
propane (0.05 mol) was added dropwise to the reaction
mass, followed by addition of dry potassium carbonate
(0.08 mol). Allowed to stir overnight at RT. Progress of
reaction was monitored by TLC and after completion.
Reaction mass was poured into the ice-cold water, solid
residue fall out. This was filtered, washed, dried, and
recrystalized using ethanol to obtain pure product 4a–j.
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General procedure for the synthesis of 2-(5-substituted-2,
3-dioxoindolin-1-yl)ethyl/propyl 4-(3,4-
dichlorophenyl)piperazine-1-carbodithioate derivatives
5a–j
145.40, 154.36 (aromatic), 162.50, 171.34 (C=O), 191.55
(C=S). Chemical formula: C21H18Cl3N3O2S2; Elemental
analysis: calculated C, 48.99; H, 3.52; N, 8.16, found C,
48.68; H, 3.50; N, 8.34 %.
In the round bottom flask, a mixture of sodium 4-(3,
4-dichlorophenyl)piperazine-1-carbodithioate 2 (0.069 mol)
and 4a–j (0.069 mol) was dissolved into the ethanol(25 ml)
and allowed to reflux for 6–8 h. Solid product obtained as
precipitate in reaction mass was checked by TLC and con-
firmed the formation of compound 5a–j. In work up process,
excess ethanol was removed by distillation, solid residue was
treated with cold water, filtered, dried, and purification was
achieved by column chromatography using 40 % ethyl
acetate in hexane to obtained pure compound 5a–j.
Unfortunately, we found and isolated new spot on TLC,
which was identified as dimer of sodium 4-(3,4-dichloro-
phenyl)piperazine-1-carbodithioate 2. This was isolated by
column chromatography in trace amount and characterized
spectroscopically.
2-(5-Bromo-2,3-dioxoindolin-1-yl)ethyl 4-(3,4-dichlorophenyl)
piperazine-1-carbodithioate 5d Brown solid, yield 80 %,
mp 179–180 °C. MS m/s: 560.1 [M?]. 1H NMR
(400 MHz, DMSO, d ppm): 2.20–4.08 (m, 12H, overlap-
ping ethyl and piperazine protons), 7.46–8.28 (m, 6H, Ar–H).
13C NMR (100 MHz, DMSO, d ppm): 33.62, 49.21, 52.94
(aliphatic), 114.23, 115.81, 119.48, 121.78, 129.53, 132.65,
133.62, 145.37, 153.23 (aromatic), 162.74, 172.46 (C=O),
191.73 (C=S). Chemical formula: C21H18BrCl2N3O2S2;
Elemental analysis: calculated C, 45.09; H, 3.24; N, 7.51,
found C, 45.13; H, 2.96; N, 7.39 %.
2-(5-Nitro-2,3-dioxoindolin-1-yl)ethyl 4-(3,4-dichlorophenyl)
piperazine-1-carbodithioate 5e Dark yellow solid, yield
1
76 %, mp 276–277 °C. MS m/s: 526.4 [M?]. H NMR
(400 MHz, DMSO, d ppm): 2.02–3.58 (m, 12H, overlap-
ping ethyl and piperazine protons), 7.35–8.16 (m, 6H,
Ar–H). 13C NMR (100 MHz, DMSO, d ppm): 34.13, 47.48,
53.35 (aliphatic), 114.28, 115.70, 118.54, 119.01, 129.25,
131.40, 132.94, 147.33, 150.15 (aromatic), 162.64, 173.87
(C=O), 193.62 (C=S). Chemical formula: C21H18Cl2N4O4S2;
Elemental analysis: calculated C, 48.00; H, 3.45; N, 10.66,
found C, 48.13; H, 3.65; N, 10.28 %.
2-(2,3-Dioxoindolin-1-yl)ethyl 4-(3,4-dichlorophenyl)piper-
azine-1-carbodithioate 5a White solid, yield 83 %, mp
1
160–161 °C. MS m/s: 481.6 [M?]. H NMR (400 MHz,
DMSO, d ppm): 2.15–3.89 (m, 12H, overlapping ethyl and
piperazine protons), 7.12–7.79 (m, 7H, Ar–H). 13C NMR
(100 MHz, DMSO, d ppm): 32.67, 48.34, 52.49 (aliphatic),
111.78, 113.34, 115.98, 119.49, 128.31, 130.92, 132.47,
146.97, 150.36 (aromatic), 162.43, 171.90 (C=O), 191.51
(C=S). Chemical formula: C21H19Cl2N3O2S2; Elemental
analysis: calculated C, 52.50; H, 3.99; N, 8.75, found C,
52.43; H, 3.76; N, 8.58 %.
3-(2,3-Dioxoindolin-1-yl)propyl 4-(3,4-dichlorophenyl)piper-
azine-1-carbodithioate 5f Yellow solid, yield 83 %, mp
195–196 °C. MS m/s: 495.2 [M?]. 1H NMR (400 MHz,
DMSO, d ppm): 2.21–4.29 (m, 14H, overlapping propyl and
piperazine protons), 7.29–8.21 (m, 7H, Ar–H). 13C NMR
(100 MHz, DMSO, d ppm): 25.56, 32.45, 41.59, 50.21, 52.87
(aliphatic), 113.85, 114.52, 116.36, 119.43, 129.39, 132.78,
133.67, 144.15, 145.31 (aromatic), 161.37, 171.59 (C=O),
194.06 (C=S). Chemical formula: C22H21Cl2N3O2S2; Ele-
mental analysis: calculated C, 53.44; H, 4.28; N, 8.50, found
C, 53.36; H, 4.01; N, 8.27 %.
2-(5-Fluoro-2,3-dioxoindolin-1-yl)ethyl 4-(3,4-dichlorophenyl)
piperazine-1-carbodithioate 5b Gray solid, yield 77 %, mp
1
174–175 °C. MS m/s: 499.4 [M?]. H NMR (400 MHz,
DMSO, d ppm): 2.31–3.94 (m, 12H, overlapping ethyl and
piperazine protons), 7.04–7.84 (m, 6H, Ar–H). 13C NMR
(100 MHz, DMSO, d ppm): 33.27, 49.46, 53.19 (aliphatic),
112.98, 113.29, 116.62, 118.53, 128.31, 131.46, 132.61,
146.71, 149.03 (aromatic), 163.12, 172.43 (C=O), 192.75
(C=S). Chemical formula: C21H18Cl2FN3O2S2; Elemental
analysis: calculated C, 50.60; H, 3.64; N, 8.43, found C,
50.68; H, 3.51; N, 8.28 %.
2-(5-Fluoro-2,3-dioxoindolin-1-yl)propyl 4-(3,4-dichlorophenyl)
piperazine-1-carbodithioate 5g Yellowish solid, yield 78 %,
mp 204–205 °C. MS m/s: 513.7 [M?]. 1H NMR (400 MHz,
DMSO, d ppm): 2.17–4.12 (m, 14H, overlapping propyl and
piperazine protons), 7.39–8.45 (m, 6H, Ar–H). 13C NMR
(100 MHz, DMSO, d ppm): 26.18, 32.58, 40.72, 51.31,
53.68 (aliphatic), 115.10, 116.49, 119.41, 128.71, 131.93,
136.51, 137.36, 147.02, 151.76 (aromatic), 162.70, 173.21
(C=O), 191.73 (C=S). Chemical formula: C22H20Cl2FN3
O2S2; Elemental analysis: calculated C, 51.56; H, 3.93; N,
8.20, found C, 51.37; H, 3.78; N, 8.39 %.
2-(5-Chloro-2,3-dioxoindolin-1-yl)ethyl 4-(3,4-dichlorophenyl)
piperazine-1-carbodithioate 5c Cream solid, yield 86 %,
mp 256–257 °C. MS m/s: 516.1 [M?]. 1H NMR (400 MHz,
DMSO, d ppm): 2.28–4.28 (m, 12H, overlapping ethyl and
piperazine protons), 7.21–7.87 (m, 6H, Ar–H). 13C NMR
(100 MHz, DMSO, d ppm): 32.33, 48.67, 52.47 (aliphatic),
114.65, 116.77, 119.41, 121.30, 130.15, 134.03, 136.72,
123

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Med Chem Res (2013) 22:4700–4707
2-(5-Bromo-2,3-dioxoindolin-1-yl)propyl 4-(3,4-dichloro-
phenyl)piperazine-1-carbodithioate 5h Dark organge
solid, yield 79 %, mp 177–178 °C. MS m/s: 574.56 [M?].
1H NMR (400 MHz, DMSO, d ppm): 2.27–4.35 (m, 14H,
overlapping propyl and piperazine protons), 7.26–8.17 (m,
6H, Ar–H). 13C NMR (100 MHz, DMSO, d ppm): 25.56,
32.45, 41.59, 50.21, 52.87 (aliphatic), 112.37, 113.36,
117.84, 119.62, 129.52, 132.57, 133.82, 145.92, 148.68
(aromatic), 162.58, 172.82 (C=O), 192.27 (C=S). Chemical
formula: C22H20BrCl2N3O2S2; Elemental analysis: calcu-
lated C, 46.09; H, 3.52; N, 7.33, found C, 45.86; H, 3.31;
N, 7.07 %.
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