Synthesis and Anticancer Activity of Thiophene-2-carboxamide Derivatives and In Silico Docking Studies

Article abstract of DOI:10.1134/S1070363219070211

A novel series of thiophene-2-carboxamide derivatives are designed and synthesized, and their structures are confirmed by ¹H and ¹³C NMR, and mass spectra. The synthesized compounds are evaluated for their in vitro cytotoxic activity by MTT assay. Among the tested compounds, the derivative with 4-Cl-phenyl ring exhibits potent inhibitory activity against MCF-7, K562, HepG2, and MDA-MB-231. The molecular docking study performed for the synthesized compounds against PTP1B exhibits essential key interactions.

Full text of DOI:10.1134/S1070363219070211

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 7, pp. 1502–1512. © Pleiades Publishing, Ltd., 2019.
Synthesis and Anticancer Activity
of Thiophene-2-carboxamide Derivatives
and In Silico Docking Studies
a
b
a
a
a
K. C. Gulipalli , P. Ravula , S. Bodige , S. Endoori , P. K. R. Cherukumalli ,
c
a
J. N. Narendra Sharath Chandra , and N. Seelam *
a
Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502 India
*
e-mail: nareshvarma.klu@gmail.com
b
Department of Pharmaceutical Chemistry, Gurunanak Institutions Technical Campus,
School of Pharmacy, Hyderabad, 501506 India
c
Department of Pharmaceutical Chemistry, Guruktupa Institute of Pharmacy, Maharashtra, 431129 India
Received March 31, 2019; revised June 28, 2019; accepted revised June 30, 2019
Abstract—Anovel series of thiophene-2-carboxamide derivatives are designed and synthesized, and their structures
1
13
are confirmed by H and C NMR, and mass spectra. The synthesized compounds are evaluated for their in vitro
cytotoxic activity by MTT assay.Among the tested compounds, the derivative with 4-Cl-phenyl ring exhibits potent
inhibitory activity against MCF-7, K562, HepG2, and MDA-MB-231. The molecular docking study performed
for the synthesized compounds against PTP1B exhibits essential key interactions.
Keywords: synthesis, thiophene-2-carboxamide, anticancer, molecular docking, protein tyrosine phosphatase
inhibitor
DOI: 10.1134/S1070363219070211
1
13
INTRODUCTION
by H and C NMR, and mass spectra.All the synthesized
compounds were evaluated for their in vitro cytotoxicity
against cancer cell lines, such as MCF-7, MDA-MB-231,
K562, HepG2, HeLa, and HEK293. The following mo-
lecular docking study was performed for the synthesized
compounds against PTP1B.
Protein tyrosine phosphatase 1B (PTP1B) has been
reported to function as an oncogene in breast cancer
making its inhibitors to be potentially important targets
in treatment of cancer [1]. In the earlier studies [2] we
designed a new series of thiophene analogues that acted
against human PTP1B active site and exhibited potent to
moderate activity against cancer cell lines, such as MCF-
RESULTS AND DISCUSSION
Synthesis of methyl 4-[4-(2-naphthamido)phenyl]-
7
, MDA-MB-231, K562, HepG2, and HeLa. Among the
tested molecular structures, the compound 5b (Fig. 1)
demonstrated the potent cyto-toxicity (IC = 0.096 μM)
3-methoxythiophene-2-carboxylate 5b was carried out
by using the protocol described in our previous paper [2]
5
0
(Scheme 1). Compound 5b was treated with LiOH·H O
2
against MCF-7 cell line, and also showed the highest
PTP1B inhibitory activity (IC = 5.25 μM).
H C
3
5
0
S
O
Many heterocyclic diamides (Fig. 2) were charac-
terized by various biological activities such as anticystic
fibrosis [3], antibacterial [4, 5], anti HIV-1 [6], antifungal
O
O
O
N
H C
3
[7], and anti-cancer [8–10].
H
Based on the above, we have designed the target
5
b
molecules by attaching various alicyclic, aliphatic and
aromatic amide linkages to the 2nd position of biologi-
cally active molecule 5b for promoting its activity. The
designed compounds were synthesized and characterized
MCF-7 cell line: IC50 = 0.09 μM
PTP1B: IC = 5.25 μM
5
0
Fig. 1. Active compound 5b.
1
502

SYNTHESIS AND ANTICANCER ACTIVITY OF THIOPHENE-2-CARBOXAMIDE DERIVATIVES 1503
(a)
(b)
(c)
R
O
Cl
Cl
O
NH
O
O
N
HN
H
H
R
N
R
O
N
NH
NHOH
N
N
O
N
O
N
O
O
S
Fig. 2. Biologically active diamides: (a) L-lysine derivative, (b) 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine, and (c) furazan-3,4-
diamide.
to afford the acid intermediate 6, formation of which
was confirmed by a broad singlet at 13.01 in its H NMR
with T P and Et N in THF at room temperature within
3 3
12 h.
1
spectrum.
Anticancer activity. The synthesized compounds
a–7p were evaluated for their anticancer activity
The intermediate 6 was introduced in the reaction
with different amines to afford the corresponding amide
derivatives 7a–7p (Scheme 2, Table 1). Their structures
7
against MCF-7, MDA-MB-231, K562, HepG2, HeLa,
and HEK293 cell lines using the MTT assay [11, 12].
Doxorubicin was used as a standard drug. The calculated
IC (μM) and presented in Table 2. The synthesized com-
1
13
were confirmed by H and C NMR and mass spectra.
The coupling reaction of acid compound 6 with
50
aromatic amines was carried out under HATU/DIPEA pounds showed potent to moderate anticancer activity.
conditions. Reaction of aliphatic amines with HATU/
DIPEA in DMF, even after lengthy process contained a
high rate of initial compounds identified by LC-MS. The
alternative coupling reaction of aliphatic amines with acid
was carried out using EDC and HOBT in DMF, but it did
not proceed to completion. Upon the action of TBTU the
presence of starting material was recorded after 12 h.
Eventually, the coupling went smoothly to completion
Among the tested compounds, the product 7m with 4-Cl-
phenyl ring exhibited potent inhibitory activity against
MCF-7, K562, HepG2, and MDA-MB-231 cell lines with
IC values of 2.25, 5.83, 6.43, and 5.36 μM respectively.
50
Replacement 4-Cl-phenyl ring with 4-CH O-phenyl in
3
6g led to decrease in anticancer activity, but essentially
it still retained. Compounds with F-phenyl ring (7n and
7o) exhibited moderate antiproliferative activity against
Scheme 1. Synthesis of the active core 5b.
S
S
S
O
O
O
b
a
Br
Br
O
O
O
O
O
OH
O N
2
1
2
3
S
O
S
O
O
O
c
d
O
O
N
O
H
H N
2
5b
4
Reagents and conditions: (a) NaH (1.2 eq.), MeI (3.0 eq.), THF, 0°C, 16 h; (b) (4-nitrophenyl)boronic acid (1.2 eq.), K CO
2
3
(
3.0 eq.), Pd(PPh ) (0.05 eq.), DME, 85°C; (c) Zn (3.0 eq.), NH Cl (3.0 eq.), EtOH, 85°C, 16 h; (d) 2-Naphthoic acid (1.2 eq.),
3
4
4
HATU (1.5 eq.), DIPEA (3.0 eq.), CH Cl , room temperature, 3 h.
2
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

1504
GULIPALLI et al.
Scheme 2. Synthesis of the title compounds.
H C
3
S
OH
S
O
e
O
O
O
O
O
O
N
H C
3
N
H C
3
H
H
5b
6
S
HN
O
R
O
O
f
N
H C
3
H
7a7h
R = Aliphatic
S
HN R
O
O
O
g
N
H C
3
H
7
i7p
R = Aryl
Reagents and conditions: (e) LiOH·H O (1.5 eq., MeOH : THF = 1 : 1), room temperature, 4 h; (f) R–NH (1.2 eq., 50% T P in
2
2
3
EtOAc (2.0 eq.), Et N (2.5 eq.), THF, room temperature, 12 h; (g) HATU (1.5 eq.), DIPEA(2.0 eq.), DMF, room temperature, 5 h.
3
cancer cell lines. Replacement of F-phenyl ring with
saturated cycles (7f, 7g, 7h) led to decreased anti-cancer
activity. The aryl ring, when replaced with aliphatic side
chain 7a–7e, caused decrease in inhibitory activity.
46, and HIS 25. The extent of docking interactions of 7c
was also equally good, its naphthyl amide N–H group was
likely to participate in polar interactions with ASP 48 of
amino acid residues with 40.5% binding at a distance of
1
.32 Å. The naphthyl amide C=O group interacted with
All the synthesized compounds were assessed against
non-cancerous HEK293 cells. It is evident from Table 2
that none of the compounds displayed significant toxic
effect on HEK293 cells, indicating their specific toxic-
ity towards the cancer cells and possible safety against
normal cells.
GLN 262 of 42.9% binding at 2.12 Å distance through
water. The propyl amide carbonyl group interacted with
ALA 217 of 35.9% binding at a distance of 2.51 Å and
with SER 216 of 32.9% binding at a distance of 2.72 Å.
The samples of two- and three-dimensional structures of
compounds 7m and 7c are showed in Figs. 3, 4.
Molecular docking. In the present study, the synthe-
sized compounds were docked into PTP1B (PDB code:
EXPERIMENTAL
4
y14) to explore their docking interactions at the active
site. Docking studies revealed that the compounds 7a–7p
interacted with key amino acid residues of PTB1B such
as ASP 48, TYR 46, ARG 24, and GLN 262 [13].
All chemicals were purchased from Sigma–Aldrich,
Merck and Combi blocks, and used without further puri-
fication. Melting points were uncorrected and determined
in open capillary tubes on a Guna Digital Melting Point
apparatus. H and C NMR spectra were measured on a
BrukerAMX 300 spectrometer operating at 400 MHz for
Compound 7m showed effective interactions withASP
1
13
4
2
8 of 27.0% binding at a distance of 1.38 Å, ARG 24 of
9.4% binding at 2.95 Å distance and ARG 24 of 10.9%
1
13
binding at 3.48 Å distance through water. The compound
was surrounded by PHE 182, ALA 27, GLN 262, TYR
H and 100 MHz for C NMR using TMS as an internal
standard and DMSO-d as a solvent. Mass spectra were
6
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

SYNTHESIS AND ANTICANCER ACTIVITY OF THIOPHENE-2-CARBOXAMIDE DERIVATIVES 1505
Table 1. Protocol for the synthesis of the title compounds 7a–7p
Comp.
no.
Time, Yield,
Comp.
no.
Yield,
%
R
mp, °C
R
Time, h
5 h
mp, °C
h
%
7
a
b
c
12
81
83
76
131–133 7i
127–129 7j
120–124 7k
79
80
82
131–135
H
H
O
7
7
12
5 h
5 h
125–230
121–124
H
O
12
7
7
d
e
12
12
71
73
131–136 7l
5 h
77
68
122–226
136–140
F
F
F
135–139 7m
5 h
F
F
Cl
F
7
f
12
71
126–129 7n
5 h
71
156–160
CN
7
7
g
12
12
81
72
135–240 7o
199–205 7p
5 h
5 h
70
65
145–148
135-139
F
F
h
O
1
measured on anAgilent technologies mass spectrometer.
Elemental analysis was performed on a Perkin-Elmer 240
CHN analyzer.
H NMR spectrum (CDCl ), δ, ppm: 3.12 s (3H), 3.22
3
s (3H), 7.32 s (1H). 13C NMR spectrum, δ, ppm: 165.1,
163.1, 133.9, 121.2, 112.7, 67.3, 57.3. MS: m/z: 252 [M +
H] . Found, %: C 33.58; H 2.92. C H BrO S. Calculated,
%
+
7
7
3
Methyl 4-bromo-3-methoxythiophene-2-carboxyl-
ate (2). To a suspension of 60% NaH (1.00 g, 25 mmol) in
THF (15 mL), a solution of methyl 4-bromo-3-hydroxy-
thiophene-2-carboxylate 1(5.00 g, 21 mmol) inTHF (60 mL)
was added. The reaction mixture was stirred at 0°C for
: C 33.48; H 2.81.
Methyl 3-methoxy-4-(4-nitrophenyl)thiophene-
-carboxylate (3). To a solution of methyl 4-bromo-
-methoxythiophene-2-carboxylate 2 (3.40 g, 13.5 mmol)
2
3
in dimethoxy ethane (60 mL), were added 4-nitro phenyl-
boronicacid(2.78g,16.4mmol),K CO (2.87g,20.8mmol), and
3
0 min, and then MeI (9.00 g, 63.4 mmol) was added.
The reaction mixture was stirred at room temperature for
6 h, quenched with cold water and extracted with ethyl
2
3
H O (8 mL) at room temperature. The reaction mixture
1
2
was degassed by purging Ar for 15 min, then Pd(PPh3)4
acetate (3× 60 mL). The organic layer was washed with
H O (60 mL), brine solution (50 mL), dried over Na SO ,
(800 mg, 0.7 mmol) was slowly added. The reaction
2
2
4
and concentrated under reduced pressure to afford the
product 2 as an off white solid. Yield 64%, mp 74–78°C.
mixture was stirred at 80°C under the atmosphere of Ar
for 16 h, and the product was further extracted with ethyl
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

1506
GULIPALLI et al.
Table 2. In vitro anti cancer activity of the synthesized compounds
IC , μM
5
0
Compound
MCF-7
37.34
K562
39.12
HepG2
42.34
MDA-MB 231
>50
HeLa
>50
HEK293
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
Not determined
29.26
22.38
19.34
24.30
19.57
23.25
33.63
19.32
14.57
8.42
27.31
12.26
29.42
16.83
35.23
17.23
18.64
25.64
36.56
24.23
35.28
19.22
17.37
8.19
28.26
>50
Not determined
Not determined
43.35
25.59
Not determined
24.36
Not determined
>50
19.23
Not determined
>50
28.63
25.18
>50
g
h
i
19.87
33.42
>50
Not determined
>50
28.15
>50
27.53
25.36
33.82
14.43
12.65
22.36
15.32
17.33
29.28
0.37
Not determined
28.58
29.89
Not determined
48.23
j
26.27
k
l
10.28
9.29
>50
12.25
2.25
14.69
16.52
8.24
42.68
m
n
o
p
5.83
6.43
5.36
Not determined
Not determined
>50
12.35
15.53
36.27
0.41
10.36
12.73
16.18
28.23
34.43
0.60
8.23
22.53
26.22
42.78
Not determined
Doxorubicin
0.07
5.00
acetate (3×100 mL). The organic layer was washed with
H O (80 mL), brine solution (80 mL), dried over Na SO ,
and concentrated under reduced pressure. The obtained
crude product was purified by column chromatography
fied by column chromatography (ethyl acetate–hexane)
to afford compound 4 as an off white solid. Yield 76.5%,
2
2
4
1
mp 115–120°C. H NMR spectrum (DMSO-d ), δ, ppm:
6
3.76 s (3H), 3.80 s (3H), 5.26 br.s (2H), 6.61 d (2H, J =
13
(
ethyl acetate–hexane) to afford com-pound 3 as an off
8.4 Hz), 7.29 d (2H, J = 8.4 Hz), 7.71 s (1H). C NMR
1
white solid. Yield 85%, mp 135–140°C. H NMR (CDCl )
spectrum (DMSO-d ), δ, ppm: 160.9, 159.6, 148.4, 136.7,
3
6
spectrum, δ, ppm: 3.88 s (3H), 3.92 s (3H), 7.61 s (1H),
7
128.0, 125.4, 120.8, 116.0, 113.7, 61.4, 51.7. MS: m/z:
264.1 [M + H] . Found, %: C 59.46; H 5.06; N 5.29.
.79 d (2H, J = 9 Hz), 8.27 d (2H, J = 9 Hz). 13C NMR
+
spectrum, δ, ppm: 161.6, 160.3, 149.1, 137.4, 128.7,
C H NO S. Calculated, %: C 59.30; H 4.98; N 5.32.
1
3
13
3
1
26.1, 121.5, 116.7, 114.4, 62.1, 52.4. MS: m/z: 294 [M +
Methyl 4-[4-(2-naphthamido)phenyl]-3-methoxythio-
+
H] . Found, %: C 54.01; H 3.89; N 4.86. C H NO S.
Calculated, %: C 53.24; H 3.78; N 4.78.
1
3
11
5
phene-2-carboxylate (5b). To a solution of 2-naphthoic
acid (1.30 g, 7.6 mmol) in dichloromethane (20 mL)
were added HATU (3.46 g, 9.10 mmol) and DIPEA
(3.31 mL, 19.0 mmol) at room temperature and the mix-
ture was stirred for 20 min. Then, methyl(4-aminophenyl)-
3-methoxythiophene-2-carboxylate 4 (2.00 g, 7.6 mmol)
was added and stirring was continued at room temperature
for 4 h. The reaction mixture was diluted with water
(40 mL) and extracted with dichloromethane (3×40 mL).
Methyl 4-(4-aminophenyl)-3-methoxythiophene-
-carboxylate (4). To a solution of methyl 3-methoxy-
-(4-nitrophenyl) thiophene-2-carboxylate 3 (3.00 g,
0.2 mmol) in ethanol (30 mL) were added zinc powder
2
4
1
(2.00 g, 30.6 mmol), NH Cl (1.60 g, 30.6 mmol) and
4
catalytic amount of acetic acid at room temperature, and
the reaction mixture was stirred at 80°C for 16 h. The
obtained compound was extracted with ethyl acetate
The organic layer was washed with H O (50 mL), brine
2
(3×70 mL). The combined organic layers were washed
solution (50 mL), dried over Na SO , and concentrated.
2
4
with H O (70 mL), brine solution (70 mL), dried over
The crude product was purified by column chromatogra-
phy (ethyl acetate–hexane) to afford the title compound
2
Na SO , and concentrated. The crude product was puri-
2
4
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SYNTHESIS AND ANTICANCER ACTIVITY OF THIOPHENE-2-CARBOXAMIDE DERIVATIVES 1507
a)
(
(b)
Fig. 3. (a) Two-dimensional representation of the interacting mode of 7m on PTP1B enzyme and (b) three-dimensional structural model
of compound 7m (purple) on PTP1B enzyme.
5
b as an off white solid. Yield 80%, mp 122–129°C.
THF (1 : 1, 20.0 mL) was added LiOH·H O (0.24 g,
2
1
H NMR spectrum (DMSO-d ), δ, ppm: 3.82 s (6H),
5.75 mmol) in H O (2 mL) and the reaction mixture was
6
2
7
.65–7.63 m (5H), 7.78 d (1H, J = 6.0 Hz), 7.91 d (2H,
stirred at room temperature for 16 h, then concentrated
and the crude mixture was washed with EtOAc (1×10.0 mL).
Aqueous layer pH was adjusted to 2 with 1 N HCl and
extracted with EtOAC (2× 20.0 mL). The combined
J = 7.6 Hz), 7.98 s (1H), 8.03 s (1H), 8.09 d (1H, J =
8
spectrum (DMSO-d ), δ, ppm: 167.3, 160.8, 159.6, 138.8,
1
3
.6 Hz), 8.21 d (1H, J = 5.2 Hz), 10.71 s (1H). C NMR
6
1
1
6
5
5
59.5, 135.7, 134.6, 133.1, 130.1, 129.6, 128.7, 128.3,
organic layers were washed with H O (10.0 mL), brine
2
27.8, 127.0, 126.3, 125.4, 125.0, 125.0, 119.7, 116.4,
solution (10.0 mL), dried over Na SO ,and concentrated
2
4
+
1.8, 51.9. MS (MM): m/z: 418 [M + H] . Found, %: C
to afford the title compound as white solid. Yield 88%,
7.72; H 3.79; N 4.89. C H NO S. Calculated, %: C
1
2
4
19
4
mp 185–187°C. H NMR spectrum (DMSO-d ), δ, ppm:
6
7.69; H 3.85; N 4.84.
-[4-(2-Naphthamido)phenyl]-3-methoxythio-
phene-2-carboxylic acid (6). To a solution of methyl
1
3.01 br.s (1H), 10.57 s (1H), 8.62 s (1H), 8.12–8.10 m
4
(1H), 8.06 br.s (2H), 8.04–8.01 m (1H), 7.95–7.94 m
13
(1H), 7.92 br.s (2H), 7.66–7.63 m (4H), 3.83 s (3H). C
4
2
-[4-(2-naphthamido)phenyl]-3-methoxythiophene-
-carboxylate (5b) (2.00 g, 4.79 mmol) in MeOH :
NMR spectrum (DMSO-d ), δ, ppm: 165.6, 161.9, 159.0,
138.7, 135.7, 134.2, 132.2, 132.0, 128.9, 128.03, 128.01,
6
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

1508
GULIPALLI et al.
a)
(
(b)
Fig. 4. (a) Two-dimensional representation of the interacting mode of 7c on PTP1B enzyme and (b) three-dimensional structural model
of compound 7c (purple) on PTP1B enzyme.
1
3
1
27.8, 127.6, 126.9, 126.8, 124.4, 120.3, 118.1, 61.78.
7.39 s (1H), 3.64 s (3H). C NMR spectrum (DMSO-d ),
6
+
MS (MM): m/z: 404.1 [M + H] . Found, %: C 68.37; H
δ, ppm: 165.69, 165.62, 154.4, 152.2, 138.9, 138.6, 134.8,
134.3, 133.6, 132.1, 132.0, 129.2, 129.1, 128.9, 128.08,
128.01, 127.7, 127.6, 127.3, 126.8, 125.9, 124.7, 124.4,
22.4, 120.5, 120.3, 118.3, 61.36. MS (MM): m/z: 403.1
M+ H] . Found, %:C68.74;H4.41;N6.88. C H N O S.
4
4
.16; N 3.58. C H NO S. Calculated, %: C 68.47; H
.25; N 3.47.
General procedure for the synthesis of title com-
23 17 4
1
[
+
pounds (7a–7h). To a solution of compound 6 (0.24
mmol) in THF (5.00 mL) was added Et N (0.6 mmol) at
23 18 2 3
Calculated, %: C 68.64; H 4.51; N 6.96.
3
room temperature and stirred for 15 min. Then, a solution
4-[4-(2-Naphthamido)phenyl]-3-methoxy-N-methyl-
thiophene-2-carboxamide (7b). Off white solid. H
1
of 50% T P in EtOAc (0.48 mmol) and an appropriate
3
amine (0.27 mmol) were added and stirred at room tem-
perature for 12 h. The reaction mixture was quenched
NMR spectrum (DMSO-d ), δ, ppm: 10.58 br.s (1H), 8.61
6
s (1H), 8.12–8.09 m (6H), 8.06–8.02 m (3H), 7.96–7.93
m (2H), 7.86–7.84 m (1H), 7.80 br.s (1H), 7.66–7.62 m
(4H), 3.61 s (3H), 2.85 d (3H, J = 4.4 Hz). 13C NMR
with saturated NaHCO solu-tion (10.0 mL) and extracted
3
with EtOAC (2× 10.0 mL). The combined organic lay-
ers were washed with H O (5.00 mL), brine solution
spectrum (DMSO-d ), δ, ppm: 165.6, 160.9, 153.9, 138.8,
2
6
(
5.00 mL), dried over Na SO , and concentrated. The
134.7, 134.2, 132.1, 132.0, 129.1, 128.9, 128.02, 128.00,
127.8, 127.6, 127.3, 126.8, 125.3, 124.4, 124.2, 120.3,
61.37, 26.20. MS (MM): m/z: 417.0 [M + H] . Found,
2
4
crude product was purified by column chromatography
methanol–dichloromethane) to afford the corresponding
title compound 7a–7h.
+
(
%: C 69.33; H 4.74; N 6.61. C H N O S. Calculated,
2
4
20
2
3
%
: C 69.21; H 4.84; N 6.73.
4
-[4-(2-Naphthamido)phenyl]-3-methoxythio-
1
phene-2-carboxamide (7a). Off white solid. H NMR
spectrum (DMSO-d ), δ, ppm: 10.67 br.s (1H), 8.67 br.s
4-[4-(2-Naphthamido)phenyl]-3-methoxy-N-pro-
1
pylthiophene-2-carboxamide (7c). White solid. H
6
(1H), 8.11–7.97 m (6H), 7.85 br.s (1H), 7.75–7.65 m (5H),
NMR spectrum, (DMSO-d ) δ, ppm: 10.59 br.s (1H),
6
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

SYNTHESIS AND ANTICANCER ACTIVITY OF THIOPHENE-2-CARBOXAMIDE DERIVATIVES 1509
8
(
1
.60 s (1H), 8.12–8.02 m (5H), 7.93 br.s (1H), 7.81 s
1H), 7.65–7.62 m (5H), 3.63 s (3H), 3.31–3.26 m (2H),
.59–1.54 m (2H), 0.91 t (3H, J = 7.6 Hz). 13C NMR
spectrum (DMSO-d ), δ, ppm: 165.6, 160.3, 153.8, 138.8,
br.s (1H), 7.67–7.62 m (4H), 7.60–7.58 m (1H), 3.81 br.s
(1H), 3.63 s (3H), 1.85 br.s (2H), 1.69 br.s (2H), 1.58–1.55
m (1H), 1.42–1.35 m (4 H),1.23–1.21 m (1H). C NMR
13
spectrum (DMSO-d ), δ, ppm: 165.6, 159.4, 153.7,
6
6
1
1
6
34.6, 134.2, 132.1, 132.0, 129.0, 128.9, 128.0, 127.9,
27.8, 127.7, 127.6, 127.3, 126.8, 125.3, 124.4, 120.3,
138.8, 134.6, 134.2, 132.1, 132.0, 128.9, 128.0, 127.9,
127.8, 127.6, 127.3, 126.8, 125.3, 124.4, 120.3, 61.23,
47.33, 32.15, 24.29, 20.61. MS (MM): m/z: 485.0 [M +
1.34, 42.96, 22.49, 11.30. MS (MM): m/z: 445.1 [M +
+
+
H] . Found, %: C 69.33; H 4.74; N 6.61. C H N O S.
H] . Found, %: C 71.97; H 5.73; N 5.69. C H N O S.
24
20
2
3
29 28
2
3
Calculated, %: C 69.21; H 4.84; N 6.73.
Calculated, %: C 71.87; H 5.82; N 5.78.
4
-[4-(2-Naphthamido)phenyl]-N-(2,2-difluoro-
4
-[4-(2-Naphthamido)phenyl]-N-(tetrahydro-2H-
ethyl)-3-methoxythiophene-2-carboxamide (7d). Off
white solid. H NMR spectrum (DMSO-d ), δ, ppm: 10.62
br.s (1H), 8.64 s (1H), 8.20–8.17 m (1H), 8.13–8.11 m
3H), 8.03–7.94 m (3H), 7.89 s (1H), 7.74–7.66 m (4H),
.36–6.07 m (1H), 3.84–3.76 m (2 H), 3.65 s (3H). C
NMR spectrum (DMSO-d ), δ, ppm: 165.7, 160.9, 154.7,
38.9, 134.8, 134.3, 132.2, 132.0, 128.94, 128.91, 128.0,
27.7, 127.6, 127.4, 126.8, 126.4, 124.4, 120.4, 120.2,
17.0, 114.6, 112.3, 61.51, 41.14. MS (MM): m/z: 467.0
pyran-4-yl)-3-methoxythiophene-2-carboxamide (7h).
White solid. H NMR spectrum (DMSO-d ), δ, ppm:
0.57 br.s (1H), 8.61 s (1H), 8.12–8.09 m (1H), 8.06–8.02
m (3H), 7.96–7.93 m (2H), 7.84 br.s (1H), 7.71–7.68 m
1H), 7.65–7.63 m (4H), 4.06–4.02 m (1H), 3.87–3.85 m
2H), 3.65 s (3H), 3.45–3.40 m (2H), 1.83–1.80 m (2H),
.67–1.57 m (2H). 13C NMR spectrum (DMSO-d ), δ,
ppm: 165.6, 159.6, 153.9, 138.8, 134.6, 134.2, 132.1,
32.0, 128.9, 128.0, 127.8, 127.6, 127.4, 126.8, 125.4,
1
6
1
6
1
(
6
13
(
(
1
6
1
1
1
[
6
1
1
4
+
M + H] . Found, %: C 64.25; H 4.41; N 6.11.
24.4, 120.3, 65.82, 61.27, 45.10, 32.98. MS (MM): m/z:
87.0 [M + H] . Found, %: C 69.21; H 5.28; N 5.66.
C H F N O S. Calculated, %: C 64.37; H 4.32; N 6.01.
2
5
20
2
2
3
+
4
-[4-(2-Naphthamido)phenyl]-N-(2,2,2-trifluoro-
C H N O S. Calculated, %: C 69.11; H 5.39; N 5.76.
2
8
26
2
4
ethyl)-3-methoxythiophene-2-carboxamide (7e). White
solid. H NMR spectrum (DMSO-d ), δ, ppm: 10.58
br.s (1H), 8.61 s (1H), 8.12–8.02 m (5H), 7.97–7.95 m
2H), 7.66–7.62 m (5H), 4.20–4.11 m (2 H), 3.64 s (3H).
1
General procedure for the synthesis of title com-
6
pounds 7i–7p. To a solution of compound 6 (0.24 mmol)
in DMF (5.00 mL) were added HATU (0.29 mmol) and
DIPEA (0.49 mmol) at room temperature and stirred for
(
1
3
C NMR spectrum (DMSO-d ), δ, ppm: 165.6, 160.9,
6
1
5 min. Then, the appro-priate amine (0.27 mmol) was
1
1
1
55.0, 138.9, 134.8, 134.2, 132.1, 132.0, 128.9, 128.0,
27.8, 127.7, 127.6, 127.4, 126.8, 124.4, 123.4, 122.7,
22.5, 120.3, 61.56, 60.42. MS (MM): m/z: 485.1 [M +
added, and the mixture was stirred at room temperature
for 5 h. Upon completion of the process the reaction
mixture was diluted with water (10.0 mL) and extracted
with EtOAC (2×10.0 mL). The combined organic layers
were washed with H O (5.00 mL), brine solution (5.00 mL),
dried over Na SO ,and concentrated. The crude product was
purified by column chromatography (methanol–dichlo-
romethane) to afford the correspond-ing title compound
i–7p.
4-[4-(2-Naphthamido)phenyl]-N-(4-methylbenzyl)-
3-methoxythiophene-2-carboxamide (7i). White solid.
H NMR spectrum (DMSO-d ), δ, ppm: 10.60 br.s (1H),
.60 s (1H), 8.38–8.35 m (1H), 8.12–8.09 m (1H), 8.07–
.02 m (3H), 7.94 br.s (3H), 7.67–7.62 m (4H), 7.26–7.24
+
H] . Found, %: C 61.88; H 3.86; N 5.88. C H F N O S.
25 19 3 2 3
Calculated, %: C 61.98; H 3.95; N 5.78.
2
4
-[4-(2-Naphthamido)phenyl]-N-(1-cyanocyclo-
2
4
propyl)-3-methoxythiophene-2-carboxamide (7f).
White solid. H NMR spectrum (DMSO-d ), δ, ppm:
0.57 br.s (1H), 8.68 s (1H), 8.12–8.01 m (5H), 7.93–7.91
m (2H), 7.66–7.61 m (5H), 3.62 s (3H), 1.60–1.56 m
2H),1.37–1.32 m (2H). C NMR spectrum (DMSO-d ),
δ, ppm: 170.9, 165.7, 166.8, 160.6, 144.1, 140.0, 139.5,
37.2, 134.1, 134.0, 133.2, 133.0, 132.9, 132.7, 132.1,
32.0, 129.6, 127.7, 127.5, 126.1, 125.6, 125.4, 66.80,
5.67, 25.56, 21.70. MS (MM): m/z: 468.1 [M + H] .
1
6
1
7
13
(
6
1
1
6
1
6
8
8
+
Found, %: C 69.47; H 4.44; N 8.89. C H N O S. Cal-
culated, %: C 69.36; H 4.53; N 8.99.
2
7
21
3
3
m (2H), 7.16–7.14 m (2H), 4.50 d (2H, J = 6.0 Hz), 3.69
s (3H), 2.28 s (3H). 13C NMR spectrum (DMSO-d ), δ,
6
4
-[4-(2-Naphthamido)phenyl]-N-cyclohexyl-3-me-
ppm: 165.6, 162.4, 154.1, 138.7, 136.3, 135.8, 134.7,
134.2, 132.08, 132.01, 129.0, 128.9, 128.8, 128.0, 127.9,
127.8, 127.6, 127.3, 127.1, 126.8, 125.8, 124.3, 124.0,
120.5, 61.43, 42.15, 20.60. MS (MM): m/z: 507.0 [M +
thoxythiophene-2-carboxamide (7g). Off white solid.
H NMR spectrum (DMSO-d ), δ, ppm: 10.57 br.s (1H),
.61 s (1H), 8.11–8.01 m (4H), 7.96–7.94 m (2H), 7.83
1
6
8
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

1510
GULIPALLI et al.
+
H] . Found, %: C 73.59; H 5.06; N 5.64. C H N O S.
J = 8.8 Hz), 7.69–7.62 m (4H), 7.44 d (2H, J = 8.8 Hz),
3
1
26
2
3
1
3
Calculated, %: C 73.49; H 5.17; N 5.53.
3.75 s (3H). C NMR spectrum (DMSO-d ), δ, ppm:
6
1
65.6, 162.2, 154.6, 138.9, 137.1, 134.7, 134.2, 132.1,
N-(2-Methoxybenzyl)-4-[4-(2-naphthamido)phenyl]-
-methoxythiophene-2-carboxamide (7j). White solid.
132.0,128.9, 128.8, 128.6, 128.4, 128.0, 127.8, 127.6, 127.5,
3
1
126.5, 124.4, 123.2, 121.8, 120.4, 115.1, 61.70. MS (MM):
m/z: 513.0 [M + H] . Found, %: C 67.82; H 4.23; N 5.35.
C H ClN O S. Calculated, %: C 67.90; H 4.13; N 5.46.
H NMR spectrum (DMSO-d ), δ, ppm: 10.62 br.s (1H),
6
+
8
.60 s (1H), 8.28–8.25 m (1H), 8.12–7.92 m (6H),
.89–7.84 m (1H), 7.67–7.64 m (4H), 7.31–7.24 m (2H),
.05–6.92 m (2H), 4.52 d (2H, J = 6.0 Hz), 3.87 s (3H),
29
21
2 3
7
7
3
1
1
1
1
4-[4-(2-Naphthamido)phenyl]-N-(2-fluorophenyl)-
.72 s (3H). 13C NMR spectrum (DMSO-d ), δ, ppm:
3-methoxythiophene-2-carboxamide (7n). White solid.
6
1
H NMR spectrum (DMSO-d ), δ, ppm: 10.61 br.s (1H),
65.79, 165.71, 160.3, 156.8, 154.0, 138.7, 134.6, 134.2,
32.07, 132.02, 129.0, 128.9, 128.4, 128.0, 127.9, 127.8,
27.7, 127.6, 127.3, 126.8, 126.3, 125.9, 124.3, 124.1,
20.5, 120.3, 120.2, 110.5, 61.38, 55.35, 38.33. MS (MM):
6
9.82 s (1H), 8.62 s (1H), 8.29–8.25 m (1H), 8.12–8.10
m (1H), 8.07 br.s (2H), 8.04–8.02 m (1H), 8.00–7.90 m
(3H), 7.69–7.62 m (4H), 7.38–7.33 m (1H), 7.27–7.16 m
13
+
(2H), 3.74 s (3H). C NMR spectrum (DMSO-d ), δ, ppm:
m/z: 523.0 [M + H] . Found, %: C 71.34; H 5.12; N 5.24.
6
1
1
1
1
65.6, 158.7, 154.5, 153.8, 151.4, 139.1, 134.8, 134.2,
32.1, 132.0, 128.9, 128.6, 128.0, 127.8, 127.6, 127.5,
26.8, 126.1, 126.0, 124.8, 124.7, 124.4, 123.6, 122.1,
C H N O S. Calculated, %: C 71.24; H 5.01; N 5.36.
31
26
2
4
4-[4-(2-Naphthamido)phenyl]-N-(4-methoxybenzyl)-
3
-methoxythiophene-2-carboxamide (7k). Off-white
20.4, 115.3, 115.1, 61.67. MS (MM): m/z: 496.9 [M +
1
solid. H NMR spectrum (DMSO-d ), δ, ppm: 10.57 br.s
6
+
H] . Found, %: C 70.25; H 4.16; N 5.53. C H FN O S.
2
9
21
2
3
(1H), 8.60 s (1H), 8.31–8.30 m (1H), 8.11–8.09 m (1H),
Calculated, %: C 70.15; H 4.26; N 5.64.
-[4-(2-Naphthamido)phenyl]-N-(3-fluorophenyl)-
-methoxythiophene-2-carboxamide (7o). White solid.
8
.06–8.01 m (3H), 7.94 d (2H, J = 8.8 Hz), 7.84 br.s
4
(1H), 7.66–7.62 m (4H), 7.29 d (2H, J = 8.8 Hz), 6.91 d
3
(
2H, J = 8.4 Hz), 4.45 d (2H, J = 6.0 Hz), 3.73 s (3H),
1
H NMR spectrum (DMSO-d ), δ, ppm: 10.62 br.s (1H),
.60 s (3H). 1 C NMR spectrum (DMSO-d ), δ, ppm:
3
6
3
1
1
1
6
6
9
.91 s (1H), 8.64 s (1H), 8.13 br.s (1H), 8.04–7.93 m (5H),
.78–7.41 m (8H), 7.00–6.95 m (1H), 3.76 s (3H). 13
NMR spectrum (DMSO-d ), δ, ppm: 165.6, 159.3, 154.7,
66.09, 162.7, 154.5, 139.0, 136.6, 136.2, 135.0, 134.5,
32.4, 132.3, 129.3, 129.2, 129.1, 128.3, 128.2, 128.1,
27.9, 127.7, 127.5, 127.2, 126.1, 124.6, 124.4, 120.8,
7
C
6
1
1
1
39.0, 134.8, 134.3, 134.2, 132.2, 132.0, 130.4, 130.3,
28.9, 128.8, 128.0, 127.6, 127.5, 126.8, 126.7, 124.4,
1.76, 55.37, 42.47, 20.92. MS (MM): m/z: 523.0 [M +
+
H] . Found, %: C 71.35; H 5.11; N 5.25. C H N O S.
3
1
26
2
4
23.1, 120.4, 120.2, 61.75. MS (MM): m/z: 496.9 [M +
Calculated, %: C 71.24; H 5.01; N 5.36.
+
H] . Found, %: C 70.26; H 4.15; N 5.54. C H FN O S.
2
9
21
2
3
Calculated, %: C 70.15; H 4.26; N 5.64.
4
-[4-(2-Naphthamido)phenyl]-3-methoxy-N-
phenethylthiophene-2-carboxamide (7l). Off-white
4-[4-(2-Naphthamido)phenyl]-3-methoxy-N-
(pyridin-3-yl)thiophene-2-carboxamide (7p). White
1
solid. H NMR spectrum (DMSO-d ), δ, ppm: 10.59 br.s
6
1
(1H), 8.62 s (1H), 8.12–8.10 m (1H), 8.07–8.02 m (3H),
solid. H NMR spectrum (DMSO-d ), δ, ppm: 10.65
6
7
7
3
.96 d (2H, J = 8.4 Hz), 7.86–7.83 m (1H), 7.81 br.s (1H),
br.s (1H), 9.91 s (1H), 8.94 s (1H), 8.37–8.36 m (1H),
8.23–8.20 m (1H), 8.13–8.09 m (2H), 8.03–8.01 m (3H),
7.97 br.s (1H), 7.74–7.65 m (6H), 7.44–7.41 m (1H), 3.77
.68–7.61 m (4H), 7.34–7.28 m (4H), 7.24–7.20 m (1H),
1
3
.62–3.57 m (2H), 3.47 s (3H), 2.88 br.s (2H). C NMR
1
3
spectrum (DMSO-d ), δ, ppm: 165.6, 162.2, 153.9, 139.2,
s (3H). C NMR spectrum (DMSO-d ), δ, ppm: 165.7,
6
6
1
1
1
5
38.8, 134.6, 134.2, 132.2, 132.0, 129.0,128.9, 128.6,
28.4, 128.0, 127.8, 127.6, 127.3, 126.8, 126.1, 125.6,
24.4, 124.2, 120.4, 61.18, 40.16, 34.99. MS (MM): m/z:
165.6, 163.2, 162.2, 159.5, 152.2, 144.8, 142.0, 139.0,
138.5, 134.9, 134.8, 134.2, 133.6, 132.1, 132.0, 129.2, 128.9,
128.8, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 126.8,
124.4, 123.5, 123.0, 122.4, 120.4, 118.3, 61.74. MS (MM):
+
07.0 [M + H] . Found, %: C 73.59; H 5.26; N 5.63.
+
m/z: 480.1 [M + H] . Found, %: C 70.22; H 4.31; N 8.66.
C H N O S. Calculated, %: C 73.49; H 5.17; N 5.53.
31
26
2
3
C H N O S. Calculated, %: C 70.13; H 4.41; N 8.76.
2
8
21
3
3
4
-[4-(2-Naphthamido)phenyl]-N-(4-chlorophenyl)-
3
-methoxythiophene-2-carboxamide (7m). White solid.
In vitro evaluation of anticancer activity. MCF-7,
1
H NMR spectrum (DMSO-d ), δ, ppm: 10.61 br.s (1H),
9
MDA-MB-231, K562, HepG2, HeLa, and HEK293
were procured from National Centre for Cell Sciences,
Pune, India. All tumour cells were grown in DMEM
6
.84 s (1H), 8.62 s (1H), 8.12–8.10 m (1H), 8.07 br.s
(
2H), 8.04–8.02 m (1H), 7.99–7.95 m (3H), 7.79 d (2H,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

SYNTHESIS AND ANTICANCER ACTIVITY OF THIOPHENE-2-CARBOXAMIDE DERIVATIVES 1511
1
13
media supplemented with 10% heat inactivated foe-
tal bovine serum (FBS), 100 mg/mL streptomycin,
H and C NMR, and mass spectra. The synthesized com-
pounds are evaluated for their in vitro cytotoxic activity
by MTT assay. The compound 7m containing the 4-Cl-
phenyl substituent exhibits the potent inhibitory activity
against MCF-7, K562, HepG2, and MDA-MB-231 cell
lines. The molecular docking study performed for the
synthesized compounds against PTP1B indicates their
possible binding interactions at the active site. The ac-
cumulated data indicate that the tested compounds may
lead to potent anticancer agents.
1
00 IU/mL penicillin, and 2 mM-glutamine. All cell
lines were maintained under humidified atmosphere
with 5% CO at 37°C. Cell viability was determined by
2
3
-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
3
bromide (MTT) assay. Cells (5×10 cells/well) were
inoculated in 96-well culture plate and cultured with or
without compounds at different concentrations (10, 5, 1,
0.5, 0.1, and 0.01 μM for dose response study) in dupli-
cates for 24 h in a final volume of 200 μl. Afterwards,
the medium was removed and 20 μL of MTT (5 mg/mL
in PBS) were added. After 3 h of incubation at 37°C,
The authors would like to thank the management
of AMRI Hyderabad research centre for giving an op-
portunity to carry out this research. The authors are also
thankful to Sai Innotech labs Pvt. Ltd. for providing
synthesis facility.
1
00 μL of DMSO were added to each well, and plates
were agitated for 1 min. The absorbance was measured
at 570 nm with a multi-well plate reader (Victor3, Perkin
Emler). Percent inhibition of proliferation was calculated
as a fraction of control.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
Molecular docking. Docking was performed on
Windows 2002, MOE 2008.10 version. Protein tyrosine
phosphatase 1B was retrieved from the protein data bank
(
PDB code: 4y14), and the enzyme was visualized using
1
. Basu, S., Prasad, U.V., Barawkar, D.A., De, S., Palle, V.P.,
Menon, S., Patel, M., Thorat, S., Singh, U.P., Sarma, K.D.,
Waman, Y., Niranjan, S., Pathade, V., Gaur, A.,
Reddy, S., and Ansari, S., Bioorg. Med. Chem. Lett.,
sequence option, and further co-factors were deleted. The
partial charge of the protein was adjusted with the help
of force field method AMBER 99. Later, the protein was
subjected to 3D protonation at cut off 12.0, and further
hydrogen was added according to standard geometry
and the receptor was energy minimized using force field
MMFF94x at 0.01 kJ/mol gradients. The ligand structures
were written by using a builder module, and adjusting
the partial charges using Hamilton MMFF94 force field
method and subsequently 3D protonation and hydrogen
addition was performed according to standard geometry.
Ligands were energy minimized at cut off 12 using force
field MMFF94x at 0.01 kJ/mol gradient and 6.0 Å grid
was generated on the active site of the enzyme. Docking
was performed using the option simulation followed by
dock on selected active site amino acids using sequence
option, and eventually docked using setting options such
as receptor and solvent, alpha triangle, selected residues,
affinity dG, force field refinement, and best 30 poses. Af-
ter obtaining docking results, the best pose was retained.
The resultant best pose score values in the series were
used for analysis of docking and interaction.
2
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CONCLUSIONS
8
. Fun, H.K., Pai, K.S.R., Shetty, P., Isloor, A.M., and
Sankappa, R.U., Arab. J. Chem., 2014, vol. 8, p. 317. doi
10.1016/j.arabjc.2014.01.018
Anovel series of thiophene-2-carboxamide derivatives
is synthesized and the molecular structures confirmed by
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

1512
GULIPALLI et al.
9
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019