Structural, Hirshfeld surface and in?vitro cytotoxicity evaluation of five new N-aryl-N’-alkoxycarbonyl thiocarbamide derivatives

Article abstract of DOI:10.1080/10426507.2020.1756809

Five new compounds, N-(2, 4-dichlorophenyl)-N’-(methoxycarbonyl) thiocarbamide (1), N-(2, 4-dichlorophenyl)-N’-(ethoxycarbonyl) thiocarbamide (2), N-(2, 4-dichlorophenyl)-N’-(2, 2, 2-trichloroethoxycarbonyl) thiocarbamide (3), N-(2,4-dichlrophenyl)-N’-(pentoxycarbonyl) thiocarbamide (4) and N-(4-nitrophenyl)-N’-(pentoxycarbonyl) thiocarbamide (5), have been synthesized by the reaction of various alkoxy chloroformates with 2, 4-dichloroaniline/4-nitroaniline.The molecular structures of the compounds were elucidated by using spectroscopic methods (FT-IR, ¹H and ¹³C NMR) and single-crystal X-ray structure analysis of compounds 2 and 5. Antiperiplanar orientation of C = O and C = S group across C–N bonds of thiocarbamide core may be due to the presence of intramolecular (N–H···O–C) hydrogen bond in the crystal structure of both the compounds. The presence of intermolecular interactions (C–H···S, C–H···O and N–H···S) in the molecular structure of the compounds has been studied in detail using Hirshfeld surfaces and their associated two-dimensional fingerprint plots. In vitro cytotoxicity screening of the synthesized compounds evaluated on a panel of seven human cancer cell lines (cervical carcinoma (2008, C13*), colorectal (HT29 and HCT116) and ovarian carcinoma (A2780, A2780/CP and IGROV-1)) demonstrated significant inhibitory properties.

Full text of DOI:10.1080/10426507.2020.1756809

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Structural, Hirshfeld surface and in vitro
cytotoxicity evaluation of five new N-aryl-
N’-alkoxycarbonyl thiocarbamide derivatives
Sunil K. Pandey, Seema Pratap, Sunil K. Rai & Gaetano Marverti
To cite this article: Sunil K. Pandey, Seema Pratap, Sunil K. Rai & Gaetano Marverti (2020):
Structural, Hirshfeld surface and in vitro cytotoxicity evaluation of five new N-aryl-N’-alkoxycarbonyl
thiocarbamide derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2020.1756809
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2020.1756809
Structural, Hirshfeld surface and in vitro cytotoxicity evaluation of five new
N-aryl-N’-alkoxycarbonyl thiocarbamide derivatives
Sunil K. Pandeya , Seema Pratapa , Sunil K. Raib , and Gaetano Marvertic
b
aDepartment of Chemistry (M.M.V), Banaras Hindu University, Varanasi, India; Organic Chemistry Division, CSIR-National Chemical
c
Laboratory (NCL), Pune, India; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia,
Modena, Italy
ABSTRACT
ARTICLE HISTORY
Received 27 December 2019
Accepted 14 April 2020
Five new compounds, N-(2, 4-dichlorophenyl)-N’-(methoxycarbonyl) thiocarbamide (1), N-(2, 4-
dichlorophenyl)-N’-(ethoxycarbonyl) thiocarbamide (2), N-(2, 4-dichlorophenyl)-N’-(2, 2, 2-trichloroe-
thoxycarbonyl) thiocarbamide (3), N-(2,4-dichlrophenyl)-N’-(pentoxycarbonyl) thiocarbamide (4)
and N-(4-nitrophenyl)-N’-(pentoxycarbonyl) thiocarbamide (5), have been synthesized by the reac-
tion of various alkoxy chloroformates with 2, 4-dichloroaniline/4-nitroaniline.The molecular struc-
KEYWORDS
Thiocarbamide; X-ray crystal
structure determination;
in vitro cytotoxicity;
1
tures of the compounds were elucidated by using spectroscopic methods (FT-IR, H and 13C NMR)
and single-crystal X-ray structure analysis of compounds 2 and 5. Antiperiplanar orientation of
C ¼ O and C ¼ S group across C–N bonds of thiocarbamide core may be due to the presence of
intramolecular (N–HꢀꢀꢀO–C) hydrogen bond in the crystal structure of both the compounds. The
presence of intermolecular interactions (C–HꢀꢀꢀS, C–HꢀꢀꢀO and N–HꢀꢀꢀS) in the molecular structure of
the compounds has been studied in detail using Hirshfeld surfaces and their associated two-
dimensional fingerprint plots. In vitro cytotoxicity screening of the synthesized compounds eval-
uated on a panel of seven human cancer cell lines (cervical carcinoma (2008, C13 ), colorectal
(HT29 and HCT116) and ovarian carcinoma (A2780, A2780/CP and IGROV-1)) demonstrated signifi-
cant inhibitory properties.
Hirshfeld surface analysis
ꢁ
GRAPHICAL ABSTRACT
Introduction
comparison, the anticancer properties of thiocarbamide
derivatives have not much been explored though some of
them have been reported to possess potent antitumor activ-
ity against several human cancer cell lines.[4,9–13] Few thio-
carbamide derivatives bearing alkyl/acyl/aroyl moieties as
substituents on the nitrogen atoms of the thiocarbamide
core have been well recognized for their anticancer activ-
ities.[15–22] Much effort has therefore been devoted for syn-
thesizing new thiocarbamide compounds by structural
variations and studying their cytotoxic properties.
N, N’-disubstituted thiocarbamide derivatives have gained
significant importance during recent decades due to their
fascinating coordination behavior and a long range of indus-
trial, analytical and medicinal applications.[1–5] These com-
pounds, bearing variable donor sites such as oxygen, sulfur
and nitrogen atoms in their structural framework, offer the
opportunity to design coordination complexes having differ-
ent coordination modes with heavy transition metal
ions.[6–8] The pharmacological importance of these com-
pounds is manifested by their use as herbicidal, fungicidal,
bactericidal, insecticidal, antithyroidal and plant growth
regulatory agents.[9–13] They have also been patented as anti-
diabetic, antiarthritic and anticoagulant agents for the treat-
Moreover, N, N0-disubstituted thiocarbamides have also
occupied a dominant position as precursors for the synthesis of
heterocyclic and organosulfur products,[1–3] as a catalyst in the
oxidation of alcohols,[6,7] as anion and cation sensors,[23,24] as
ment of cognitive problems and prostate disorders.[14] In liquid crystal materials,[3,5] as effective corrosion inhibitors,[25]
CONTACT Seema Pratap
drseemapratap@gmail.com
Department of Chemistry (M.M.V), Banaras Hindu University, Varanasi 221005, UP, India.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2020.1756809.
ß 2020 Taylor & Francis Group, LLC

2
S. K. PANDEY ET AL.
NMR spectra
In the NMR spectra of the compounds in DMSO-d6, two
conspicuous singlets observed at ꢂ12.20 and ꢂ11.58 ppm
can be assigned to intramolecular hydrogen-bonded thioa-
mide (C ¼ OꢀꢀꢀH–N) and intermolecular hydrogen-bonded
amide (with DMSO-d6) hydrogens, respectively. The latter
peak appears at ꢂ8.50 ppm when the spectrum is recorded
in CDCl3. The resonances observed between 7.32 and
8.34 ppm correspond to aromatic protons. In the spectra of
compounds 1, 2, 4 and 5, the methyl protons were observed
at 3.72, 1.23, 0.93 and 0.92 ppm, respectively.[6–8] The 13C
NMR spectra of the compounds displayed the carbon reso-
nances present in –CONH and –CSNH groups at 153–156
and 178–181 ppm respectively.[12,36] The signals due to aro-
matic and aliphatic carbon atoms appear around 120–140
and 74.6–13.2 ppm, respectively.[12–15]
Scheme 1. Synthetic route to new methoxy/ethoxy/trichloroethoxy/pentoxy
carbonyl thiocarbamides (1–5).
as collectors in froth flotation processes,[26,27] as catalysts in the
palladium-catalyzed Suzuki and Heck reactions,[28–30] as pre-
cursors for the synthesis of metal sulfide nanoparticles/nano-
crystals,[31,32] as nonlinear optical materials in electronic
industries[33,34] and in preconcentration and separation of plat-
inum group metals.[3,20] Due to the nonlinear optical properties,
single crystals of substituted thiocarbamides are being exten-
Crystal structure description
Crystal and structure refinement data, bond lengths and
bond angles and selected hydrogen bonds of compounds 2
and 5 are gathered in Tables 1–3, respectively. The crystal
structure, unit cell diagram and packing pattern of both the
sively employed in the electronic industry as polarization filters, compounds are depicted in Figures 1a,b and 2a,b, respect-
electronic light shutters, electronic modulators, and as compo- ively.[6–9] Compounds 2 and 5 crystallize in a monoclinic
nents in electro-optic and electro-acoustic devices.[21,35]
crystal system with the space groups P21/c and C2/c,
With the aim to develop better antitumor compounds respectively (Table 1). C ¼ O and C ¼ S bond lengths show
typical double-bond characteristics, whereas the C–N bond
lengths are shorter than the normal C–N single-bond length
of about 1.48 Å.[15–23] The shortening of these C–N bonds
reveals the effect of resonance in this part of the molecule.
All the bond lengths and bond angles are consistent with
the related substituted thiocarbamides.[11,12]
than the ones reported by us previously, herein, we report
the synthesis and anticancer properties of five new N, N0-
disubstituted thiocarbamides.
Result and discussion
Crystal structures showed
a
strong intramolecular
Synthesis and characterization
N–Hꢀ ꢀ ꢀO contact with Hꢀ ꢀ ꢀO distance 1.99 Å in compound
2 and 1.90 Å in compound 5 (Table 3). These intramolecular
interactions stabilized the molecular conformation in such a
way that carbonyl and thiocarbonyl groups are oriented in
an opposite direction. In the crystal packing of both the
compounds, it was found that two neighboring molecules
formed a cyclic dimer of graph set R22ð8Þ utilizing the syn
S ¼ C–N–H group and N–Hꢀ ꢀ ꢀS hydrogen bonding with
Hꢀ ꢀ ꢀS distances 2.43 Å in compound 2 and 2.45 Å in com-
pound 5. Although compound 2 has o- and p-chloro-substi-
tuted aromatic ring, there were no strong contacts for
chlorine atoms. However, p-nitro-substituted aromatic ring
The condensation reaction of ethoxy/methoxy/trichloroe-
thoxy/pentoxy carbonyl isothiocyanate with 2, 4-dichloroani-
line/4-nitroaniline in dry acetone yielded the desired
compounds 1–5 (Scheme 1). Crystals suitable for single-
crystal X-ray structure determination could be obtained only
for compounds 2 and 5.
FT-IR spectra
The vibrational frequencies observed at ꢂ3440 and
ꢂ3160 cm–1 in the IR spectra of the compounds can be
assigned to free N–H and intramolecular hydrogen-bonded
N–H (C ¼ OꢀꢀꢀH–N) stretching modes, respectively. A strong
and a medium intensity band occurring at 1680–1690 cm–1
and 741–748 cm–1 regions may be ascribed to the stretching
vibrations of C ¼ O and C ¼ S in all the compounds,
respectively. The appearance of ꢀ(C ¼ O) mode at a lower
wavenumber is due to the formation of C ¼ OꢀꢀꢀH–N intra-
molecular hydrogen bond.[6–8] Further, the C–Cl asymmetric
and symmetric stretching vibrations in all the compounds
appear at 657–667 and 455–461 cm–1, respectively.[21–23]
in compound
5
showed intermolecular interactions
C9–H9Bꢀ ꢀ ꢀO2 and C13–H13Cꢀ ꢀ ꢀO1 with Hꢀ ꢀ ꢀO distances
2.46 Å and 2.57 Å, respectively. Additionally, compound 5
showed a C2–H2Aꢀ ꢀ ꢀO3 intermolecular interaction with
Hꢀ ꢀ ꢀO distance 2.46 Å between hydrogen atom of aryl group
and carbonyl oxygen atom of the ester group, and such con-
tacts were also expected in compound 2 but it was not
observed. Yet, crystal density of compound 2 was higher
than the 5, and it showed that packing in compound 2 was
more close than 5. The crystal packing analysis revealed that
aromatic rings in compound 2 were stacked with Cgꢀ ꢀ ꢀCg

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Figure 1. ORTEP diagrams of (a) compound 2 and (b) compound 5. Thermal ellipsoids are drawn at 50 % probability level.
Figure 2. Packing diagram of (a) compound 2 and (b) compound 5. Inter- and interamolecular interactions for compounds 2 and 5 are shown in (c) and (d),
respectively.
distance 3.88 Å; however, there was no stacking observed in interactions are present, but also the relative area of the sur-
face corresponding to each interaction.[37,38]
compound 5.[20–23]
The 2D fingerprint plots and bar graph for percentage
contributions of various interactions are shown in Figure
3a–d (decomposed fingerprint plots are shown in Table S1).
Fingerprint plot of compound 2 showed two sharp spikes
which represented the Sꢀ ꢀ ꢀH interactions (i.e., shortest de þ
di ꢂ2.40 Å) but no prominent spikes were observed for
Oꢀ ꢀ ꢀH interactions (but a small pointed spike at de þ di
ꢂ2.60 Å). The decomposed fingerprint plots showed 11.1%
Sꢀ ꢀ ꢀH and 10.3% Oꢀ ꢀ ꢀH interactions (Figure 3c). Although
no direct contact was observed in the crystal packing for the
Cl atoms vs others, decomposed fingerprint plots showed
Hirshfeld surface analysis
Hirshfeld surface analysis provided a comprehensive and
quantitative analysis of intermolecular interactions by
exploring the packing modes. CrystalExplorer 17.5 software
was used for the visualizing and exploring the intermolecu-
lar contacts by enabling their two-dimensional (2D) finger-
prints. These 2D fingerprint plots provided a summary of
the frequency of each combination of de and di across the
surface of the molecule and so indicated not only which 26.6% Clꢀ ꢀ ꢀH, 3.5% Clꢀ ꢀ ꢀCl and 1.6% Cꢀ ꢀ ꢀCl interactions.

4
S. K. PANDEY ET AL.
Table 1. Crystallographic data for compounds 2 and 5.
Table 2. Selected bond lengths and bond angles of compounds 2 and 5.
Compounds
2
5
Compounds
Bond length (Å)
Bond angle (ꢄ)
Empirical formula
Formula weight
Crystal system/space group
C10H10Cl2N2O2S
293.16
Monoclinic/P21/c
14.972(3)
3.8821(7)
21.293(4)
90
C13H17N3O4S
311.35
Monoclinic/C2/c
24.5274(17)
4.5136(3)
26.9386(18)
90
2.
S(1)–C(7)
1.671(3)
1.349(3)
1.372(4)
1.375(3)
1.416(4)
1.332(3)
1.219(3)
1.738(3)
1.735(3)
1.504(4)
(1)–C(6)–N(1)
120.3(3)
124.7(2)
118.8(2)
125.9(3)
107.1(2)
125.4(3)
128.1(2)
121.3(2)
124.9(2)
110.2(4)
N(1)–C(7)
N(2)–C(7)
N(2)–C(8)
N(1)–C(6)
O(2)–C(8)
O(1)–C(8)
C(1)–Cl(1)
C(3)–Cl(2)
C(9)–C(10)
S(1)–C(7)–N(1)
S(1)–C(7)–N(2)
O(1)–C(8)–O(2)
O(2)–C(9)–C(10)
N(2)ꢆC(8)ꢆO(1)
C(7)–N(2)–C(8)
C(5)–C(6)–N(1)
C(6)–N(1)–C(7)
C(8)–O(2)–C(9)
a / Å
b / Å
c / Å
ꢄ
a /
ꢄ
b / ꢄ
V / Å3
102.525(6)
90
1208.1(4)
4
1.612
0.700
97.371(2)
90
2957.6(3)
8
1.398
0.238
c /
Z
5.
C(7)–S(1)
N(2)–C(6)
N(3)–C(7)
N(3)–C(8)
O(3)–C(8)
O(4)–C(8)
O(4)–C(9)
N(3)–C(8)
N(1)–O(2)
N(1)–O(1)
1.667(9)
C(6)–N(2)–C(7)
N(2)–C(7)–N(3)
N(2)–C(7)–S(1)
N(3)–C(7)–S(1)
N(3)–C(8)–O(3)
O(4)–C(8)–O(3)
C(3)–N(1)–O(2)
C(3)–N(1)–O(1)
C(8)–O(4)–C(9)
C(3)–C(4)–C(6)
131.67(8)
114.35(8)
127.55(7)
118.09(7)
125.09(8)
126.15(8)
118.41(9)
118.22(9)
116.96(7)
109.00(8)
Dcalc (g/cm3)
1.403(11)
1.383(11)
1.381(12)
1.222(11)
1.324(11)
1.465(11)
1.381(12)
1.224(12)
1.221(13)
l (mm–1
)
Crystal size (mm)
Color/shape
Temp (K)
Theta range for collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2r(I)]
0.35 ꢅ 0.3 ꢅ 0.25
Yellow/rod
100 (2)
5.28 to 51.978
11854
2369
2369/0/155
1.032
R1 ¼ 0.0435,
wR2 ¼ 0.0855
R1 ¼ 0.0658,
wR2 ¼ 0.0941
0.33/–0.39
0.5 ꢅ 0.4 ꢅ 0.3
Yellow/rod
100 (2)
6.996 to 66.344
64939
5605
5605/0/191
1.039
R1 ¼ 0.0376,
wR2 ¼ 0.0993
R1 ¼ 0.0420,
wR2 ¼ 0.1038
0.41/–0.43
R indices (all data)
Table 3. Geometrical parameters of potential intra- and intermolecular inter-
actions in compounds 2 and 5.
Largest difference peak/hole
S. no.
D ꢆ HꢀꢀꢀA
HꢀꢀꢀA (Å)
DꢀꢀꢀA (Å)
D ꢆ HꢀꢀꢀA (deg)
Compound 2
Among them, only Clꢀ ꢀ ꢀH contacts were closer, which
showed de þ di ꢃ 3.0 Å. In the case of compound 5, sharp
spikes were observed for both Sꢀ ꢀ ꢀH and Oꢀ ꢀ ꢀH interactions
with de þ di > 2.40 Å. The decomposed fingerprint plots
showed 8.8% Sꢀ ꢀ ꢀH and 22.9% Oꢀ ꢀ ꢀH interactions (Figure
3d). Since both the molecules were showing parallel dis-
placed stacking in the crystal packing, only compound 2
showed the prominent red area for Cꢀ ꢀ ꢀC contacts in the
fingerprint which indicated the significant overlapping of
aromatic rings to impart the pꢀ ꢀ ꢀp interactions. However,
fingerprint of compound 5 did not show red bins in finger-
print region of Cꢀ ꢀ ꢀC contacts (Figure 3d), which revealed
that there were no overlapping of aromatic rings to make a
contact of p electron clouds of aromatic rings.[38–44]
1.
2.
N1–H1ꢀ ꢀ ꢀO1 (Intra)
1.99
2.43
2.685(3)
3.295(2)
135.3
3.295(2)
N2–H2ꢀ ꢀ ꢀS1
Compound 5
1.
2.
3.
4.
5.
N2–H2ꢀ ꢀ ꢀO3 (Intra)
1.90
2.45
2.46
2.46
2.57
2.653(1)
3.3224(9)
3.396(2)
3.112(1)
3.325(2)
142.61
168.33
166.92
123.08
133.69
N3–H3ꢀ ꢀ ꢀS1
C2–H2Aꢀ ꢀ ꢀO3
C9–H9Bꢀ ꢀ ꢀO2
C13–H13Cꢀ ꢀ ꢀO1
aromatic ring increases the lipophilicity of molecules and is
responsible for enhanced cytotoxicity of the compounds.[15–22]
Experimental procedure
Chemicals, instruments and methods
Analytical grade isobutoxy chloroformate, ethoxy chlorofor-
mate and other chemicals used in the synthesis of com-
pounds were purchased from Merck (Darmstadt, Germany).
The acetone was freshly distilled and dried prior to use.
Melting points were measured on an X–4 digital melting-
point apparatus (KRUSS, Germany) and were uncorrected.
Elemental analyses were performed on a CE-440 Exeter
Analytical CHN analyzer (Kyoto, Japan). The infrared spec-
tra of the title compounds as KBr pellets (4000–400 cm–1)
were recorded on a Varian 3100 FT-IR Excalibur series spec-
In vitro cytotoxic screening
The cytotoxicity of the compounds (1–5) was evaluated by
means of MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl
tetrazolium bromide) assay method with cells of human cer-
ꢁ
vical (2008 and C13 ), colorectal (HT29 and HCT116) and
ovarian carcinoma (IGROV-1, A2780 and A2780/CP), and
the results in the form of IC50 values are presented in Table
S2. 5-Fluorouracil was used as control.[45–47] The compara-
tive cytotoxicity of the compounds is depicted in Figure S1.
It is evident from Table S2 that all the compounds exhibited
appreciable activity against all the cell lines tested but the
1
trophotometer (MCE 1325, The University of Utah). H and
13C NMR spectra were recorded in DMSO-d6 by using TMS
as an internal standard on a JEOL FT-NMR AL 500
Spectrometer (Tokyo, Japan).
ꢁ
stronger inhibitory property was obtained for 2008, C13
and IGROV-1 cell lines in comparison with others. Results
also showed that the cytotoxicity of compounds decreases
with increase in the chain length of alkoxy group. It has also
been observed that the compound 5 bearing R1¼ 4-NO2
group exerted the highest cytotoxic effect. Based on the pre-
vious reports,[4,6–9] it can be stated that the presence of elec-
X-ray data collection and structure refinement
Single-crystal X-ray diffraction data were collected on a
Bruker SMART APEX II single crystal X-ray CCD diffract-
ometer having graphite monochromatized (Mo-Ka,
tronegative atom/group at ortho and/or para position of the k ¼ 0.71073 Å) radiation at low temperature(100 K).[48] The

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
Figure 3. Representation of 2D fingerprint plots of compounds (a) 2 and (b) 5. Bar graphs (c) and (d) represent the percentage contributions of various interactions
in compounds 2 and 5, respectively.
X-ray generator was operated at 50 kV and 30 mA. The data the above isothiocyanate was reacted with equimolar quan-
reduction was performed using APEX-II Software. tity of 2, 4-dichloroaniline/4-nitroaniline in acetone
Intensities were corrected for absorption using SADABS, (1.0 mmol, 30 mL) and further refluxed for 2 h at 70 ꢄC. The
and the structure was solved and refined using SHELX- precipitated ammonium chloride was filtered off, and the
97.[49] All non-hydrogen atoms were refined anisotropically, pale yellow solutions were evaporated in vacuum to get the
and hydrogen atoms were geometrically fixed with thermal desired products. The well-shaped crystals of compounds 2
parameters equivalent to 1.2 times than those of the atom to and 5 were grown by the slow evaporation techniques using
which they are bonded. Molecular diagrams, packing dia- acetone as a solvent.
grams and ORTEP diagrams were generated using Mercury
version 3.10.[50] PLATON was used for the analysis of bond
N-(2, 4-dichlorophenyl)-N’-(methoxycarbonyl)
thiocarbamide (1)
lengths, bond angles and other geometrical parameters.[51]
Yield: 86%; light yellow; m.p.; 140 – 141 ꢄC; FT–IR (KBr,
Synthesis of compounds (1–5)
cmꢆ1): 3423, 3145, ꢀ(N–H); 3087, ꢀ(Ar, C–H); 2925,
The compounds were synthesized by following the proced- ꢀ(Aliphatic, C–H); 1692, ꢀ(–C ¼ O); 1135, ꢀ(NCN); 748,
1
ure reported in the literature after a slight modifica- ꢀ(C ¼ S); 647, ꢀas(C–Cl); 455, ꢀs(C–Cl). H NMR (500 MHz,
tion.[15–22] The refluxing of the mixture of acetonic solution DMSO-d6, 25 ꢄC): dH; 11.58 (s, 1H, –CS–NH–), 11.48 (s,
of ethoxy/methoxy/trichloroethoxy/pentoxy chloroformate 1H, –CO–NH–); 7.88 (s, 1H, Ar-H); 7.68 (d, 1H, J ¼ 8.0 Hz,
(1.0 mmol, 30 mL) and ammonium thiocyanate solution in Ar–H); 7.42 (d, 1H, J ¼ 6.0 Hz, Ar–H); 3.72 (s, 3H, –CH3).
acetone (1.0 mmol, 30 mL) for 50 min at 75 ꢄC resulted in 13C NMR (125, MHz, DMSO-d6, 25 ꢄC): 180.1 (C@S), 154.5
the formation of respective carbonyl isothiocyanate. Each of (C@O), 135.2, 131.9, 130.5, 130.2, 129.5, 127.9 (Ar–C), 53.7

6
S. K. PANDEY ET AL.
(–COOCH3). Anal. Calcd for C9H8 N2O2SCl2 (279.14): C, (500 MHz, CDCl3, 25 ꢄC): dH; 11.46 (s, 1H, –CS–NH–), 8.34
38.73; H, 2.89; N, 10.04. Found: C, 38.68; H, 2.86; N, 9.98%.
(s, 1H,–CO–NH–), 7.58 (d, 1H, J ¼ 6.1 Hz, –C6H4), 7.54 (dd,
1H, J ¼ 6.1, 2.5 Hz, –C6H4), 7.51 (dt,1H, J ¼ 6.1, 2.5, 2.0 Hz,
–C6H4), 6.97 (d, 1H, J ¼ 2.5 Hz, –C6H4), 4.23 (t, 2H,
N-(2, 4-dichlorophenyl)-N’-(ethoxycarbonyl)
thiocarbamide (2)
J ¼ 7.0 Hz, –OCH2), 2.57 (m, 2H, –(CH2)–), 1.69 (m, 2H,
2x(–CH2), 0.92 (t, 3H, J ¼ 5.0 Hz, –CH3). 13C NMR
(125 MHz, CDCl3, 25ꢄ): 181.7 (C@S), 156.9(C@O), 149.3,
147.4, 142.8, 136.4, 129.9, 120.6 (Ar–C), 67.2 (–OCH2),
28.6–22.2 –(CH2)3–, 13.9 (–CH3). Anal. Calcd for
C13H17N3O4S (311.35): C, 50.15; H, 5.50; N, 13.50. Found:
C, 50.11; H, 5.47; N, 13.47%.
Yield: 90%; dark yellow; m.p.; 165–166 ꢄC; FT–IR (KBr,
cmꢆ1): 3407, 3155, ꢀ(N–H); 3091, ꢀ(Ar, C–H); 2940,
ꢀ(Aliphatic, C–H); 1680, ꢀ(–C ¼ O); 1196, ꢀ(NCN); 741,
1
ꢀ(C ¼ S); 650, ꢀas(C–Cl); 452, ꢀs(C–Cl). H NMR (500 MHz,
DMSO-d6, 25 ꢄC): dH; 11.51 (s, 1H, –CS–NH–), 11.50 (s, 1H,
–CO–NH–); 7.89 (s, 1H, Ar–H); 7.68 (d, 1H, J ¼ 9.0 Hz,
Ar–H); 7.43 (d, 1H, J ¼ 6.5 Hz, Ar–H); 4.20 (q, 2H, J ¼ 7.5 Hz,
–OCH2–); 1.23 (t, 3H, J ¼ 6.5 Hz, –CH3).13C NMR (125, MHz,
DMSO-d6, 25 ꢄC): 180.2 (C@S), 154.1 (C@O), 135.3, 131.9,
130.4, 130.1,129.4, 128.1(Ar–C), 62.7 (–OCH2–), 14.9, (–CH3).
Anal. Calcd for C10H10 N2O2SCl2 (293.17): C, 40.97; H, 3.44;
N, 9.56. Found: C, 40.75; H, 3.30; N, 9.41%.
Biological evaluations
Cell lines
Seven human cancer cell lines, namely cervical (2008 and
*
C13 ), colorectal (HT29 and HCT116) and ovarian carcin-
oma (IGROV-1, A2780 and A2780/CP), were used. Among
*
these, C13 and A2780/CP are cisplatin (ccDDP)-resistant
cells.[52,53] Cells were grown as monolayers in RPMI 1640
medium containing 10% heat-inactivated fetal bovine serum
and 50 mg/mL gentamycin sulfate. All cell media and serum
were purchased from Lonza (Verviers, Belgium). Cultures
were equilibrated with humidified 5% CO2 in air at 38 ꢄC.
All studies were performed in mycoplasma negative cells, as
routinely determined with the MycoAlert Mycoplasma
detection kit (Lonza, Walkersville, MD, USA).
N-(2, 4-dichlorophenyl)-N’-(2, 2, 2-
trichloroethoxycarbonyl) thiocarbamide (3)
Yield: 80%; yellow; m.p.; 130–131 ꢄC; FT–IR (KBr, cmꢆ1):
3450, 3165, ꢀ(N–H); 3047, ꢀ(Ar, C–H); 2935, ꢀ(Aliphatic,
C–H); 1685, ꢀ(–C ¼ O); 1148, ꢀ(NCN); 743, ꢀ(C ¼ S); 641,
ꢀas(C–Cl); 457, ꢀs(C–Cl). 1H NMR (500 MHz, DMSO-d6,
25 ꢄC): dH; 12.00 (s, 1H, –CS–NH–), 11.23 (s, 1H, –CO–NH–);
7.79 (s, 1H, Ar-H); 7.70 (d, 1H, J ¼ 8.0 Hz, Ar–H); 7.46 (d, 1H,
J ¼ 6.5 Hz, Ar–H); 4.98 (s, 2H, –OCH2). 13C NMR (125, MHz,
DMSO-d6, 25 ꢄC): 180.0 (C@S), 152.4 (C@O), 135.4, 132.2,
130.9, 130.5, 129.5, 128.0 (Ar–C), 95.4(–OCH2), 74.6 (–CCl3).
Anal. Calcd for C10H7N2O2SCl5 (396.50): C, 30.29; H, 1.78; N,
7.07. Found: C, 30.20; H, 1.76; N, 7.02%.
In vitro cytotoxicity screening
In vitro cytotoxicity of compounds in this study was deter-
mined by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl
tetrazolium bromide) assay method.[54,55] The cells were
seeded into 96-well plates and cultured overnight. Various
concentrations of the test compounds dissolved in DMSO
were then added and incubated for 72 h. After incubation,
the medium was removed and fresh culture medium 100 mL
containing 0.5 mg mLꢆ1MTT (3-(4, 5-dimethylthiazol-2-yl)-
2, 5-diphenytetrazolium bromide, Sigma Aldrich, Bengaluru,
India) was added and then, the plates were incubated at
38 ꢄC for 4 h. The medium was removed and 100 mL DMSO
was added to dissolve the dark blue crystals. After incuba-
tion for 30 min at room temperature to ensure that all crys-
tals were dissolved, absorbance at 500 nm was measured
using an ELISA plate reader at 570 nm with a reference
wavelength of 650 nm.
N-(2, 4-dichlrophenyl)-N’-(pentoxycarbonyl)
thiocarbamide (4)
Yield: 80%; light yellow; m.p.; 90–91 ꢄC; FT–IR (KBr, cmꢆ1):
3467, 3156, ꢀ(N–H); 3117, ꢀ(Ar, C–H); 2950, ꢀ(Aliphatic
C–H); 1690, ꢀ(–C ¼ O); 1167, ꢀ(NCN); 743, ꢀ(C ¼ S); 657,
1
ꢀas(C–Cl); 455, ꢀs(C–Cl). H NMR (500 MHz, CDCl3, 25 ꢄC):
dH; 11.66 (s, 1H, –CS–NH–), 8.33 (s, 1H,–CO–NH–), 8.32 (d,
1H, J ¼ 3.0 Hz, –C6H3), 7,46 (dd, 1H, J ¼ 8.5, 3.1 Hz, –C6H3),
6.45(d, 1H, J ¼ 8.5 Hz, –C6H3), 4.25 (t, 2H, J ¼ 7.0 Hz,
–OCH2), 2.43 (m, 2H, –(CH2)–), 1.71 (m, 4H, 2x(–CH2), 0.93
(t, 3H, J ¼ 4.0 Hz, –CH3). 13C NMR (125 MHz, CDCl3, 25 ꢄC):
178.1 (C@S), 152.7 (C@O), 133.6, 132.2, 129.3, 128.5, 127.1,
126.9 (Ar–C), 67.3 (–OCH2), 27.7 ꢆ 21.2 –(CH2)3–, 13.2
(–CH3). Anal. Calcd for C13H16N2O2SCl2 (335.25): C, 46.58;
H, 4.81; N, 8.36. Found: C, 46.45; H, 4.77; N, 8.30%.
Conclusions
We have synthesized five new N-Aryl-N’-alkoxycarbonyl thi-
ocarbamide derivatives. The structure of these compounds
was confirmed by FT-IR, 1H and 13C NMR spectroscopic
and single-crystal X-ray analysis of compounds 2 and 5. The
intermolecular contacts of compounds 2 and 5 were exam-
ined by Hirshfeld surfaces and fingerprint plots. The
molecular structure of the compounds is virtually planar
N-(4-nitrophenyl)-N’-(pentoxycarbonyl)
thiocarbamide (5)
Yield: 78%; dark yellow; m.p.; 140–141 ꢄC; FT–IR (KBr,
cmꢆ1): 3430, 3126, ꢀ(N–H); 3098, ꢀ(Ar, C–H); 2923,
ꢀ(Aliphatic, C–H); 1703, ꢀ(–C ¼ O); 1547, ꢀas(–NO2); 1345,
ꢀs(–NO2); 1169, ꢀ(NCN); 735, ꢀ(C ¼ S). 1H NMR favoring the existence of N–HꢀꢀꢀO and C–HꢀꢀꢀO

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Asymmetric
Transfer
Hydrogenation
of
Ketones.
intramolecular hydrogen bonds. The crystal packing is stabi-
lized by C–HꢀꢀꢀO and C–HꢀꢀꢀS intermolecular hydrogen
bonds. In vitro cytotoxic activities of the compounds tested
on seven human cancer cell lines revealed them to be poten-
Organometallics 2014, 33, 540–550. DOI: 10.1021/om4010548.
[8] Mahendiran, D.; Pravin, N.; Bhuvanesh, N. S. P.; Kumar, R. S.;
Viswanathan, V.; Velmurugan, D.; Rahiman, A. K. Bis
(Thiosemicarbazone) Copper (I) Complexes as Prospective
Therapeutic Agents: Interaction with DNA/BSA Molecules, and
In Vitro and In Vivo Anti-Proliferative Activities.
ChemistrySelect 2018, 3, 7100–7111.
[9] Tahir, S.; Badshah, A.; Hussain, R. A.; Tahir, M. N.; Tabassum,
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Biological Activities of New Nitrosubstituted Acyl Thioureas. J.
Mol. Struct. 2015, 1099, 215–225. DOI: 10.1016/j.molstruc.2015.
06.024.
[10] Sethukumar, A.; Kumar, C. U.; Agilandeshwari, R.; Prakasam,
B. A. Synthesis, Stereochemical, Structural and Biological
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Thiosemicarbazones. J. Mol. Struct. 2013, 1047, 237–248. DOI:
10.1016/j.molstruc.2013.05.008.
*
tial inhibitors of cervical (2008, C13 ) and ovarian
(IGROV-1) cancer cells. Among these compounds, com-
pound 5 showed the highest activities against all the cell
lines which may be due to the presence of nitro group at
the para position of the aromatic ring.
Acknowledgment
Prof. G. Marverti acknowledges, Department of Biomedical Sciences,
Metabolic and neurosciences, University of Modena, 41125 Modena,
Italy for cytotoxicity studies.
[11] Saeed, A.; Zaib, S.; Ashraf, S.; Iftikhar, J.; Muddassar, M.;
Zhang, K. Y. J.; Iqbal, J. Synthesis, Cholinesterase Inhibition
and Molecular Modelling Studies of Coumarin Linked Thiourea
Derivatives. Bioorg. Chem. 2015, 63, 58–63. DOI: 10.1016/j.bio-
org.2015.09.009.
[12] Asegbeloyin, J. N.; Oyeka, E. E.; Okpareke, O.; Ibezim, A.
Synthesis, Structure, Computational and In-Silico Anticancer
Studies of N, N-diethyl-N’-Palmitoyl Thiourea. J. Mol. Struct.
2018, 1153, 69–77. DOI: 10.1016/j.molstruc.2017.09.093.
[13] Keche, A. P.; Hatnapure, G. D.; Tale, R. H.; Rodge, A. H.;
Kamble, V. M. Synthesis, Anti-Inflammatory and Antimicrobial
Evaluation of Novel 1-Acetyl-3,5-Diaryl-4,5-Dihydro (1H)
Pyrazole Derivatives Bearing Urea, Thiourea and Sulfonamide
Moieties. Bioorg. Med. Chem. Lett. 2012, 22, 6611–6615. DOI:
10.1016/j.bmcl.2012.08.118.
Funding
The author SKP is grateful to University Grant Commission, New
Delhi, India, for the financial assistance. SKR is thankful to SERB, New
Delhi, for National Postdoctoral Fellowship, for single-crystal X-ray dif-
fraction and Hirshfeld surface analysis.
ORCID
Sunil K. Pandey
Seema Pratap
Sunil K. Rai
http://orcid.org/0000-0003-3439-846X
http://orcid.org/0000-0001-9723-8506
http://orcid.org/0000-0001-5509-3142
Gaetano Marverti
http://orcid.org/0000-0002-9074-0795
[14] Haynes, C. J. E.; Busschaert, N.; Kirby, I. L.; Herniman, J.;
ꢀ
Light, M. E.; Wells, N. J.; Marques, I.; Felix, V.; Gale, P. A.
Acylthioureas as Anion Transporters: The Effect of
Intramolecular Hydrogen Bonding. Org. Biomol. Chem. 2014,
12, 62–72. DOI: 10.1039/C3OB41522H.
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