Synthesis, characterization and antitumor activities of some novel thiazinones and thiosemicarbazones derivatives

Article abstract of DOI:10.1080/10426507.2020.1757672

Two series of thiazinone and thiosemicarbazone derivatives (1-12) were synthesized using 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (ABNs) and 3–alkyl–2,6–diarylpiperidin–4–ones as the starting materials. The structures of newly synthesized compounds were established on the basis of FT–IR, NMR spectroscopy and mass spectrometry. From the spectroscopic data, we identified that the cyclization reaction of thioamide with dialkyl acetylenedicarboxylate selectively gives six membered methyl 2-(2-(2,4-disubstituted-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carboxylates (1-6). In order to investigate the antitumor activities of the synthesized compounds, in?vitro cytotoxicity studies were carried out using human prostate cancer cell lines. Tested compounds showed good/moderate activities against cancer cell lines and further investigation carried out by live/dead assay.

Full text of DOI:10.1080/10426507.2020.1757672

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis, characterization and antitumor
activities of some novel thiazinones and
thiosemicarbazones derivatives
Selvam Athavan Alias Anand, Kiran George, Nisha Susan Thomas &
Senthamaraikannan Kabilan
To cite this article: Selvam Athavan Alias Anand, Kiran George, Nisha Susan Thomas &
Senthamaraikannan Kabilan (2020): Synthesis, characterization and antitumor activities of some
novel thiazinones and thiosemicarbazones derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2020.1757672
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2020.1757672
Synthesis, characterization and antitumor activities of some novel thiazinones
and thiosemicarbazones derivatives
Selvam Athavan Alias Ananda, Kiran Georgeb, Nisha Susan Thomasc, and Senthamaraikannan Kabilana
b
aDrug Discovery Lab, Department of Chemistry, Annamalai University, Annamalainagar, Tamilnadu, India; Department of Biomedical
c
Engineering, Chennai Institute of Technology, Chennai, Tamilnadu, India; Department of Bio-Chemistry and Bio-Technology, Annamalai
University, Annamalainagar, Tamilnadu, India
ABSTRACT
ARTICLE HISTORY
Received 4 November 2019
Accepted 15 April 2020
Two series of thiazinone and thiosemicarbazone derivatives (1-12) were synthesized using 2,4-dia-
ryl-3-azabicyclo[3.3.1]nonan-9-ones (ABNs) and 3–alkyl–2,6–diarylpiperidin–4–ones as the starting
materials. The structures of newly synthesized compounds were established on the basis of FT–IR,
NMR spectroscopy and mass spectrometry. From the spectroscopic data, we identified that the
cyclization reaction of thioamide with dialkyl acetylenedicarboxylate selectively gives six mem-
bered methyl 2-(2-(2,4-disubstituted-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazinyl)-4-oxo-4H-1,3-
thiazine-6-carboxylates (1-6). In order to investigate the antitumor activities of the synthesized
compounds, in vitro cytotoxicity studies were carried out using human prostate cancer cell lines.
Tested compounds showed good/moderate activities against cancer cell lines and further investi-
gation carried out by live/dead assay.
KEYWORDS
Thiazinone; thiosemicarba-
zone; piperidone; prostate
cancer; apoptosis; live/
dead assay
GRAPHICAL ABSTRACT
1. Introduction
discovery research,[7–10] we synthesized few novel thiazi-
none, thiosemicarbazone derivatives of modified piperidones
and their anti-prostate cancer activities were investigated
using LNCaP (androgen sensitive) and PC-3 (androgen
insensitive) cell lines.
Organosulfur compounds are frequently found in phar-
macophores and play an important role in the medicinal
chemistry field [11,12]. Among them, heterocyclic compounds
with thiazinone and thiosemicarbazone scaffolds have been
reported to furnish various biological activities. For exam-
ples thiazinone derivatives exhibit significant biological
activities including antimalarial,[13] antifungal,[14] anticon-
Prostate cancer (PC) is the most common cancer in men,
particularly in the western world and the majority of diag-
nosed patients are over the age of 50. PC has been reported
as the second leading cause of cancer-related death among
men worldwide and more than two million men are PC sur-
vivors in the United States of America.[1] In recent years,
androgen receptor signal blockage is targeted for anti-pros-
tate cancer drug development.[2,3] Some sulfur and nitrogen
containing heterocyclic compounds such as apalutamide,
casodex and enzalutamide are reported as anti-androgens to
cure PC[4–6]. In continuation of our anti-cancer drug vulsant[15] and anticancer properties.[16] On the other hand,
CONTACT Senthamaraikannan Kabilan
profskabilanau@gmail.com
Drug Discovery Lab, Department of Chemistry, Annamalai University, Annamalainagar,
Tamilnadu 608002, India.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2020.1757672.
ß 2020 Taylor & Francis Group, LLC

2
S. A. A. ANAND ET AL.
Scheme 1. Synthesis of Methyl 2-(2-(2,4-disubstituted-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carboxylates (1-6).
thiosemicarbazone moieties are also a class of small mole- NMR spectral data of the novel compounds were compared
with our previous research work to confirm the reaction mech-
anism.[33] This unequivocally indicates that the compounds 1-6
involved in conjugate addition of the sulfur center and N-acyl-
ation furnishing a six-membered thiazinone ring but not a five
membered thiazolidinone[34–37] as the final product (Figure 1).
In Scheme 2, the compound N-(4-chlorophenyl)hydrazine-
carbothioamide (IIa) was obtained by reacting 4-chloroaniline
with carbon disulfide in the presence of sodium hydroxide and
then with hydrazine hydrate.[38] The 1,3-disubstituted-2,6-diary-
lpiperidin-4-ones were synthesized by an optimized successive
Mannich condensation of corresponding ketones, substituted
benzaldehydes and ammonium acetate or methylamine in 1:2:1
ratio in ethanol. The N-(4-chlorophenyl)hydrazinecarbothioa-
mide was refluxed with the 1,3-disubstituted-2,6-diarylpiperidin-
4-ones in the presence of the catalytic amount of concentrated
hydrochloric acid to yield the compounds 7-12.
cules that have been discovered for various pharmacological
properties such as antibacterial,[17] antiviral,[18] antimalar-
ial,[19] anti HIV,[20] anticancer,[21] antitubercular,[22] anticor-
rosion[23] and antileishmanicidal effects.[24] In addition, they
also display significant inhibition against mushroom tyrosin-
ase,[25] phenoloxidase,[26] Trypanosoma Cruzi,[27] and urease
enzymes.[28] Considering the diverse biological properties,
we synthesized a new series of thiazinone and thiosemicar-
bazone derivatives of piperidone and their anticancer activ-
ities were evaluated using human prostate cancer cell lines.
2. Results and discussion
2.1. Chemistry
The starting materials, 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-
ones (ABNs) and 3–alkyl–2,6–diarylpiperidin–4–ones were pre-
pared in good yields through consecutive steps as reported in
the literature.[29–31] In Scheme 1, we have considered a reaction
of 2,4-diaryl-3-azabicyclo[3.3.1] nonan-9-ones thiosemicarbazone
derivatives with DMAD/DEAD (Dimethyl/Diethyl acetylenedi-
carboxylate) to examine the reactivity. To a warm solution of
substituted 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones thiosemi-
carbazones in methanol, a methanolic solution of DMAD/
DEAD was added dropwise with stirring. The reaction mixture
was allowed to stir at 60 ꢀC for 1 h to obtain the product.
The reaction between thiosemicarbazones and acetylene
dicarboxylate starts with the conjugate addition of sulfur atom
onto the triple bond of DMAD. Through the aminolysis of ester
group and the elimination of an alcohol molecule, the inter-
mediate undergoes intra-molecular condensation. The cycliza-
tion of this intermediate resulting in the formation of six-
The structures of newly synthesized compounds (1-12) were
elucidated by spectral analyses such as FT–IR, Mass, and NMR
spectra. The numbering pattern followed for the compounds 1
and 7 to explain the spectral data was given in Figure 2.
2.2. FT–IR and mass spectral analyses
In FT-IR spectrum of ABN derivative compound 1, the ester
carbonyl and amide carbonyl of showed sharp bands at
1728 cmꢁ1 and 1703 cmꢁ1 (Figure S 1 in the Supplemental
Materials). The bands at 1642 cmꢁ1 and 1609 cmꢁ1 corres-
pond to the imino groups of thiazinone and piperidine rings.
The –NH- appeared at 3450 cmꢁ1 and –CH- stretching at
2782-3157 cmꢁ1. In FT-IR spectra of compounds 7-12,
(Figures S 25, S 29, S 33, S 37, S 41 and S 45 in the
Supplemental Materials) the bands appeared in the region of
membered thiazinones regioselectively.[32] In addition, the 3301-3440 cmꢁ1 owing to the –NH- groups of the

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Figure 1. Formation of six membered thiazinone (1i) in the reaction of DMAD with thioamide.
Scheme 2. Synthesize of N-(4-chlorophenyl)-2-(1,3-disubstituted-2,6-diarylpiperidin-4-ylidene)hydrazinecarbothioamides (7-12).
compounds. The aliphatic and the aromatic -CH stretching of thiosemicarbazones 7-12. Mass spectra were recorded for all
the synthesized compounds showed absorptions in the region
the novel compounds and the observed peaks with mass val-
of 2776-3000 cmꢁ1. The presence of C ¼ N stretching was
ues (M þ H)þ confirmed the purity of the products.
confirmed by the absorption in the region of 1592-1528 cmꢁ1
.
There is a sharp band absorbed in the region of 1491-
1509 cmꢁ1 owing to the characteristic C ¼ S stretching vibra-
tion of compounds 7-12. The observed NH, C ¼ S stretching
vibrational bands and the absence of carbonyl group around
1
2.3 H and 13C NMR spectral analyses of compounds 1
and 7
1
In H NMR of compound 1 (Figure S 2 in the Supplemental
1700 cmꢁ1 are supporting the formation of corresponding Materials), two singlets at 4.10 and 4.22 ppm with one

4
S. A. A. ANAND ET AL.
observed at 113.82 ppm. The amide carbonyl in the thiazi-
none ring and the ester carbonyl carbons are assigned at
165.51 and 165.90 ppm in the deshielded region. Also, the
imine carbon C-9 is found in the deshielded region at
176.71 ppm. The signal at 54.98 ppm is assigned for the
methoxy carbons of phenyl ring attached to the 2nd and 4th
positions of the piperidine ring.
1
The H NMR spectrum of compound 7, (Figure S 26 in
the Supplemental Materials) a doublet observed at 0.91 ppm
with three protons integral which is assignable to H-3a’ methyl
protons. Similarly, N-CH3 protons (H7) are resonated as a
singlet at 1.66 ppm with three protons integral. The H-5a pro-
ton of compound 7 appeared as a triplet at 2.48 ppm. In the
aliphatic region, there are two signals as doublet at 2.90 ppm
and doublet at 2.95 ppm with one proton integral each.
Among the said two signals, the aliphatic signal 2.90 ppm is
assigned as H-2a proton and relatively higher frequency signal
2.95 ppm is assigned as H-6a proton. The multiplet at
2.79 ppm with one proton integral is assigned for H-3a proton.
The equatorial proton H-5e resonated as a doublet of doublet
at 3.27 ppm. The signals appeared as doublet and multiplet in
the region of 7.30-7.67 ppm is due to the phenyl protons pre-
sent at the chlorophenyl thiosemicarbazone, C2 and C6. The
two N-H protons of the thiosemicarbazone 7 appeared as a
sharp singlet at 8.77 ppm and 9.34 ppm with one proton inte-
gral each. In the 13C NMR of compound 7 (Figure S 27 in the
Supplemental Materials), the signals in the aliphatic regions
12.9, 36.7, 41.4 and 45.0 ppm are assigned for C3’, C5, C7 and
C3 carbons of the piperidyl ring. The two peaks appeared at
69.3 ppm and 77.7 ppm is assigned for C6 and C2 carbons.
For thiosemicarbazone, the C ¼ S carbon appeared at
154.2 ppm whereas the ipso carbons displayed peaks at 142.4
and 143.1 ppm. The phenyl groups attached to the C2 and C6
positions of the piperidyl ring and the chlorophenyl carbons
appeared in the aromatic region from 125.2 ppm to 128.9 ppm.
Figure 2. Numbering pattern of compounds 1 and 7 for the spectral data
explanation.
Figure 3. Interaction between H-7a proton and the nitrogen atom in com-
pound 1 is shown by dotted line.
proton integral each are assigned to benzylic protons H-4
and H-2 respectively. The methine proton H-e in the thiazi-
none ring is observed at 6.65 ppm as a singlet. Also, the two
singlets at 3.45 and 2.46 ppm are attributed to the bridge-
head protons H-5 and H-1. The multiplets appeared at
shielded regions 1.40 and 1.68 ppm with two protons inte-
gral each are assigned for H-6a & H-8a and H-6e & H-8e
protons. Besides, the unassigned signals at 1.46 and
2.80 ppm are attributed to H-7e and H-7a protons. The
chemical shift difference between H-7e and H-7a is about
1.34 ppm shows that H-7a is oriented toward piperidine
nitrogen atom and hence there may be a weak interaction
between the lone pair electrons of nitrogen and H-7a
(Figure 3). As a result of this interaction, C-7 gets partial
negative charge and H-7a gains a slight positive charge and
thus the carbon signal is shielded and the proton signal is
deshielded. The ester methoxy and phenyl substituted
methoxy protons appeared at 3.78 and 3.76 ppm. The signals
at deshielded regions 6.97, 7.42 and 7.51 ppm are assigned
for aromatic protons.Similarly, in the 13C NMR spectrum of
compound 1 (Figure S 3 in the Supplemental Materials), the
carbon resonance at 63.99 and 62.71 ppm are assigned to C-
2 and C-4 carbons of the piperidine ring. The bridgehead
carbons C-1 is observed at 45.98 ppm and C-5 peak might
be merged with DMSO peaks. The cyclohexyl ring methy-
2.4. Anticancer studies
The anticancer activities of the synthesized compounds (1-
12) were evaluated against LNCaP and PC-3 human prostate
cancer cell lines. The concentrations of the compounds that
inhibited 50% of cell growth (IC50) in lM are calculated.
With the intention of further anticancer investigation, the
synthesized compounds were evaluated for the cell death
studies using live/dead assay.
2.4.1. Evaluation of cytotoxicity
The anticancer activities of the synthesized compounds 1-12
were evaluated against LNCaP (androgen sensitive) and PC-
3 (androgen insensitive) human prostate cancer cell lines
(Table S 11 and Figure S 49 in the Supplemental Materials).
The results clearly indicate that almost half of the synthe-
sized compounds inhibit cell viability against prostate cancer
cell lines at micromolar concentrations. Compounds 3 and 4
exhibited a high inhibition of cell viability against LNCaP
lene carbons C6, C7 and C8 are observed at 27.18, 21.04 cells, obtaining IC50 values 30.4 4 and 35.2 3lM respect-
and 28.55 ppm. The methyl carbon C-e of thiazinone ring is ively. The compounds 1, 2, 5, and 6 accounted moderate

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
inhibition of LNCaP cell viability with the IC50 values 1H and 13C NMR spectra and mass spectrometry scans for
the products.(Figures S 1 – S 48)
45.1 3, 70.3 3, 60.3 2, and 67.4 2 lM respectively. In
PC-3 cells, the treatment with compounds 1, 2, and 4 exhib-
ited good cytotoxicity with IC50 values 40.3 3, 50.4 2 and
45.6 3 lM respectively and compounds 3, 5, and 6 showed
moderate cytotoxicity. However, the compounds 7-12 exhib-
ited no significant reduction in the viability of both the cells.
3.2. Synthetic procedures
General procedures for the synthesis of substituted azabicy-
clo[3.3.1]nonan-9-ones (Ia-If) and piperidin-4-ones (IIb-IIg),
The above results showed that the compounds (1-6) with azabicyclo[3.3.1]nonan-9-ones thiosemicarbazones (Ig-Il)
and N-(4-chlorophenyl)hydrazinecarbothioamide (IIa) are
given in the Supplemental Materials
thiazinone moiety exhibited better anticancer activities than
the compounds (7-12) with thiosemicarbazone scaffolds.
3.2.1 General procedure for the synthesis of methyl 2-(2-
(2,4-disubstituted-3-azabicyclo[3.3.1]nonan-9-ylide-
ne)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carboxylates
derivatives (1-6)
2.4.2. Evaluation of apoptosis in LNCaP and PC-3 cells
To validate the results obtained from cytotoxicity studies,
the compounds were further subjected to live/dead assay
studies to evaluate the cell death percentage in LNCaP and
PC-3 cells. Compounds 1-6 exhibited loss of membrane
integrity in both the tested cells as a result of permitting
EthD-1 to bind with nucleic acids of the cells with the dam-
aged membrane and emits bright red fluorescence signal.
Whereas the polyanionic dye calcein AM binds with live
cells and produce uniform green fluorescent signal. The per-
centage of live and dead cells were quantified and depicted
in Figures S 50, S 51 and S 52 in the Supplemental
Materials. On comparing the results of compounds 1-6, the
compound 3 induced maximum (60 3%) and compound 2
induced minimum (34 1%) cell deaths and in LNCaP cells.
Whereas in PC-3 cells, the treatment with compound 1
shows maximum (55 3%) and compound 3 shows min-
imum (34 2%) percentage of cell deaths. However, the thi-
osemicarbazone derivatives 7-12 showed low level of cell
death in both LNCaP and PC-3 cells. The results of cytotox-
icity and live/dead studies showed that the compounds with
methoxy-substitution (1) and fluoro-substitution (3) exhibit
better activities against PC-3 and LNCaP cells among the
tested compounds and the thiosemicarbazone derivatives (7-
12) showed poor activities against the prostate cancer cells.
To a warm solution of substituted 2,4-diaryl-3-azabicy-
clo[3.3.1]nonan-9-one thiosemicarbazones (1.0 mmol) in
methanol (15 mL), methanolic solution of DMAD/DEAD
(1.0 mmol in 5 mL methanol) was added dropwise with stir-
ring. The reaction mixture was allowed to stir at 60 ꢀC for
1 h. The completion of the reaction was confirmed by TLC
and the reaction mixture was cooled to room temperature.
The yellow solid obtained was filtered and washed with
warm methanol. The crude products were recrystallised
from methanol.
3.2.2. General method for the synthesis of N-(4-chloro-
phenyl)-2-(1,3-disubstituted-2,6-diarylpiperidin-4-
ylidene)hydrazinecarbo thioamide (7-12)
To the substituted 3–alkyl–2,6–diphenylpiperidin–4–one
(1.0 mmol) in methanol (20 mL), concentrated hydrochloric
acid (0.2 mL) and methanolic solution of N-(4-chlorophe-
nyl)hydrazinecarbothioamide (1.0 mmol in 5 mL methanol)
was added dropwise with stirring. The reaction mixture
heated to reflux with water condenser for 2 h. After comple-
tion, the reaction mixture was cooled to room temperature
and the solid separated was filtered. The crude products
were recrystallised from methanol.
3. Experimental
Methyl 2-(2-(2,4-bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]-
nonan-9-ylidene)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carb-
oxylate (1)
3.1. Instrumentation and general techniques
The melting points of the novel compounds were deter-
mined in open capillary tubes and are uncorrected. Infrared
spectra were recorded on Thermo Nicolet FT–IR model iS5
spectrophotometer using KBr pellet. The NMR spectra were
recorded at 400 MHz Bruker instruments using
Tetramethylsilane (TMS) as an internal standard. Deuterated
chloroform and deuterated dimethyl sulfoxide were used to
record NMR spectra and the chemical shifts are reported in
d units (parts per million) relative to the standard. Mass
spectra were recorded on Thermo Nicolet Exactive Plus
mass spectrometers. All the chemical reactions were moni-
tored by thin-layer chromatography using silica gel pre-
coated aluminum sheets of Merck TLC 60 F254 and visual-
ized in UV light chamber. All the chemical reactions were
carried out using analytical grade solvents without further
Chemical formula: C28H30N4O5S; Yellow powder; Yield:
72%; mp: 174–176 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3430 (N-
H), 3157, 2962, 2922 (C-H), 1728, 1703 (ester C ¼ O), 1642
1
(amide C ¼ O), 1609 (C ¼ N); H NMR (400 MHz, DMSO-
d6, d ppm): 1.40 (m, 2H, 6CH2), 1.46 (m, 1H), 1.68 (m, 2H,
7CH2), 2.46 (s, 1H, bridgehead 1CH), 2.80 (m, 1H), 3.45 (s,
1H, Bridgehead 5CH), 3.76 (s, 6H, phenyl methoxy CH3),
3.78 (s, 3H, ester methoxy CH3), 4.10 (s, 1H, Benzylic pro-
tons 4CH), 4.22 (s, 1H, Benzylic protons 2CH), 6.65 (s, 1H,
thiazinone ring CH), 6.97 (m, 4H, Aromatic-H), 7.42 (d,
J ¼ 8.4 Hz, 2H, Aromatic-H), 7.51 (d, J ¼ 8 Hz, 2H,
Aromatic-H); 13C NMR (100 MHz, DMSO-d6): d 21.04
(CH2, C-7), 27.18 (CH2, C-6), 28.55(CH2, C-8), 45.98 (CH,
C-1), 52.37, 54.98 (C6H4-O-CH3), 62.71 (CH, C-4), 63.99
(CH, C-2), 113.53, 113.57, 113.82 (CH in thazinone ring),
purification. The Supplemental Materials contains sample 127.81, 127.86, 134.53, 143.18, 157.73, 158.18, 158.22, 165.51

6
S. A. A. ANAND ET AL.
(Amide C ¼ O in thiazinone ring), 165.90 (ester C ¼ O in (CH, C-1), 48.56, 52.40, 52.48, 60.06, 61.39(CH, C-4), 113.82
thiazinone ring), 176.71 (C ¼ N, C-9); HRMS (ESI/ (CH in thazinone ring), 114.60, 127.05, 127.82, 129.48,
(M þ H)þ) calculated 535.2015 found 535.2708.
129.56, 130.67, 131.42, 133.92, 139.17, 142.62, 143.19,
154.38, 165.53 (Amide C ¼ O in thiazinone ring), 165.88
(ester C ¼ O in thiazinone ring), 175.34 (C ¼ N, C-9);
HRMS (ESI/(M þ H)þ) calculated 543.1024 found 544.2947.
Methyl 2-(2-(2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-yli-
dene)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carboxylate (2)
Chemical formula: C26H26N4O3S; Yellow powder; Yield:
81%; mp: 182–184 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3437 (N-
H), 3059, 2958, 2782 (C-H), 1724, 1704 (ester C ¼ O), 1651
Methyl
2-(2-(2,4-bis(3-chlorophenyl)-3-azabicyclo[3.3.1]-
nonan-9-ylidene)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carb-
oxylate (5)
1
(amide C ¼ O), 1623 (C ¼ N); H NMR (400 MHz, DMSO-
d6, d ppm): 1.33 (m, 2H, 6CH2), 1.41 (m, 2H), 1.61 (m, 2H,
Chemical formula: C26H24Cl2N4O3S; Yellow powder;
7CH2), 2.57 (s, 1H, bridgehead 1CH), 3.28 (s, 1H), 3.53 (s, Yield: 79%; mp: 173–175 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3429
1H, Bridgehead 5CH), 3.78 (s, 3H, phenyl methoxy CH3), (N-H); 3105, 2921, 2854, 2794 (C-H); 1728 (ester C ¼ O);
4.17 (s, 1H, Benzylic protons 4CH), 4.30 (s, 1H, Benzylic 1651 (amide C ¼ O); 1611 (C ¼ N); 1H NMR (400 MHz,
protons 2CH), 6.65 (s, 1H, thiazinone ring CH), 7.38-7.66 DMSO-d6, d ppm): 1.31 (m, 1H), 1.40 (m, 1H), 1.61 (m,
(m, aromatic H), 12.72 (bs, 1H, NH); 13C NMR (100 MHz, 2H, 7CH2), 2.58 (s, 1H, bridgehead 1CH), 2.66 (m, 1H),
DMSO-d6): d 20.65 (CH2, C-7), 27.32 (CH2, C-6), 35.88 3.28 (s, 1H, Bridgehead 5CH), 3.79 (s, 3H, ester methoxy
(CH2, C-8), 41.57 (CH, C-1), 52.39, 60.05, 61.38 (CH, C-4), CH3), 4.18 (s, 1H, Benzylic proton 4CH), 4.30 (s, 1H,
115.12 (CH in thazinone ring), 118.63, 127.15, 131.43, Benzylic proton 2CH), 6.66 (s, 1H, thiazinone ring CH),
147.63, 154.43, 157.34, 165.92(ester C ¼ O in thiazinone 7.36 - 7.67 (m, aromatic H), 12.70 (bs, 1H, NH); 13C NMR
ring), 175.52 (C ¼ N, C-9); HRMS (ESI/(M þ H)þ) calcu- (100 MHz, DMSO-d6): d 20.94 (CH2, C-7), 27.14 (CH2, C-
lated 475.1804 found 475.1950.
6), 28.62 (CH2, C-8), 45.30 (CH, C-1), 52.39, 62.35 (CH, C-
4), 63.54 (CH, C-2), 113.96 (CH in thazinone ring), 125.58,
126.66, 130.19, 133.00, 143.09, 144.96, 145.01, 165.49
(Amide C ¼ O in thiazinone ring), 165.87 (ester C ¼ O in
thiazinone ring), 175.54 (C ¼ N, C-9); HRMS (ESI/
(M þ H)þ) calculated 543.1024 found 544.2943.
Methyl
2-(2-(2,4-bis(4-fluorophenyl)-3-azabicyclo[3.3.1]-
nonan-9-ylidene)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carb-
oxylate (3)
Chemical formula: C26H24F2N4O3S; Yellow powder;
Yield: 78%; mp: 171–173 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3423
(N-H), 3071, 2929, 2850, 2802, 2770 (C-H), 1734, 1706
Methyl
2-(2-(2,4-bis(4-chlorophenyl)-3-azabicyclo[3.3.1]-
1
(ester C ¼ O), 1645 (amide C ¼ O), 1605 (C ¼ N); H NMR
nonan-9-ylidene)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carb-
oxylate (6)
(400 MHz, DMSO-d6, d ppm): 1.47 (m, 2H, 6CH2), 1.55 (m,
1H), 1.63 (m, 2H, 7CH2), 2.72 (t, J ¼ 6 Hz, 1H, bridgehead
Chemical formula: C26H24Cl2N4O3S; Yellow powder;
1CH), 3.08 (s, 1H), 3.49 (s, 1H, Bridgehead 5CH), 3.78 (s, Yield: 84%; mp: 164–166 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3425
3H, ester methoxy CH3), 4.17 (s, 1H, Benzylic protons (N-H); 3164, 3065, 2929, 2794 (C-H); 1716, 1704 (ester
4CH), 4.29 (s, 1H, Benzylic protons 2CH), 6.65 (s, 1H, thia- C ¼ O); 1641 (amide C ¼ O); 1621 (C ¼ N); 1H NMR
zinone ring CH), 7.20 – 7.27 (m, 4H, Aromatic-H), 7.55 (t, (400 MHz, DMSO-d6, d ppm): 1.48 (m, 2H, 6CH2), 1.54 (m,
J ¼ 6.4 Hz, 2H, Aromatic-H), 7.66 (t, J ¼ 6.4 Hz, 2H, 1H), 1.61 (m, 2H, 7CH2), 2.69 (m, 1H, bridgehead 1CH),
Aromatic-H), 12.71 (bs, 1H, NH); 13C NMR (100 MHz, 3.17 (s, 1H), 3.50 (s, 1H, Bridgehead 5CH), 3.78 (s, 3H, ester
DMSO-d6): d 20.93 (CH2, C-7), 27.11 (CH2, C-6), 28.56 methoxy CH3), 4.16 (s, 1H, Benzylic proton 4CH), 4.28 (s,
(CH2, C-8), 45.62 (CH, C-1), 52.36, 62.37, 63.58 (CH, C-2), 1H, Benzylic proton 2CH), 6.65 (s, 1H, thiazinone ring CH),
113.91(CH in thazinone ring), 128.66, 128.74, 138.61, 7.45 – 7.85 (m, Aromatic-H), 12.77 (bs, 1H, NH); 13C NMR
143.10, 157.97, 159.98, 162.39, 165.47 (amide C ¼ O in thia- (100 MHz, DMSO-d6): d 20.92 (CH2, C-7), 27.12 (CH2, C-
zinone ring), 165.88 (ester C ¼ O in thiazinone ring), 176.07 6), 28.56 (CH2, C-8), 45.43 (CH, C-1), 52.39, 62.36 (CH, C-
(C ¼ N, C-9); HRMS (ESI/(M þ H)þ) calculated 511.1615 1), 63.54 (CH, C-2), 113.93 (CH in thazinone ring), 128.10,
found 511.1273.
128.66, 129.08, 129.59 131.36, 131.42, 132.58, 135.73, 141.47,
143.10, 157.42, 165.50 (Amide C ¼ O in thiazinone ring),
165.88 (ester C ¼ O in thiazinone ring), 175.74 (C ¼ N, C-9);
HRMS (ESI/(M þ H)þ) calculated 543.1024 found 544.1170.
(E)-N-(4-chlorophenyl)-2-(1,3-dimethyl-2,6-diphenylpiperi-
din-4-ylidene)hydrazinecarbothioamide (7)
Methyl
2-(2-(2,4-bis(2-chlorophenyl)-3-azabicyclo[3.3.1]-
nonan-9-ylidene)hydrazinyl)-4-oxo-4H-1,3-thiazine-6-carb-
oxylate (4)
Chemical formula: C26H24Cl2N4O3S; Yellow powder;
Yield: 74%; mp: 169–171 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3429
(N-H), 3182, 3061, 2943, 2765 (C-H), 1730, 1698 (ester
Chemical formula: C26H27ClN4S; White powder; Yield:
C ¼ O), 1643 (amide C ¼ O), 1607 (C ¼ N); 1H NMR 81%; mp: 202–204 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3327 (NH),
1
(400 MHz, DMSO-d6, d ppm): 1.29 (bs, 1H), 1.42 (bs, 2H, 3084, 3026, 2973, 2932, 2776 (CH), 1584, 1536 (C ¼ N); H
6CH2), 1.52 (m, 2H, 7CH2), 2.78 (s, 1H, bridgehead 1CH), NMR (400 MHz, CDCl3, d ppm): 0.91 (d, J ¼ 6.8 Hz, 3H,
3.05 (s, 1H, Bridgehead 5CH), 3.78 (s, 3H, ester methoxy 3’CH3) , 1.66 (s, 3H, N-CH3), 2.48 (t, J ¼ 12.4 Hz, 1H,
CH3), 4.46 (s, 1H Benzylic proton 4CH), 4.59 (s, 1H, 5CHa), 2.80 (m, 1H, 3CH), 2.90 (d, J ¼ 2.8 Hz, 1H, 2CH),
Benzylic proton 2CH), 6.65 (s, 1H, thiazinone ring CH), 2.95 (d, J ¼ 10.4 Hz, 1H, 6CH), 3.27 (dd, J ¼ 11.8 Hz, 1H,
7.34–8.10 (m, Aromatic-H), 8.75 (s, 1H, Aromatic-H), 12.70 5CHe), 7.67-7.30 (m, 14H, Aromatic-H), 8.77 (s, 1H, NH),
(bs, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d 20.47 9.34 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): d 12.97
(CH2, C-7), 27.31 (CH2, C-6), 28.57 (CH2, C-8), 35.88, 41.56 (CH3, C-30), 36.73 (CH, C-5), 41.43 (N-CH3, C-7), 45.06

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
(CH, C-3), 69.34 (CH, C-6), 77.71 (CH, C-2), 125.23,
127.77, 127.96, 128.09, 128.65, 128.87, 128.96 (Aromatic-
CH), 131.21, 136.57, 142.44 (ipso carbon, C-20), 143.12 (ipso
carbon, C-60), 154.27, 176.52; HRMS (ESI/(M þ H)þ) calcu-
lated 463.1723 found 463.1641.
(E)-2-(2,6-bis(4-chlorophenyl)-3-methylpiperidin-4-ylidene)-
N-(4-chlorophenyl)hydrazinecarbothioamide (11)
Chemical formula: C25H23Cl3N4S; White powder; Yield:
77%; mp: 206-208 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3272, 3207
(NH), 2969, 2930, 2802, 2625, 2551, 2498, 2430 (CH), 1589,
1
1540 (C ¼ N); H NMR (400 MHz, DMSO-d6, d ppm): 0.88
(E)-N-(4-chlorophenyl)-2-(3-ethyl-2,6-diphenylpiperidin-4-
ylidene)hydrazinecarbothioamide (8)
(d, J ¼ 6.4 Hz, 3H, 3’CH3), 2.34 (bs, 1H, 5CHa), 2.79 (bs, 1H,
3CH), 4.08 (bs, 1H, 6CH), 7.40-7.62 (m, 14H, Aromatic-H),
9.71 (s, 1H, NH), 11.06 (s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d 10.62 (CH3, C-30), 12.13, 56.40 (CH, C-3),
58.89, 62.22 (CH, C-6), 66.96 (CH, C-2), 126.57, 127.87,
128.09, 128.29, 130.09, 132.28, 132.87, 137.87 (Aromatic
CH), 176.95, 179.47; HRMS (ESI/(M þ H)þ) calculated
517.0787 found 517.0701.
Chemical formula: C26H27ClN4S; White powder; Yield:
75%; mp: 218–220 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3372, 3305
(NH), 3058, 3041, 2967, 2877, 2677, 2545, 2427 (CH), 1586,
1
1528 (C ¼ N); H NMR (400 MHz, DMSO-d6, d ppm): 0.81
(t, J ¼ 7.2 Hz, 3H, 3’CH3), 1.54 (m, 2H, 3’CH2), 3.18 (t,
J ¼ 14 Hz, 1H, 5CHa), 3.67 (d, J ¼ 12.4 Hz, 1H, 3CH), 4.56
(d, J ¼ 9.6 Hz, 1H, 2CH), 4.65 (d, J ¼ 9.2 Hz, 1H, 6CH), 7.44
(m, 8H, Aromatic-H), 7.63 (d, J ¼ 8.8 Hz, 2H, Aromatic-H),
7.84 (m, 4H, Aromatic-H) 9.89 (bs, 1H, NH), 10.47 (bs, 1H,
(E)-N-(4-chlorophenyl)-2-(3-ethyl-1-methyl-2,6-diphenylpi-
peridin-4-ylidene)hydrazinecarbothioamide (12)
13
NH); C NMR (100 MHz, DMSO-d6): d 10.36 (CH3, C-30),
Chemical formula: C27H29ClN4S; White powder; Yield:
79%; mp: 212-214 ꢀC; FTIR: (KBr) (ꢀmax, cmꢁ1): 3328, 3263,
(NH), 2968, 2955, 2869, 2829, 2775, 2471 (CH), 1592, 1534
18.25 (CH2, C-30), 31.88 (CH, C-5), 45.44 (CH, C-3), 59.34
(CH, C-6), 64.65 (CH, C-2), 126.15, 128.14, 128.33, 128.57,
128.64, 129.05, 129.32 (Aromatic-CH), 131.95, 134.85,
135.69, 137.77, 150.53, 177.04; HRMS (ESI/(M þ H)þ) calcu-
lated 463.1723 found 463.1640.
1
(C ¼ N); H NMR (400 MHz, DMSO-d6, d ppm): 0.73 (bs,
3H, 3’CH3), 1.09 (bs, 1H), 1.57 (s, 3H, N-CH3), 1.66 (bs,
2H, 3’CH2), 2.08 (s, 1H, 5CHa), 2.32 (m, 1H, 3CH), 2.61
(bs, 1H, 2CH), 3.04 (d, J ¼ 8.8 Hz, 1H, 6CH), 3.26 (d,
J ¼ 11.6 Hz, 1H, 5CHe), 7.28-7.80 (m, 14H, Aromatic H),
9.66 (s, 1H, NH), 11.08 (s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d 18.99 (CH3, C-30), 20.26 (CH2, C-30), 21.68,
29.68, 31.52 (CH, C-5), 48.55 (N-CH3, C-7), 66.15 (CH, C-
6), 72.05 (CH, C-2), 126.21, 128.05, 128.64, 129.01, 129.41,
129.63 (Aromatic CH), 134.22, 136.08, 137.70, 137.99 (ipso
carbon, C-20), 138.20 (ipso carbon, C-60), 148.04, 156.32,
176.99; HRMS (ESI/(M þ H)þ) calculated 477.1879
found 477.1795.
(E)-2-(2,6-bis(4-chlorophenyl)-3-ethylpiperidin-4-ylidene)-
N-(4-chlorophenyl)hydrazinecarbothioamide (9)
Chemical formula: C26H25Cl3N4S; White powder; Yield:
79%; mp: 188-190 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3382, 3274
(NH), 3028, 2973, 2935, 2874, 2635, 2546, 2442, 2390 (CH),
1
1589, 1540 (C ¼ N); H NMR (400 MHz, DMSO-d6, d ppm):
0.80 (t, J ¼ 7.2 Hz, 3H, 3’CH3), 1.57 (m, 2H, 3’CH2), 3.12 (s,
1H, 5CHa), 3.65 (d, 1H, J ¼ 12.8 Hz, 3CH), 4.58 (d,
J ¼ 10.4 Hz, 1H, 2CH), 4.66 (d, J ¼ 11.2 Hz, 1H, 6CH),
7.41(d, J ¼ 8.8 Hz, 2H, Aromatic-H), 7.54 (m, 4H, Aromatic-
H), 7.62 (d, J ¼ 8.8 Hz, 2H, Aromatic-H), 7.82 (d, J ¼ 8.4 Hz,
2H, Aromatic-H), 7.88 (d, J ¼ 8.4 Hz, 2H, Aromatic-H) 9.73
(bs, 1H, NH), 10.57 (bs, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d 10.33 (CH3, C-30), 18.20 (CH2, C-30), 31.61
(CH, C-5), 45.29 (CH, C-3), 58.51 (CH, C-6), 63.74 (CH, C-
2), 126.20, 128.13, 128.33, 128.54, 128.68, 130.52, 131.29,
133.67, 133.78, 134.04, 134.52 (Aromatic-CH), 137.75,
149.90, 177.07; HRMS (ESI/(M þ H)þ) calculated 531.0943
found 531.0825.
3.3. In vitro biological studies
3.3.1. Cell culture
PC-3 and LNCaP human prostate cancer cell lines were
sourced from the National Center for Cell Science (NCCS,
Pune, India). PC-3 and LNCaP cells were cultured by fol-
lowing standard procedures.[39] The PC-3 cells were cultured
in F12-K medium (HiMedia laboratories, India) and LNCaP
cells were cultured in RPMI-1640 medium (Gibco, Grand
Island, USA). The media were supplemented with 10% fetal
bovine serum (FBS) and with 1% antibiotics of 1X
Streptomycin/Penicillin. Both the cells were grown in a
humidified incubator at 37 ꢀC supplemented with 5% car-
bon-di-oxide.
(E)-N-(4-chlorophenyl)-2-(3-methyl-2,6-diphenylpiperidin-
4-ylidene)hydrazinecarbothioamide (10)
Chemical formula: C25H25ClN4S; White powder; Yield:
73%; mp: 194-196 ꢀC; FTIR (KBr) (ꢀmax, cmꢁ1): 3440, 3295
(NH), 3085, 3028, 2963, 2928, 2871, 2783 (CH), 1586, 1533
(C ¼ N); 1H NMR (400 MHz, CDCl3, d ppm): 0.96 (d,
J ¼ 6.8 Hz, 3H, 3’CH3), 2.30 (t, J ¼ 12 Hz, 1H), 2.64 (m, 1H,
5CHa), 2.94 (dd, J ¼ 14 Hz, 1H, 3CH), 3.55 (d, J ¼ 10 Hz,
1H, 2CH), 3.90 (dd, J ¼ 11.6 Hz, 1H, 6CH), 7.63-7.26 (m,
14H, Aromatic-H), 8.80 (s, 1H, NH), 9.32 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3): d 12.18 (CH3, C-30), 36.33 (CH,
C-5), 45.20 (CH, C-3), 60.98 (CH, C-6), 69.23 (CH, C-2),
125.18, 126.67, 127.85, 128.12, 128.20, 128.60, 128.81,
128.86, (Aromatic CH), 131.18, 136.57, 142.11, 142.52,
155.00, 176.51; HRMS (ESI/(M þ H)þ) calculated 449.1566
found 449.1487.
3.3.2. Cytotoxicity
The cytotoxic effect of the synthesized compounds 1–12 on
prostate cancer cell lines (LNCaP and PC-3) was evaluated
through 3(4,5-Dimethyl-thiazol-2-yl)2,5-diphenyl-tetrazolium
bromide (MTT) assay.[40] The cells (1 ꢂ 106 cells/mL) were
seeded into 96 well plates and treated with different concen-
trations of the compounds (1-12) ranging from 5, 25, 50, 75,
100, 125 and 150 lM obtained by appropriate dilution with
dimethylsulfoxide (DMSO, Sigma, USA) and incubated for

8
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saline) was added to each micro well and incubated for
another 4 h. The supernatant was removed and replaced
with DMSO (200 lL) and the optical density of each well
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Novel series of thiazinone and thiosemicarbazone derivatives
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using methanol as a solvent. The structures of the novel
compounds were elucidated using FTIR, NMR and mass
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and 3 showed better activity against the human prostate
cancer cell lines. Moreover, fluoro-substituted compound 3
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methoxy-substituted compound 1 shows activity against PC-
3 cell lines. When comparing the anticancer results, it is
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prostate cancer cell lines. Further, the apoptotic characteris-
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Acknowledgements
We gratefully acknowledge the funding support from University Grants
Commission (UGC) Grant No. 39–689–2010 SR New Delhi, India.
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