Synthesis, characterization and anticancer activity of 5-substituted 4,5,6,7-tetrahydro-N-(tetrahydro-2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carboxamide derivatives

Article abstract of DOI:10.14233/ajchem.2018.21418

4,5,6,7-Tetrahydrothieno pyridine (THTP) and their derivatives are an important heterocyclic compounds that exhibits various biological activities viz.,antimicrobial activity, antileishmanial activity, antiarrhythmic activity, antiinflammatory activity, antihyperlipidemic activity, antidepressant activity, anticancer activity, antiplatelet activity and antidiabetic etc. The present study describes the synthesis, characterization and in vitro cytotoxic potential against human lung carcinoma of some novel derivatives of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (7A-M) with benzylic and amide substitution on the nitrogen atom of tetrahydro theino pyridine ring. The synthetic steps involves (i) Vilsmeyer protocol in step 1 (ii) formation of tetrahydothieno[3,2-c]pyridine ring in presence of 2-mercaptoacetate in step 2 (iii) alkaline hydrolysis followed by amide coupling with tetrahydro-2H-pyran-4-amine in step 3 and step 4. The newly synthesized compounds 7A-M was sufficiently characterized by ¹ H NMR, IR and mass techniques. Furthermore, these derivatives were screened for their in vitro cytotoxic potential against human lung carcinoma (HCT-116) cell line using the MTT assay. Compound 7B (IC50: 69.52 μg) and compound 7K (IC50: 66.35 μg) exhibited significant activity at micro molar concentration when compared to standard drug camptothecin.

Full text of DOI:10.14233/ajchem.2018.21418

Asian Journal of Chemistry; Vol. 30, No. 9 (2018), 2063-2068
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21418
Synthesis, Characterization and Anticancer Activity of 5-Substituted 4,5,6,7-Tetrahydro-
N-(tetrahydro-2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carboxamide Derivatives
1
1
N. SREE LAKSHMANA RAO , MANDAVA V. BASAVESWARA RAO2,* and K.R.S. PRASAD
1Department of Chemistry, K.L. University, Vaddeswaram, Guntur-522 502, India
2Department of Chemistry, Krishna University, Machilipatnam-521 001, India
*Corresponding author: E-mail: mandavabasaveswararaov@gmail.com
Received: 2 May 2018;
Accepted: 9 June 2018;
Published online: 31 July 2018;
AJC-19021
4,5,6,7-Tetrahydrothieno pyridine (THTP) and their derivatives are an important heterocyclic compounds that exhibits various biological
activities viz.,antimicrobial activity, antileishmanial activity, antiarrhythmic activity, antiinflammatory activity, antihyperlipidemic activity,
antidepressant activity, anticancer activity, antiplatelet activity and antidiabetic etc. The present study describes the synthesis, characterization
and in vitro cytotoxic potential against human lung carcinoma of some novel derivatives of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (7A-
M) with benzylic and amide substitution on the nitrogen atom of tetrahydro theino pyridine ring. The synthetic steps involves (i)Vilsmeyer
protocol in step 1 (ii) formation of tetrahydothieno[3,2-c]pyridine ring in presence of 2-mercaptoacetate in step 2 (iii) alkaline hydrolysis
followed by amide coupling with tetrahydro-2H-pyran-4-amine in step 3 and step 4. The newly synthesized compounds 7A-M was
sufficiently characterized by 1 H NMR, IR and mass techniques. Furthermore, these derivatives were screened for their in vitro cytotoxic
potential against human lung carcinoma (HCT-116) cell line using the MTT assay. Compound 7B (IC50: 69.52 µg) and compound 7K
(IC50: 66.35 µg) exhibited significant activity at micro molar concentration when compared to standard drug camptothecin.
Keywords: Anticancer activity, Camptothecin, Synthesis, Tetrahydothieno[3,2-c]pyridine, Villsmeyer-Hack.
in vitro cytotoxic potential against human lung carcinoma of
some novel derivatives of 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine (7A-M) with benzylic and amide substitution on
the nitrogen of the thieno pyridine ring.
INTRODUCTION
4,5,6,7-Tetrahydrothieno-pyridine (THTP) represents a
widely used lead structure with multitude of interesting
applications in numerous pharmacological fields. Thus, various
biological activities such as antimicrobial activity [1-15], anti-
leishmanial activity [16], antiarrhythmic activity [17], anti-
inflammatory activity [18-22], antihyperlipidemic activity
[23], antidepressant activity [24], anticancer activity [25,26],
antiplatelet activity [27,28], antidiabetic [29-31] and anti-
tuberculosis activity [32,33] have been reported and explored
till date. Fusion of other nuclei like benzene, indole, oxadiazole,
triazole rings to THTP nucleus enhances the pharmacological
activities than its parent nucleus.
EXPERIMENTAL
The solvents were purified according to standard proce-
dures prior to use and all commercial chemicals were used as
received. For thin-layer chromatography (TLC) analysis, Merck
pre-coated plates (silica gel 60 F254) were used and eluting
solvents are indicated in the procedures. Merck silica gel 60
(230-400 mesh) was used for flash column chromatography.
Melting point determinations were performed by using Mel-
1
temp apparatus and are uncorrected. H NMR spectra were
The incorporation of benzylic or substituted benzylic
groups on the nitrogen of the thienopyridine ring can bring an
extensive modification in the biological activities of parent
compound [34-36]. Hence, different substitutions at nitrogen
of the biological activity of the new chemical entities (NCEs).
The present study describes the synthesis, characterization and
recorded on a Varian Unity instrument at room temperature at
400 MHz. Chemical shifts are reported in δ parts per million
(ppm) downfield from tetramethylsilane (TMS) with reference
to internal solvent and coupling constants in Hz. The mass
spectra were recorded onAgilent ion trap MS. Infrared spectra
were recorded on a Perkin Elmer FT-IR spectrometer.
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2064 Lakshmana Rao et al.
Asian J. Chem.
tert-Butyl 3-formyl-4-oxopiperidine-1-carboxylate (2):
To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxy-
late (1) (40 g, 0.20 mol) in dichloromethane (500 mL) was
added DMF (30.9 mL, 0.40 mol) followed by POCl3 (30 mL,
0.32 mol) at 0 °C and the reaction mixture was stirred at room
temperature for 4 h.After completion of the reaction (monitored
byTLC), the reaction mixture was quenched with aqueous sodium
acetate solution (at 0 °C), diluted with water and extracted
with ethyl acetate (2 × 100 mL). The organic layer was washed
with water (3 × 50 mL), brine solution, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure
to obtain compound 2. The crude compound was used in the
next step without any purification.Yellow oil;Yield: 30 g, 65 %;
Elemental analysis, C11H17NO4, calcd. (found) %: C 58.14 (58.11),
H 7.54 (7.56), N 6.16 (6.12). IR (KBr, νmax, cm–1): 2926 (-CH
str.), 1695, 1635 (-C=O str.), 1122 (-C-OC- str.); 1H NMR (500
MHz, CDCl3) δ: 10.14 (s, 1H), 4.15 (d, J = 7.0 Hz, 2H), 3.72
(t, J = 6.0 Hz, 2H), 2.44 (t, J = 6.0 Hz, 2H), 2.09 (brs, 2H),
1.45 (s, 9H); MS: calcd. for C15H21NO4S [m/z] 311.40; found:
312.6 [M+H]+.
5-tert-Butyl 2-ethyl-6,7-dihydrothieno[3,2-c]pyridine-
2,5-(4H)-dicarboxylate (3): To a stirred solution of compound
2 (30 g, 0.132 mol) in dichloromethane (150 mL) was added
triethyl amine (29.1 mL, 0.211 mol) and ethyl 2-mercapto-
acetate (17.3 mL, 0.158 mol) at 0 °C. The reaction mixture
was stirred at 45 °C for 16 h. After completion of reaction, the
reaction mixture was diluted with ice cold water and extracted
with dichloromethane (3 × 50 mL). The organic layer was washed
with water, brine solution, dried over anhydrous sodium sulphate,
filtered and evaporated under reduced pressure to afford com-
pound 3. The crude compound (30 g) was used in the next step
without any further purification. Elemental analysis, C15H21NO4S,
calcd. (found) %: C 57.86 (57.84), H 6.80 (6.77), N 4.50 (4.53).
5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-
c]pyridine-2-carboxylic acid (4): To a stirred solution of
compound 3 (30g, 0.096 mol) in a mixture of tetrahydrofuran,
methanol and water (250 mL, 3:1:1) was added sodium
hydroxide (11.5 g, 0.288 mol) and stirred at room temperature
for 16 h. After completion of reaction, the reaction mixture
was evaporated under reduced pressure to obtain a yellow
viscous residue. The residue was acidified with aqueous citric
acid solution to about pH 4 and the resulting mixture was stirred
at 0 °C for 15 min. The obtained solid was filtered, washed with
water and dried under vacuum to afford compound 4. Yellow
solid;Yield: 15 g, 55 %; m.p.: 179-181 °C; Elemental analysis,
C13H17NO4S, calcd. (found) %: C 55.11 (55.15), H 6.05 (6.09),
N 4.94 (4.97). IR (KBr, νmax, cm–1): 3598, 3492, 2982, 2441,
1658, 1560, 1465, 1416, 1256, 1156, 1012, 947, 856, 759, 601,
506. 1H NMR (400 MHz, CDCl3) δ: 7.57 (s, 1H), 4.50 (brs, 2H),
3.73 (d, J = 6.0 Hz, 2H), 2.89 (brs, 2H), 1.49 (s, 9H); MS:
calcd. for C13H17NO4S [m/z] 283.34; found: 282.21 [M-H]+.
tert-Butyl 2-(tetrahydro-2H-pyran-4-ylcarbamoyl)-
6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (5):
The a stirred mixture of compound 4 (8 g, 28.26 mmol) in
DMF (80 mL) was sequentially added EDC·HCl (8.2 g, 42.3
mmol), HOBt (4.5 g, 33.8 mmol), diisopropylethylamine (14.7
mL, 84.6 mmol) and tetrahydro-2H-pyran-4-amine (4.2 g, 31.0
mmol) at room temperature stirred for 5 h. After completion
of reaction, the reaction mixture was quenched with water and
extracted with ethyl acetate (4 × 25 mL). The organic layer
was washed with water, brine solution, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure
to afford compound 5. White solid;Yield: 5 g, 77 %; m.p.: 146-
149 °C. Elemental analysis, C18H26N2O4S, calcd. (found) %:
C 58.99 (58.96), H 7.15 (7.12), N 7.64 (7.62). IR (KBr, νmax
,
cm–1): 3274, 2964, 2845, 2360, 1696, 1616, 1539, 1402, 1244,
1164, 1093, 869, 777, 661; 1H NMR (400 MHz, DMSO-d6) δ:
8.21 (d, J = 6.4 Hz, 1H), 7.53 (s, 1H), 4.40 (s, 1H), 3.94-3.85
(m, 3H), 3.63 (t, J = 5.6 Hz, 2H), 3.38-3.33(m, 2H), 2.78 (s, 2H),
1.74-1.70 (m, 2H), 1.58-1.54 (m, 4H), 1.42 (s, 9H); 13C NMR
(100 MHz, DMSO-d6): δ160.3, 153.9, 137.9, 137.3, 132.9, 125.9,
79.2, 66.0 (2C), 45.6 (2C), 43.5 (2C), 32.4 (2C), 28.0 (4C);
MS: calcd. for C18H26N2O4S [m/z] 366.48; found: 367.30 [M+H]+.
N-(Tetrahydro-2H-pyran-4-yl)-4,5,6,7-Tetrahydro-
thieno[3,2-c]pyridine-2-carboxamide.TFA salt (6): To a
stirred solution of compound 5 (2 g, 5.46 mmol) in DCM (25
mL) was added trifluoroacetic acid (0.8 mL, 10.0 mmol) and
the reaction mixture was stirred at 0 °C for 16 h.After completion
of reaction, the reaction mixture was evaporated under reduced
pressure to afford compound 6. White solid;Yield: 1.2 g, 77 %;
m.p.: 194-197 °C; Elemental analysis, C13H18N2O2S, calcd.
(found) %: C 58.62 (58.60), H 6.81 (6.78), N 10.52 (10.54).
IR (KBr, νmax, cm–1): 3295, 2991, 2839, 2360, 1687, 1623, 1687,
1623, 1538, 1204, 1145, 836, 792, 719; 1H NMR (400 MHz,
DMSO-d6) δ: 9.06 (brs, 1H), 8.33 (d, J = 7.6 Hz, 1H), 7.56 (s,
1H), 4.20 (brs, 2H), 3.93-3.84 (m, 3H), 3.0 (t, J = 5.6 Hz, 2H),
1.74-1.71 (m, 2H), 1.58-1.49 (m, 2H); 13C NMR (100 MHz,
DMSO-d6): δ160.1, 138.48, 136.42, 128.84, 126.0, 66.1, 45.81,
41.97, 40.75, 32.42, 21.75. MS: calcd. for C15H18F3N2O3S [m/z]
363.38; found: 267.0 [M-TFA]+.
General experimental procedure for the synthesis of
5-substituted 4,5,6,7-tetrahydro-N-(tetrahydro-2H-pyran-
4-yl)thieno[3,2-c]pyridine-2-carboxamide derivatives (7A-
7M): To a stirred solution of compound 6 (150 mg, 0.57 mmol)
in DMF (5 mL) was added K2CO3 (0.23 g, 1.7 mmol) followed
by respective aryl/hetero aryl halides (0.08 mL, 0.67 mmol).
The reaction mixture was stirred at 0 °C for 15 min and later
to room temperature for 6 h. The progress of the reaction was
monitored by TLC. After completion of reaction, the reaction
mixture was quenched with water (10 mL) and extracted with
ethyl acetate (2 × 10 mL). The organic layer was washed with
water, brine solution, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure to produce
compound 7A-M.Yields of the compounds vary between 74-
92 %.
5-Benzyl-4,5,6,7-tetrahydro-N-(tetrahydro-2H-pyran-
4-yl)thieno[3,2-c]pyridine-2-carboxamide (7A):White solid;
Yield: 135 mg, 92 %; m.p.: 181-183 °C; Elemental analysis,
C20H24N2O2S, calcd. (found) %: C 67.38 (67.36), H 6.79 (6.77),
N 7.86 (7.85). IR (KBr, νmax, cm–1): 3445, 3209, 3053, 2966,
2925, 2843, 2791, 1695, 1607, 1542, 1460, 1331, 1305, 1275,
1242, 1142, 1086, 1054, 1008, 885, 745, 706, 605, 570; 1H NMR
(400 MHz, DMSO-d6) δ: 7.37-7.20 (m, 5H), 7.12 (s, 1H), 5.65
(d, J = 8.0 Hz, 1H), 4.17-4.16 (m, 1H), 3.98 (t, J = 2.0 Hz, 2H),
3.70 (s, 2H), 3.54-3.47 (m, 4H), 2.88 (d, J = 4.8 Hz, 2H), 2.81
(t, J = 4.5 Hz, 2H), 1.99-1.95 (m, 2H); 13C NMR (100 MHz,

Vol. 30, No. 9 (2018)
Synthesis, Characterization and Anticancer Activity of 4,5,6,7-Tetrahydrothieno Pyridine Derivatives 2065
DMSO-d6): δ 161.1, 141.6, 137.7, 137.0, 135.9, 135.6, 128.9
(2C), 64.0 (2C), 60.0, 55.1, 52.8, 51.9, 36.6 (2C), 24.5; MS:
calcd. for C20H24N2O2S [m/z] 356.48; found: 357.41 [M+H]+.
5-(2-Chlorobenzyl)-4,5,6,7-tetrahydro-N-(tetrahydro-
2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carboxamide (7B):
Light brown solid; Yield: 139 mg, 86 %; m.p.: 153-155 °C;
Elemental analysis, C20H23N2O2SCl, calcd. (found) %: C 61.45
(61.46), H 5.93 (5.91), N 7.17 (7.15). IR (KBr, νmax, cm–1):
3280, 3065, 2949, 2924, 2846, 1614, 1571, 1535, 1466, 1440,
1327, 1245, 1135, 1090, 1047, 874, 798, 747, 657; 1H NMR
(400 MHz, DMSO-d6) δ: 8.15 (d, J = 7.6 Hz, 1H), 7.53 (d, J =
6.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J
= 8.0 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 3.92-3.84 (m, 2H), 3.77
(s, 2H), 3.54 (s, 2H), 3.38-3.33 (m, 3H), 2.82-2.78 (m, 4H), 1.72
(t, J = 10.8 Hz, 2H), 1.57-1.47 (m, 2H); 13C NMR (100 MHz,
DMSO-d6): δ 160.4, 138.1, 136.8, 135.7, 134.5, 133.2, 130.6,
129.2, 128.6, 127, 126.2, 66.1 (2C), 57.5, 52.1, 49.6, 45.6,
32.4 (2C), 25.1; MS: calcd. for C20H23N2O2SCl [m/z] 390.93;
found: 391.76 [M+H]+.
1.46 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ160.62, 140.6,
138.7, 136.7, 135.5, 134.3 (2C), 132.3, 131.5, 128.3, 115.8,
112.8, 65.09 (2C), 59.12, 56.21, 55.32, 55.16, 36.44 (2C),
22.2; MS: calcd. for C21H23N3O2S [m/z] 381.49; found: 382.53
[M+H]+.
5-(2,4,6-Triethylbenzyl)-4,5,6,7-tetrahydro-N-(tetra-
hydro-2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carbox-
amide (7F): Off white solid;Yield: 155 mg, 85 %; m.p.: 163-
165 °C; Elemental analysis, C26H36N2O2S, calcd. (found) %:
C 70.87 (70.89), H 8.23 (8.25), N 6.36 (6.38). IR (KBr, νmax, cm–1):
3307, 2962, 2837, 2763, 1618, 1568, 1532, 1459, 1367, 1323,
1
1240, 1139, 1093, 1008, 872, 618; H NMR (400 MHz,
DMSO-d6)) δ: 8.10 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 6.87 (s,
2H), 3.85 (d, J = 11.6 Hz, 3H), 3.64 (s, 1H), 3.38-3.28 (m,
2H), 2.72-2.68 (m, 8H), 2.56-2.50 (m, 3H), 1.69 (brs, 2H),
1.54-1.48 (m, 2H), 1.23-1.10 (m, 8H); 13C NMR (100 MHz,
DMSO-d6): δ 161.92, 146.6, 142.7, 136.7, 136.2 (2C), 135.5,
134.3 (2C), 131.5, 65.11 (2C), 57.12, 56.6, 55.7, 55.16, 36.34
(2C), 27.8, 26.2 (2C), 22.2, 14.6 (2C), 14.3; MS: calcd. for
C26H36N2O2S [m/z] 440.64; found: 441.33 [M+H]+.
5-(2-Fluorobenzyl)-4,5,6,7-tetrahydro-N-(tetrahydro-
2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carboxamide (7C):
Off white solid;Yield: 140 mg, 90 %; m.p.: 139-141 °C. Elem-
ental analysis, C20H23N2O2SF, calcd. (found) %: C 64.15 (64.13),
H 6.19 (6.20), N 7.48 (7.46). IR (KBr, νmax, cm–1): 3429, 3266,
2948, 2847, 1631, 1541, 1448, 1383, 1309, 1237, 1139, 1079,
878, 770, 605; 1H NMR (400 MHz, DMSO-d6) δ: 8.40 (d, J =
7.6 Hz, 1H), 7.68-7.61 (m, 3H), 7.42-7.34 (m, 2H), 4.90 (d, J
= 13.2 Hz, 2H), 4.63 (d, J = 13.2 Hz, 2H), 4.33 (s, 2H), 3.95-
3.80 (m, 6H), 3.40-3.28 (m, 1H), 1.72 (t, J = 10.4 Hz, 2H),
1.59-1.53 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 161.4,
161.1, 141.6, 137.7, 137.0, 135.9, 130.5, 128.9, 125.4, 124.1,
115.2, 64.0 (2C), 51.9, 55.1, 52.8, 49.2, 36.6 (2C), 24.5; MS:
calcd. for C20H23N2O2SF [m/z] 374.47; found: 375.37 [M+H]+.
5-(3-Fluorobenzyl)-4,5,6,7-tetrahydro-N-(tetrahydro-
2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carboxamide (7D):
Brown solid; Yield: 145 mg, 92 %; Elemental analysis,
C20H23N2O2SF, calcd. (found) %: C 64.12 (64.10), H 6.16 (6.17),
N 7.46 (7.44); IR (KBr, νmax, cm–1): 3248, 2952, 2923, 2224,
1613, 1535, 1447, 1331, 1137, 1088, 1011, 761; 1H NMR (400
MHz, DMSO-d6): δ: 8.12 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.6
Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 2H), 3.87
(t, J = 10.4 Hz, 4H), 3.73 (s, 2H), 3.48-3.44 (m, 2H), 2.79 (d,
J = 5.2 Hz, 2H), 2.74 (t, J = 4.8 Hz, 2H), 1.71 (d, J = 11.2 Hz,
2H), 1.56-1.49 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ
162.56, 161.17, 141.6, 137.7, 136.9, 135.9, 130.5, 128.9, 125.4,
124.1, 115.2, 65.5 (2C), 52.0, 55.7, 53.1, 50.1, 36.8 (2C), 24.2;
MS: calcd. for C20H23N2O2SF [m/z] 374.14; found: 374.47
[M+H]+.
4,5,6,7-Tetrahydro-N-(tetrahydro-2H-pyran-4-yl)-5-
[(1-methyl-1H-pyrazol-4-yl)methyl]thieno[3,2-c]pyridine-
2-carboxamide (7G): White solid;Yield: 124 mg, 83 %; m.p.:
164-168 °C; Elemental analysis, C18H24N4O2S, calcd. (found) %:
C 59.97 (59.95), H 6.71 (6.73), N 15.54 (15.52). IR (KBr, νmax
,
cm–1): 3494, 3274, 2930, 2841, 1618, 1540, 1461, 1324, 1139,
1087, 984, 871, 792, 677; 1H NMR (400 MHz, DMSO-d6) δ:
8.45 (s, 1H), 8.25 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H),
7.72 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H),
3.90 (s, 2H), 3.88-3.84 (m, 5H), 3.68 (s, 2H), 3.48 (s, 2H), 2.80
(s, 2H), 2.73 (d, J = 5.2 Hz, 2H), 1.71 (d, J = 1.6 Hz, 2H), 1.53-
1.49 (m, 2H); ); 13C NMR (100 MHz, DMSO-d6): δ161.1, 139.5,
137.4 (2C), 136.9, 135.7, 125.2, 116.0, 65.6 (2C), 56.9, 55.7,
55.2 (2C), 40.5, 36.7 (2C), MS: calcd. for C18H24N4O2S [m/z]
360.47; found: 361.43 [M+H]+.
4,5,6,7-Tetrahydro-N-(tetrahydro-2H-pyran-4-yl)-5-
[(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl]thieno-
[3,2-c]pyridine-2-carboxamide (7H): Light yellow solid;
Yield: 140 mg, 77 %; m.p.: 171-174 °C; Elemental analysis,
C23H27N5O2S, calcd. (found) %: C 63.13 (63.11), H 6.22 (6.20),
N 16.01 (15.99). IR (KBr, νmax, cm–1): 3297, 2944, 2356, 1613,
1531, 1454, 1319, 1290, 1137, 1089, 968, 863; 1H NMR (400
MHz, DMSO-d6) δ: 8.11 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.43
(s, 1H), 7.33 (s, 1H), 3.98-3.84 (m, 3H), 3.82 (s, 3H), 3.54 (s,
2H), 3.42-3.32 (m, 5H), 2.80 (s, 2H), 2.73 (s, 2H), 1.65-1.62
(m, 2H), 1.51-1.40 (m, 2H); 13C NMR (100 MHz, DMSO-d6):
δ160.45, 150.67, 149.64, 138.21, 137.26, 136.96, 134.48, 130.78,
129.35, 126.28, 122.68, 118.89, 66.10 (2C), 57.86, 51.96, 49.33,
45.63, 38.70, 32.48 (2C), 25.09. MS: calcd. for C23H27N5O2S
[m/z] 437.56; found: 438.4 [M+H]+.
5-(2-Cyanobenzyl)-N-(tetrahydro-2H-pyran-4-yl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide
(7E): Off white solid;Yield: 145 mg, 92 %; m.p.: 142-144 °C;
Elemental analysis, C21H23N3O2S, calcd. (found) %: C 66.12
(66.09), H 6.08 (6.10), N 11.01 (11.04). IR (KBr, νmax, cm–1):
3248, 2952, 2923, 2224, 1613, 1535, 1447, 1331, 1137, 1088,
1011, 761; 1H NMR (400 MHz, DMSO-d6): δ: 8.14 (d, J = 7.6
Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.71-7.61 (m, 1H), 7.63 (d, J =
7.2 Hz, 1H), 7.51-7.45 (m, 2H), 3.92-3.85 (m, 5H), 3.53 (s, 2H),
3.80-3.32 (m, 2H), 2.81-2.77 (m, 4H), 1.73-1.69 (m, 2H), 1.56-
5-(Cyclobutylmethyl)-4,5,6,7-tetrahydro-N-(tetra-
hydro-2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carboxa-
mide (7I): Off white solid; Yield: 103 mg, 74 %; m.p.: 151-
153 °C; Elemental analysis, C18H26N2O2S, calcd. (found) %:
C 64.64 (64.65), H 7.84 (7.86), N 8.38 (8.37). IR (KBr, νmax
,
cm–1): 3531, 3275, 2955, 2929, 2759, 1705, 1615, 1537, 1459,
1434, 1368, 1326, 1238, 1131, 1086, 1009, 977, 873, 793, 660,
539, 508; 1H NMR (400 MHz, DMSO-d6) δ: 8.19 (d, J = 7.6

2066 Lakshmana Rao et al.
Asian J. Chem.
Hz, 1H), 7.46 (s, 1H), 3.91-3.84 (m, 3H), 3.39-3.34 (m, 4H),
3.29-3.23 (m, 2H), 2.77-2.67 (m, 4H), 2.06-1.99 (m, 2H), 1.91-
1.65 (m, 6H), 1.58-1.51 (m, 2H), 1.30 (brs, 1H); 13C NMR
(100 MHz, DMSO-d6): δ 160.17, 140.55, 136.44, 134.79,
126.31, 65.10 (2C), 61.34, 50.96, 49.61, 45.31, 34.47 (2C),
29.22, 24.8 (2C), 22.51, 18.74; MS: calcd. for C18H26N2O2S
[m/z] 334.48; found: 335.21 [M+H]+.
5-(Cyclopropylmethyl)-4,5,6,7-tetrahydro-N-(tetra-
hydro-2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carboxa-
mide (7J): Off white solid; Yield: 101 mg, 76 %; m.p.: 154-
156 °C; Elemental analysis, C17H24N2O2S, calcd. (found) %:
1379, 1238, 1088, 1009, 757, 575; 1H NMR (400 MHz, DMSO-
d6) δ: 8.10 (d, J = 6.0 Hz, 1H), 7.52 (t, J = 5.6 Hz, 1H), 7.43-
7.41 (m, 2H), 7.28-7.25 (m, 2H), 4.81 (s, 1H), 3.90-3.84 (m, 3H),
3.54 (q, J = 5.2 Hz, 2H), 3.37-3.32 (m, 1H), 2.83 (brs, 3H),
2.71 (t, J = 7.2 Hz, 1H), 2.38 (d, J = 3.6 Hz, 1H), 1.71 (d, J =
9.6 Hz, 2H), 1.54-1.47 (m, 2H), 1.23 (s, 1H), 0.90-0.89 (m, 5H);
13C NMR (100 MHz, DMSO-d6): δ 207.39, 170.31, 161.58,
160.38, 138.05, 136.98, 134.13, 130.72, 130.17, 126.27, 124.70,
115.83, 115.65, 71.26, 66.06 (2C), 49.67, 47.56, 45.60, 32.44
(2C), 25.29, 17.71, 11.58, 11.19; MS: calcd. for C24H28N2O3S
[m/z] 442.5; found: 443.6 [M+H]+.
C 63.72 (63.70), H 7.55 (7.53), N 8.74 (8.75). IR (KBr, νmax
,
Anticancer activity: Human lung carcinoma (HCT-116)
cell lines were obtained from NCCS Pune and were kept in
RPMI 1640 medium (#AL199A, Himedia) supplemented with
10 % Fetal Bovine Serum (#RM10432, Himedia). The cells
were made to confluency at 37 °C in a CO2 incubator (Healforce,
China) with humidified atmosphere and 5 % CO2. Seeded 200
µL cell suspension in a 96-well plate at required cell density
(20,000 cells per well) without the test agent and allowed the
cells to grow for about 12 h. Test samples in the concentrations
of 25 µg, 50 µg, 75 µg, 100 µg, 125 µg/mL of compounds and
50 µg/mL drugs were added for the growth of the cells sepa-
rately and incubated the plate for 24 h at 37 °C in a 5 % CO2
atmosphere.After the incubation period, the plates were taken
out of the incubator and removed spent media and added MTT
reagent (camptothecin) to a final concentration of 0.5 mg/mL
of total volume and the plates were incubated for 3 h, removed
the MTT reagent and 100 µL of solubilization solution (DMSO)
was added. The absorbance was recorded on an ELISA reader
at 570nm and 630nm used as the reference wavelength. The
IC50 value was obtained by using linear regre-ssion equation
i.e., y = mx + c where, y = 50, m and c values were derived
from the viability graph.
cm–1): 3289, 2923, 2842, 1619, 1539, 1462, 1322, 1239, 1137,
1085, 873, 660; 1H NMR (400 MHz, DMSO-d6) δ: 8.15 (d, J
= 6.4 Hz, 1H), 7.48 (s, 1H), 3.91-3.68 (m, 3H), 3.51 (s, 2H),
3.38-3.33 (m, 2H), 2.80-2.76 (m, 4H), 2.37 (d, J = 5.2 Hz,
2H), 1.72 (d, J = 10.0 Hz, 2H), 1.56-1.50 (m, 2H), 0.89 (d, J
= 4.4 Hz, 1H), 0.49 (d, 6.0 Hz, 2H), 0.12 (d, J = 3.2 Hz, 2H);
13C NMR (100 MHz, DMSO-d6): δ 160.47, 138.23, 136.74,
134.79, 126.31, 66.10 (2C), 61.84, 51.96, 49.81, 45.61, 32.47
(2C), 25.22, 8.51, 3.71 (2C); MS: calcd. for C17H24N2O2S [m/z]
320.45; found: 321.5 [M+H]+.
4,5,6,7-Tetrahydro-N-(tetrahydro-2H-pyran-4-yl)-5-
(2-(naphthalen-2-yl)-2-oxoethyl)thieno[3,2-c]pyridine-2-
carboxamide (7K): Light yellow solid;Yield: 143 mg, 80 %;
m.p.: 160-163 °C; Elemental analysis, C25H26N2O3S, calcd.
(found) %: C 69.10 (69.13), H 6.03 (6.06), N 6.45 (6.46). IR
(KBr, νmax, cm–1): 3248, 3056, 2953, 2914, 2841, 1687, 1608,
1530, 1457, 1375, 1332, 1293, 1242, 1165, 1123, 1091, 1004,
869, 804, 752, 675, 579; 1H NMR (400 MHz, DMSO-d6) δ:
8.72 (s, 1H), 8.17-8.11 (m, 2H), 8.02-7.96 (m, 2H), 7.99 (s, 1H),
7.69-7.60 (m, 2H), 7.46 (s, 1H), 4.25 (s, 2H), 3.92-3.84 (m, 3H),
3.69 (s, 2H), 3.38-3.32 (m, 2H), 2.94 (brs, 2H), 2.83 (brs, 2H),
1.72 (d, J = 12.4 Hz, 2H), 1.56-1.48 (m, 2H); 13C NMR (100
MHz, DMSO-d6): δ 197.11, 160.43, 138.02, 136.84, 135.02,
134.40, 133.09, 132.07, 129.76, 129.53, 128.58, 128.14, 127.61,
126.87, 126.18, 123.68, 66.08 (2C), 62.59, 51.69, 49.76, 45.61,
32.45 (2C), 25.10; MS: calcd. for C25H26N2O3S [m/z] 434.55;
found: 435.53 [M+H]+.
5-[2-(3,4-Difluorophenyl)-2-oxoethyl]-N-(tetrahydro-
2H-pyran-4-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-
carboxamide (7L): Light Brown solid;Yield: 145 mg, 83 %;
m.p.: 158-162 °C; Elemental analysis, C21H22N2O3SF2, calcd.
(found) %: C 59.99 (59.94), H 5.27 (5.28), N 6.66 (6.64). IR
(KBr, νmax, cm–1): 3248, 2955, 2914, 2841, 1695, 1608, 1530,
1467, 1332, 1293, 1175, 1123, 1091, 1004, 869, 806, 754, 675,
670; 1H NMR (400 MHz, DMSO-d6) δ: 8.16 (d, J = 6.0 Hz, 1H),
8.06-8.02 (m, 2H), 7.91 (s, 1H), 7.44 (s, 1H), 4.06 (s, 2H); 13C
NMR (100 MHz, DMSO-d6): δ 194.6, 160.78, 152.75, 149.1,
141.73, 137.75, 136.92, 135.83, 132.96, 126.08, 125.44, 115.34,
71.26, 66.06 (2C), 54.57, 52.88, 51.60, 32.44 (2C), 22.43;
MS:calcd. forC21H22N2O3SF2 [m/z]420.47;found:421.53[M+H]+.
5-(2-Cyclopropyl-2-oxo-1-phenylethyl)-4,5,6,7-
tetrahydro-N-(tetrahydro-2H-pyran-4-yl)thieno[3,2-
c]pyridine-2-carboxamide (7M): Semi solid;Yield: 155 mg,
85 %; Elemental analysis, C24H28N2O3S, calcd. (found) %: C
RESULTS AND DISCUSSION
The synthesis of 5-substituted 4,5,6,7-tetra-hydro-
N-(tetrahydro-2H-pyran-4-yl)thieno[3,2-c]pyridine-2-car-
boxamide derivatives (7A-M) is illustrated in Scheme-I.
Formylation of tert-butyl 4-oxopiperidine-1-carboxylate (1)
under Villsmeyer-Hack protocol was carried out in presence
of DMF and POCl3 to achieve the desired compound tert-butyl
3-formyl-4-oxopiperidine-1-carboxylate (2). Treatment of
aldehyde 2 with 2-mercaptoacetate in presence of triethyl
amine in dichloromethane at 45 °C for 16 h produced the
cyclized product, 5-tert-butyl-2-ethyl-6,7-dihydrothieno[3,2-
c]pyridine-2,5(4H)-dicarboxylate (3). Alkaline hydrolysis of
ethyl ester 3 followed by coupling with tetrahydro-2H-pyran-
4-amine in presence of EDC·HCl, HOBt and di-isopropyl
amine in DMF at room temperature for 5 h produced the desired
compound N-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine-2-carboxamide (6). De-protection of the
Boc group in presence of trifluoroacetic acid followed by
coupling with various aryl/alkyl/acyl halides in presence of
K2CO3 in DMF at room temperature for 16 h resulted in the
formation of desired compounds 7A-M in moderate yields.
1
These derivatives have been characterized by H NMR,
mass and IR spectroscopic tools. The structural determination
of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydro-N-(tetrahydro-2H-
67.90 (67.87), H 6.65 (66.67), N 6.60 (6.56). IR (KBr, νmax
,
cm–1): 3322, 2925, 2849, 1702, 1626, 1572, 1532, 1485, 1456,

Vol. 30, No. 9 (2018)
Synthesis, Characterization and Anticancer Activity of 4,5,6,7-Tetrahydrothieno Pyridine Derivatives 2067
O
N
O
OH
O
S
O
O
O
S
c
b
a
O
N
O
N
N
Step 3
Step 2
Step 1
O
O
O
O
O
O
4
3
1
2
d
Step 4
HN
O
O
S
HN
O
O
HN
O
S
S
f
e
O
N
R
N
HN
Step 5
O
Step 6
O
5
6
7A-M
F
N
N
Cl
F
CN
G
A
B
D
E
F
C
O
R =
O
O
N
F
N
F
N
F
I
H
J
K
L
M
Reaction conditions: a) DMF, POCl3, DCM, 0 °C-room temperature, 4 h; b) 2-mercaptoacetate, triethyl amine, DCM, 45 °C, 16 h; c)
NaOH, THF:MeOH:H2O, room temperature, 16 h; d) tetrahydro-2H-pyran-4-amine, EDC·HCl, HOBt, di-isopropyl amine, DMF, room
temperature, 5 h; e) TFA, DCM, 0 °C-room temperature, 16h; f) R-X, K2CO3, DMF, room temperature, 16 h
Scheme-I: Synthesis of novel 5-substituted 4,5,6,7-tetrahydro-N-(tetrahydro-2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carboxamide derivatives
(7A-7M)
1
pyran-4-yl)thieno[3,2-c]pyridine-2-carboxamide (7B). In H
NMR, the proton signals resonating at 8.15 ppm (doublet) and
7.36 ppm (singlet) corresponds to –NH and thiophene ring
proton, while the proton signals resonating at 7.53, 7.45, 7.33
and 7.23 ppm as doublets is assigned to 2-chloro-phenyl ring,
respectively. The characteristic benzylic -CH2- resonated at 3.77
ppm as singlet and the remaining aliphatic protons such as
piperidine and morpholine ring protons resonated in the expected
region. The structure of compound 7B was further confirming
by its molecular weight m/z, 390.76 (LC-MS purity: 93.86 %)
which was found to be in agreement with the desired structure.
In the IR spectra of compound 7B, the characteristic peaks in
the region 3280, 3065, 2949, 1614, 1571 cm-1 are assigned to
–NH,Ar-C-H, aliph. -C-H, -CO-NH- and –C=C- groups respec-
tively. The above spectroscopic techniques, thus confirms the
structure of compound 7B. Similarly, the structures of remaining
compounds in the series have been confirmed.
compounds 7C, 7D, 7E, 7G, 7H and 7M exhibited moderate
activity and compounds 7A, 7F, 7I, 7J and 7L showed weak
activity (Table-1). It is evident from the cytotoxic activity
results that the compounds containing 2-chloro-benzyl (7B)
and 2-acetyl naphthalene (7K) ring substituted to the main
scaffold exhibited potent anticancer activities compared to the
standard drug.
TABLE-1
in vitro CYTOTOXIC ACTIVITY OF COMPOUNDS (7A-M)
Compound
IC50 (µg/mL)
82.36 0.02
69.52 0.02
78.48 0.01
77.21 0.02
75.35 0.01
80.05 0.01
79.45 0.01
Compound
IC50 (µg/mL)
72.15 0.01
80.35 0.01
80.21 0.02
66.35 0.02
83.25 0.01
71.25 0.01
47.36 0.02
7A
7B
7C
7D
7E
7F
7G
7H
7I
7J
7K
7L
7M
Camptothecin (SD)
Anticancer activity: Compounds (7A-M) were screened
for their in vitro cytotoxic potential against human lung carci-
noma (HCT-116) cell line using the MTT assay and the obtained
IC50 values are tabulated in Table-1. Among all the compound
7B (IC50: 69.52 µg) and compound 7K (IC50: 66.35 µg) showed
significant potent activity at micro molar concentration when
compared with the standard drug camptothecin, while the
Conclusion
In conclusion, we have described the synthesis and charac-
terization of some novel 5-substituted 4,5,6,7-tetrahydro-N-
(tetrahydro-2H-pyran-4-yl)thieno[3,2-c]pyridine-2-carbo-
xamide derivatives (7A-M). These derivatives were screened
for their in vitro cytotoxic potential against human lung carci-

2068 Lakshmana Rao et al.
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17. A.M.R. El-Sayed, A.G. Abdel-Hafez, N.N.S. Mohamed and S.F.
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noma (HCT-116) cell line using the MTT assay. The anticancer
activity results revealed that compound 7B (IC50: 69.52 µg)
and compound 7K (IC50: 66.35 µg) showed moderate potent
activity at micro molar concentration when compared with
the standard drug camptothecin, while compounds 7C, 7D,
7E, 7G, 7H and 7M exhibited moderate activity and compounds
7A, 7F, 7I, 7J and 7L showed weak activity.
CONFLICT OF INTEREST
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Composition Containing same, US Patent 4,075,340 (1978).
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regarding the publication of this article.
https://doi.org/10.1016/S0960-894X(02)00228-7.
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