Synthesis of Novel Trifluoromethyl Group Containing Pyrido Furo/Thieno Pyrimidinone Derivatives and Their Anticancer Activity

Article abstract of DOI:10.1002/jhet.3566

A series of novel trifluoromethyl group containing pyridofuro/thieno pyrimidinone derivatives 5a–p were prepared starting from 2-oxo/thioxo-6-phenyl/thien-2-yl-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile 1 compound on reaction with bromoethylac

Full text of DOI:10.1002/jhet.3566

Month 2019 Synthesis of Novel Trifluoromethyl Group Containing Pyrido Furo/Thieno
Pyrimidinone Derivatives and Their Anticancer Activity
*
Hanumandlu Racha, Balakishan Vadla, Kavitha Peddolla, and Sailu Betala
Department of Chemistry, Telangana University, Dichpally, Nizamabad, Telangana 503322, India
*E-mail: bethalasailu@gmail.com
Received August 17, 2018
DOI 10.1002/jhet.3566
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel trifluoromethyl group containing pyridofuro/thieno pyrimidinone derivatives 5a–p were
prepared starting from 2-oxo/thioxo-6-phenyl/thien-2-yl-4-(trifluoromethyl)-1,2-dihydropyridine-3-car-
bonitrile 1 compound on reaction with bromoethylacetate and further different primary aliphatic amines, un-
der their refluxing conditions to afford amide tagged furo/thieno pyridine derivatives 4. Compound 4 on
reaction with trifluoroacetic acid and obtained novel trifluoromethyl group containing pyridofuro/thieno
pyrimidinone derivatives 5a–p. All the synthesized compounds 5a–p were tested for anticancer activity
on four cancer cell lines such as HeLa cervical cancer (CCL-2), COLO 205 colon cancer (CCL-222), HepG2
liver cancer (HB-8065), MCF7 breast cancer (HTB-22), and one normal cell line (HEK 293); compounds
5m, 5n, and 5p are found to be more promising anticancer activity at micromolar concentration and found
to be nontoxic on normal cell line.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
the year of 2018, Santhosh Kumar et al. was reported the
synthesis of pyrido[30,20:4,5]furo[3,2-d]pyrimidin-4(3H)-
one derivatives, which molecules doesn’t contain trifluoro
methyl group at 2nd position [23].
As per the reports of the World Health Organization,
around 8.8 million people died due to cancer disease
among all over the world in 2015 [1]. Among all over the
drugs, anticancer drugs that were synthesized from
molecules play a central and lead position in medicinal
chemistry [2–4] and are essential part of the chemical and
life sciences. Heterocyclic compounds are powerful
scaffolds for many biological systems [5] and play an
important role to design and discovery of new
physiologically/pharmacologically active molecules [6].
Five-membered and six-membered fused heterocycles
that consist nitrogen and oxygen or sulfur atoms have
played an important role and reported to exhibit a broad
spectrum of biological activities [7] like antimalarial [8],
antifolate [9–13], antiviral [14], and potential radiation
protection agents [15–19]. Based on the importance of
fused heterocyclic compounds and we encouraged by
previous reports, we are encouraged by them and focused
our attention on the synthesis of tricyclic and bicyclic
hetero cyclic ring systems and their biological activity to
find promising anticancer agents. Moreover, literature
says that the fluorine [20] or trifluoromethyl [21,22]
groups at an appropriate position of an organic molecule
effectually change the properties of molecule in terms of
lipid solubility and oxidative thermal stability and after
that enhance the transport mechanism and bio-efficacy. In
We are encouraged by them, and based on the
importance [24–26], we drafted and synthesized a series
of novel trifluoromethyl group containing pyrido
furo/thieno pyrimidinone derivatives and submitted for
anticancer activity against four cancer cell lines such as
HeLa cervical cancer, COLO 205 colon cancer, HepG2
liver cancer, MCF7 breast cancer, and one (healthy)
normal cell line (HEK 293). Among all the compounds,
5m, 5n, and 5p compounds showed promising anticancer
activity at micromolar concentration and found to be
nontoxic to normal cell line.
CHEMISTRY
The 2(1H) pyridine 1 was treated with 2-bromoethyl
acetate in basic conditions (K2CO3) to produce
selectively 2-O-ethylacetoxy-3-cyano-4-trifluoromethyl-6-
substituted pyridine derivatives 2. For cyclization of
compounds 2, treated with DMF using potassium
carbonate as base to produce furo[2,3-b]pyridine
derivatives 3, the reaction sequence involves selective
O-alkylation and abstraction of proton by base from an
active methylene followed by cyclization onto nitrile
© 2019 Wiley Periodicals, Inc.

H. Racha, B. Vadla, K. Peddolla, and S. Betala
Vol 000
carbon. This type of cyclization is also known as Thorpe–
Ziegler cyclization. Compound 3 was further treated with
various types of primary aliphatic amines under neat
conditions and reflux at their own boiling points to afford
amide derivatives 4. Amide derivatives 4 on reaction with
trifluoroacetic acid in the presence of HCl, H2O reflux
condition and obtained 2-trifluoromethyl pyridofuro/
thieno pyrimidinone derivatives 5a–p. All the synthesized
compounds 5a–p were screened for anticancer activity
against four cancer cell lines such as HeLa cervical
cancer (CCL-2), COLO 205 colon cancer (CCL-222),
HepG2 liver cancer (HB-8065), MCF7 breast cancer
(HTB-22), and one (healthy) normal cell line (HEK 293).
Compounds 5m, 5n, and 5p showed promising
anticancer activity at micromolar concentration. The
synthetic sequence is drawn in Scheme 1, and products
are tabulated in Table 1.
Compounds were tested for in vitro against four cancer
cell lines such as HeLa cervical cancer (CCL-2), COLO
205 colon cancer (CCL-222), HepG2 liver cancer
(HB-8065), MCF7 breast cancer (HTB-22), and HEK 293
human embryonic kidney cells (CRL-1573) using MTT
Scheme 1. Synthesis of novel trifluoromethyl group containing pyrido furo/thieno pyrimidinone derivatives 5a–p.
Table 1
Preparation of novel trifluoromethyl group containing pyrido furo/thieno pyrimidinone derivatives 5a–p.
Entry
Compound
R
X
R0
Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
O
O
O
O
S
S
S
S
O
O
O
O
S
S
S
S
─CH3
─CH2CH3
─CH2CH2CH3
─Cyclopentyl
─CH3
89
90
91
86
88
89
85
81
92
88
89
80
91
92
89
82
─CH2CH3
─CH2CH2CH3
─Cyclopentyl
─CH3
9.
10.
11.
12.
13.
14.
15.
16.
─CH2CH3
─CH2CH2CH3
─Cyclopentyl
─CH3
─CH2CH3
─CH2CH2CH3
─Cyclopentyl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Novel Trifluoromethyl Group Containing Pyrido Furo/Thieno
Pyrimidinone Derivatives and Their Anticancer Activity
Table 2
In vitro cytotoxicity of compounds 5a–p.
IC50 values (in μM)
Compound
HeLa
COLO 205
HepG2
MCF7
HEK 293
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
31.1 0.23
—
27.6 0.13
—
21.1 0.21
54.2 0.52
30.1 0.11
48.5 0.23
65.6 0.11
—
22.2 0.13
—
34.6 0.31
—
31.5 0.34
—
41.8 0.18
27.7 0.24
—
26.1 0.61
52.2 0.41
41.4 0.26
—
61.2 0.41
52.6 0.61
64.7 0.30
21.5 0.51
79.6 0.31
—
29.5 0.21
49.1 0.45
25.2 0.22
112.5 0.16
—
63.7 0.12
52.8 0.28
36.8 0.54
—
68 0.18
102 0.24
78 0.16
75 0.46
59 0.29
—
83 0.12
87 0.59
61 0.25
96 0.47
78 0.28
109 0.22
—
—
—
—
—
—
—
55.3 0.29
10.1 0.22
12.2 0.18
21.4 0.28
11.8 0.14
58.9 0.33
13.5 0.46
16.1 0.11
22.8 0.28
8.8 0.24
50.9 0.39
11.8 0.53
18.3 0.28
21.8 0.52
9.5 0.13
68.4 0.54
12.6 0.28
12.8 0.32
18.5 0.42
14.2 0.14
—
56 0.37
—
5-Fluorouracil (standard control)
1.8 0.09
1.9 0.11
1.7 0.08
1.8 0.07
19.6 0.18
“—” indicates IC50 value >112.5 μg/mL. Cell lines used are as follows: HeLa cervical cancer (CCL-2), COLO 205 colon cancer (CCL-222), HepG2 liver
cancer (HB-8065), MCF7 breast cancer (HTB-22), and HEK 293 human embryonic kidney cells (CRL-1573).
assay [27]. IC50 values of the test compounds for 24 h on
each cell line were calculated and presented in Table 2.
5a–p were prepared and submitted for anticancer activity
against four human cancer cell lines and one normal cell
line. Among all the compounds tested, the compounds
5m, 5n, and 5p showed significant anticancer activity
against all the cell lines at micromolar concentration and
found to be nontoxic on normal cell line.
RESULTS AND DISCUSSIONS
Anticancer activity. All the compounds, except 5d, 5j,
and 5k, showed activity against four cancer cell lines at
micromolar concentration. Among all the compounds,
5m, 5n, and 5p showed promising activity, while the
remaining compounds showed moderate activity. Among
the derivatives, compound 5p exhibited significant
activity on COLO 205 and HepG2 cells at
IC50 < 9.5 μg/mL, and other derivatives 5m, 5n, and 5o
also showed promising activity on all cell lines at
IC50 < 22.8 μg/mL. Compound 5m was considered as
the more potent towards all the cancer cell lines. The
structure–activity relationship studies revealed that the
thieno-2-yl group at the sixth position shows more
activity compared with phenyl group at the sixth position
and also (─CF3) trifluoromethyl groups at a strategic
position. The presence of CF3 group increases the
properties of lipid solubility and after that enhances the
transport mechanism and bio-efficacy. Thieno fused
pyridine is an additional advantage in promoting
cytotoxicity compared with furo fused pyridine ring.
EXPERIMENTAL
Cytotoxicity assay.
The cytotoxicity was assessed
using the MTT assay [27].
General
2,3-dimethyl-7-substituted-9-(trifluoromethyl)
pyrido[30,20:4,5]furo[3,2-d]pyrimidin-4(3H)-one derivatives
(5a–p).
procedure
for
the
preparation
of
3-Amino-N-methyl-6-substituted-4-
(trifluoromethyl)furo[2,3-b]pyridine-2-carboxamide
4
(4 mmol) and trifluoroacetic acid (4 mmol) were taken in
an RB. To this solution, added 5 ml HCl and 5 ml H2O.
The mixture was refluxed at 100°C for 2 h, and after
completion of the reaction, reaction mixture was poured
on crushed ice, and solid was formed and washed with
excess water and dried.
3-Methyl-7-phenyl-2,9-bis(trifluoromethyl)pyrido[30,20:4,5]
furo[3,2-d]pyrimidin-4(3H)-one (5a).
Whitish solid; mp
191–193°C; IR (KBr, cmꢀ1): 1692 (═NCO─); H NMR
(CDCl3, 300 MHz): δ 3.74 (s, 3H, ─CH3), 7.53–7.59 (m,
3H, Ar─H), 8.17 (s, 1H, Ar─H), 8.18–8.21 (m, 2H,
Ar─H); 13C NMR (CDCl3, 75 MHz): 35.6, 119.5, 124.0,
125.2, 126.3, 127.1, 128.2, 130.0, 132.0, 134.7, 137.4,
139.6, 141.9, 143.3, 145.6, 157.0; MS (ESI): m/z
[(M + H)+]: 414. Anal. Calcd for C18H9F6N3O2: C,
1
CONCLUSION
In conclusion, a series of novel trifluoromethyl group
containing pyridofuro/thieno pyrimidinone derivatives
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. Racha, B. Vadla, K. Peddolla, and S. Betala
Vol 000
52.31; H, 2.20; N, 10.17%. Found: C, 52.32; H, 2.19; N,
10.19%.
NMR (CDCl3, 75 MHz): 11.5, 33.7, 120.5, 123.9, 125.0,
126.6, 127.9, 129.2, 130.4, 130.9, 133.7, 136.2, 139.8,
143.3, 145.3, 147.9, 160.6; MS (ESI): m/z [(M + H)+]:
444. Anal. Calcd for C19H11F6N3OS: C, 51.47; H, 2.50;
3-Ethyl-7-phenyl-2,9-bis(trifluoromethyl)pyrido[30,20:4,5]
furo[3,2-d]pyrimidin-4(3H)-one (5b).
Whitish solid; mp
209–211°C; IR (KBr, cmꢀ1): 1682 (═NCO─); H NMR
(CDCl3, 300 MHz): δ 1.48 (t, J = 6.79, 3H, ─CH3), 4.22
(q, J = 6.79, 2H, ─CH2), 7.52–7.59 (m, 3H, Ar─H),
8.16–8.24 (m, 2H, Ar─H), 8.28 (s, 1H, Ar─H); 13C
NMR (CDCl3, 75 MHz): 12.6, 38.0, 120.7, 123.6, 124.0,
125.3, 126.3, 127.6, 128.0, 130.9, 133.7, 136.1, 138.1,
139.7, 141.9, 143.6, 158.5; MS (ESI): m/z [(M + H)+]:
428. Anal. Calcd for C19H11F6N3O2: C, 53.41; H, 2.59;
1
N, 9.48%. Found: C, 51.49; H, 2.52; N, 9.50%.
7-Phenyl-3-propyl-2,9-bis(trifluoromethyl)pyrido[30,20:4,5]
thieno[3,2-d]pyrimidin-4(3H)-one (5g). Whitish solid; mp
1
201–203°C; IR (KBr, cmꢀ1): 1678 (═NCO─); H NMR
(CDCl3, 300 MHz): δ 1.03 (t, J = 6.35, 3H, ─CH3),
1.82–1.86 (m, 2H, ─CH2), 4.15 (t, J = 7.34, 2H, ─CH2),
7.56–7.62 (m, 3H, Ar─H), 8.12 (s, 1H, Ar─H), 8.20–
8.24 (m, 2H, Ar─H); 13C NMR (CDCl3, 75 MHz): 11.9,
21.3, 46.7, 120.8, 123.7, 124.3, 125.0, 126.4, 127.7,
129.5, 133.3, 133.9, 135.1, 139.2, 141.7, 144.3, 146.4,
161.1; MS (ESI): m/z [(M + H)+]: 458. Anal. Calcd for
C20H13F6N3OS: C, 52.52; H, 2.86; N, 9.19%. Found: C,
N, 9.83%. Found: C, 53.40; H, 2.61; N, 9.84%.
7-Phenyl-3-propyl-2,9-bis(trifluoromethyl)pyrido[30,20:4,5]
furo[3,2-d]pyrimidin-4(3H)-one (5c).
Whitish solid; mp
198–200°C; IR (KBr, cmꢀ1): 1678 (═NCO─); H NMR
(CDCl3, 300 MHz): δ 1.03 (t, J = 6.31, 3H, ─CH3),
1.60–1.69 (m, 2H, ─CH2), 4.38 (t, J = 7.32, 2H, ─CH2),
7.52–7.58 (m, 3H, Ar─H), 8.11–8.18 (m, 2H, Ar─H),
8.23 (s, 1H, Ar─H); 13C NMR (CDCl3, 75 MHz): 11.8,
21.7, 46.3, 120.7, 123.5, 125.5, 126.6, 128.2, 129.0,
129.5, 133.4, 133.9, 135.1, 139.4, 141.8, 144.4, 146.3,
158.6; MS (ESI): m/z [(M + H)+]: 442. Anal. Calcd for
C20H13F6N3O2: C, 54.43; H, 2.97; N, 9.52%. Found: C,
1
52.53; H, 2.87; N, 9.20%.
3-Cyclopentyl-7-phenyl-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (5h).
Whitish solid; mp 212–214°C; IR (KBr, cmꢀ1): 1648
(═NCO─); 1H NMR (CDCl3, 300 MHz): δ 1.32–1.50
(m, 4H, ─CH2─), 1.52–1.58 (m, 2H, ─CH2─), 1.78–
1.84 (m, 2H, ─CH2─), 5.32–5.38 (m, 1H, ─CH─),
7.99–8.05 (m, 3H, Ar─H), 8.15–8.21 (m, 2H, Ar─H),
8.35 (s, 1H, Ar─H); 13C NMR (CDCl3, 75 MHz):
23.4, 43.3, 46.2, 120.4, 122.2, 123.5, 124.7, 125.4,
125.9, 126.9, 130.0, 132.7, 133.5, 139.4, 142.6, 143.5,
146.9, 160.3; MS (ESI): m/z [(M + H)+]: 484. Anal.
Calcd for C22H15F6N3OS: C, 54.66; H, 3.13; N, 8.69%.
54.44; H, 2.98; N, 9.53%.
3-Cyclopentyl-7-phenyl-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]furo[3,2-d]pyrimidin-4(3H)-one
(5d).
Whitish solid; mp 204–206°C; IR (KBr, cmꢀ1): 1678
(═NCO─); 1H NMR (CDCl3, 300 MHz): δ 1.57–1.66
(m, 4H, ─CH2─), 1.68–1.76 (m, 2H, ─CH2─), 1.94–
1.99 (m, 2H, ─CH2─), 5.32–5.39 (m, 1H, ─CH─),
7.95–8.03 (m, 3H, Ar─H), 8.12–8.18 (m, 2H, Ar─H),
8.35 (s, 1H, Ar─H); 13C NMR (CDCl3, 75 MHz):
23.8, 32.5, 48.8, 120.4, 122.2, 122.9, 123.5, 124.7,
125.8, 127.2, 130.6, 133.3, 134.0, 139.4, 142.5, 143.4,
147.2, 158.5; MS (ESI): m/z [(M + H)+]: 400. Anal.
Calcd for C22H15F6N3O2: C, 56.54; H, 3.23; N, 8.99%.
Found: C, 54.67; H, 3.14; N, 8.71%.
3-Methyl-7-(thiophen-2-yl)-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]furo[3,2-d]pyrimidin-4(3H)-one
(5i).
Whitish solid; mp 191–193°C; IR (KBr, cmꢀ1): 1685
1
(═NCO─); H NMR (CDCl3, 300 MHz): δ 3.73 (s, 3H,
─CH3), 7.19 (dd, J = 4.91, 1H, Ar─H), 7.57 (dd,
J = 4.91, 1H, Ar─H), 7.89 (dd, J = 3.77, 1H, Ar─H),
8.02 (s, 1H, Ar─H); 13C NMR (CDCl3, 75 MHz): 36.4,
119.5, 121.7, 123.4, 124.1, 125.1, 127.4, 128.4, 133.5,
134.7, 137.3, 139.9, 142.2, 143.3, 147.4, 161.5; MS
Found: C, 56.55; H, 3.24; N, 9.01%.
3-Methyl-7-phenyl-2,9-bis(trifluoromethyl)pyrido[30,20:4,5]
thieno[3,2-d]pyrimidin-4(3H)-one (5e). Whitish solid; mp
(ESI): m/z [(M
+
H)+]: 420. Anal. Calcd for
1
188–190°C; IR (KBr, cmꢀ1): 1678 (═NCO─); H NMR
C16H7F6N3O2S: C, 45.83; H, 1.68; N, 10.02%. Found: C,
(CDCl3, 300 MHz): δ 3.53 (s, 3H, ─CH3), 7.52–7.58 (m,
3H, Ar─H), 7.94 (s, 1H, Ar─H), 8.10–8.17 (m, 2H,
Ar─H); 13C NMR (CDCl3, 75 MHz): 34.0, 119.4, 124.0,
125.4, 126.3, 128.1, 130.0, 130.6, 132.0, 134.5, 137.3,
139.7, 143.2, 145.3, 146.9, 161.5; MS (ESI): m/z
[(M + H)+]: 430. Anal. Calcd for C18H9F6N3OS: C,
50.35; H, 2.11; N, 9.79%. Found: C, 50.36; H, 2.12; N,
9.78%.
45.84; H, 1.69; N, 10.03%.
3-Ethyl-7-(thiophen-2-yl)-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]furo[3,2-d]pyrimidin-4(3H)-one
(5j).
Whitish solid; mp 186–188°C; IR (KBr, cmꢀ1): 1685
(═NCO─); 1H NMR (CDCl3, 300 MHz): δ 1.38 (t,
J = 6.76, 3H, ─CH3), 4.39 (q, J = 6.76, 2H, ─CH2),
7.19 (dd, J = 4.88, 1H, Ar─H), 7.50 (dd, J = 4.88, 1H,
Ar─H), 7.78 (dd, J = 3.76, 1H, Ar─H), 7.85 (s, 1H,
Ar─H); 13C NMR (CDCl3, 75 MHz): 12.4, 42.5, 120.6,
123.5, 124.5, 126.9, 127.4, 128.8, 132.4, 134.6, 136.5,
137.1, 140.7, 143.3, 144.5, 146.9, 161.0; MS (ESI): m/z
[(M + H)+]: 434. Anal. Calcd for C17H9F6N3O2S: C,
47.12; H, 2.09; N, 9.70%. Found: C, 47.13; H, 2.10; N,
9.72%.
3-Ethyl-7-phenyl-2,9-bis(trifluoromethyl)pyrido[30,20:4,5]
thieno[3,2-d]pyrimidin-4(3H)-one (5f).
Whitish solid; mp
1
205–207°C; IR (KBr, cmꢀ1): 1682 (═NCO─); H NMR
(CDCl3, 300 MHz): δ 1.51 (t, J = 6.79, 3H, ─CH3), 4.21
(q, J = 6.79, 2H, ─CH2), 7.54–7.62 (m, 3H, Ar─H),
8.21 (s, 1H, Ar─H), 8.24–8.29 (m, 2H, Ar─H); 13C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Novel Trifluoromethyl Group Containing Pyrido Furo/Thieno
Pyrimidinone Derivatives and Their Anticancer Activity
3-Propyl-7-(thiophen-2-yl)-2,9-bis(trifluoromethyl)
(═NCO─); 1H NMR (CDCl3, 300 MHz): δ 1.07 (t,
J = 6.32, 3H, ─CH3), 1.61–1.72 (m, 2H, ─CH2), 4.39 (t,
J = 7.32, 2H, ─CH2), 7.19 (dd, J = 4.91, 1H, Ar─H),
7.52 (dd, J = 4.91, 1H, Ar─H), 7.78 (dd, J = 3.76, 1H,
Ar─H), 7.87 (s, 1H, Ar─H); 13C NMR (CDCl3,
75 MHz): 12.5, 23.3, 45.4, 119.7, 122.8, 123.1, 124.0,
125.6, 126.7, 128.8, 132.0, 133.9, 135.0. 139.4, 142.0,
144.6, 146.7, 160.7; MS (ESI): m/z [(M + H)+]: 464.
Anal. Calcd for C18H11F6N3OS2: C, 46.65; H, 2.39; N,
pyrido[30,20:4,5]furo[3,2-d]pyrimidin-4(3H)-one
(5k).
Whitish solid; mp 222–224°C; IR (KBr, cmꢀ1): 1682
(═NCO─); 1H NMR (CDCl3, 300 MHz): δ 1.04 (t,
J = 6.31, 3H, ─CH3), 1.62–1.67 (m, 2H, ─CH2─), 4.12
(t, J = 7.31, 2H, ─CH2─), 7.18 (dd, J = 4.90, 1H,
Ar─H), 7.56 (dd, J = 4.90, 1H, Ar─H), 7.83 (dd,
J = 3.77, 1H, Ar─H), 8.01 (s, 1H, Ar─H); 13C NMR
(CDCl3, 75 MHz): 11.2, 22.7, 45.4, 120.6, 124.0, 124.5,
126.5, 127.9, 129.2, 130.9, 131.9, 133.6, 136.2, 139.7,
143.3, 146.4, 161.6; MS (ESI): m/z [(M + H)+]: 448.
Anal. Calcd for C18H11F6N3O2S: C, 48.33; H, 2.48; N,
9.07%. Found: C, 46.66; H, 2.40; N, 9.08%.
3-Cyclopentyl-7-(thiophen-2-yl)-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (5p).
Whitish solid; mp 218–220°C; IR (KBr, cmꢀ1): 1682
(═NCO─); 1H NMR (CDCl3, 300 MHz): δ 1.79–1.85
(m, 4H, ─CH2─), 1.89–1.95 (m, 2H, ─CH2─), 2.26–
2.46 (m, 2H, ─CH2─), 5.29–5.38 (m, 1H, ─CH─), 7.19
(dd, J = 4.92, 1H, Ar─H), 7.59 (dd, J = 4.92, 1H,
Ar─H), 7.89 (dd, J = 3.77, 1H, Ar─H), 8.02 (s, 1H,
Ar─H); 13C NMR (CDCl3, 75 MHz): 24.0, 43.3, 45.4,
120.5, 122.4, 123.7, 125.2, 126.5, 127.1, 128.2, 130.0,
132.1, 134.5, 139.3, 142.1, 145.2, 160.7; MS (ESI): m/z
[(M + H)+]: 490. Anal. Calcd for C20H13F6N3OS2: C,
49.09; H, 2.68; N, 8.59%. Found: C, 49.10; H, 2.69; N,
8.60%.
9.39%. Found: C, 43.34; H, 2.49; N, 9.40%.
3-Cyclopentyl-7-(thiophen-2-yl)-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]furo[3,2-d]pyrimidin-4(3H)-one
(5l).
Whitish solid; mp 201–203°C; IR (KBr, cmꢀ1): 1678
(═NCO─); 1H NMR (CDCl3, 300 MHz): δ 1.60–1.69
(m, 2H, ─CH2─), 1.83–1.92 (m, 4H, ─CH2─), 2.29–
2.38 (m, 2H, ─CH2─), 5.36–5.49 (m, 1H, ─CH─), 7.20
(dd, J = 4.91, 1H, Ar─H), 7.58 (dd, J = 4.91, 1H,
Ar─H), 7.87 (dd, 1H, Ar─H), 8.00 (s, 1H, Ar─H); 13C
NMR (CDCl3, 75 MHz): 23.0, 32.3, 46.6, 119.3, 121.0,
123.7, 124.5, 127.8, 129.3, 130.5, 131.5, 132.1, 132.9,
139.4, 142.9, 143.8, 146.6, 160.9; MS (ESI): m/z
[(M + H)+]: 474. Anal. Calcd for C20H13F6N3O2S: C,
50.74; H, 2.77; N, 8.88%. Found: C, 50.75; H, 2.78; N,
8.89%.
Acknowledgments. The authors are grateful to the Department of
Chemistry, Telangana University, Dichpally, Nizamabad,
Telangana, India, for providing lab facilities and chemicals and
also thankful to research supervisor Dr. Sailu Betala.
3-Methyl-7-(thiophen-2-yl)-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (5m).
Whitish solid; mp 208–209°C; IR (KBr, cmꢀ1): 1675
1
(═NCO─); H NMR (CDCl3, 300 MHz): δ 3.75 (s, 3H,
─CH3), 7.20 (dd, J = 4.89, 1H, Ar─H), 7.59 (dd,
J = 4.89, 1H, Ar─H), 7.88 (dd, J = 3.78, 1H, Ar─H),
8.01(s, 1H, Ar─H); 13C NMR (CDCl3, 75 MHz): 45.3,
120.5, 122.8, 124.3, 125.0, 126.7, 128.5, 129.7, 130.9,
133.0, 135.4, 140.5, 143.3, 146.0, 160.4; MS (ESI): m/z
[(M + H)+]: 366. Anal. Calcd for C16H7F6N3OS2: C,
44.14; H, 1.62; N, 9.65%. Found: C, 44.15; H, 1.63; N,
REFERENCES AND NOTES
[1] World Health Organization report—2016 https://www.who.
int/cancer/en/
[2] Polshettiwar, V.; Varma, R. S. Curr Opin Drug Discov Devel
2007, 10, 723.
[3] Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341.
[4] D’Souza, D. M.; Muller, T. J Chem Soc Rev 2007, 36, 1095.
[5] Eren, G.; Unlu, S.; Nunez, M. T.; Labeaga, L.; Ledo, F.;
Entrena, A.; Lu, E. B.; Costantino, G.; Sahin, M. F. Bioorg Med Chem
2010, 18, 6367.
[6] Welsch, M. W.; Snyder, S. A.; Stockwell, B. R. Curr Opin
Chem Biol 2010, 14, 347.
[7] De Oliveira, C. S.; Lira, B. F.; Barbosa-Filho, J. M.; Lorenzo,
J. G. F.; De Athayde-Filho, P. F. Molecules 2012, 17, 10192.
[8] Campaigne, E.; Ellis, R. L.; Bradford, M.; Ho, J. J Med Chem
1969, 12, 339.
[9] Gangjee, A.; Devraj, R.; McGuire, J. J.; Kisliuk, R. L.;
Queener, S. F.; Barrews, L. R. J Med Chem 1994, 37, 1169.
[10] Gangjee, A.; Devraj, R.; McGuire, J. J.; Kisliuk, R. L. J Med
Chem 1995, 38, 3798.
[11] Gangjee, A.; Zeng, Y.; McGuire, J. J.; Kisliuk, R. L. J Med
Chem 2002, 45, 1942.
9.66%.
3-Ethyl-7-(thiophen-2-yl)-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (5n).
Whitish solid; mp 225–227°C; IR (KBr, cmꢀ1): 1672
(═NCO─); 1H NMR (CDCl3, 300 MHz): δ 1.41 (t,
J = 6.79, 3H, ─CH3), 4.41 (q, J = 6.79, 2H, ─CH2),
7.19 (dd, J = 4.90, 1H, Ar─H), 7.51 (dd, J = 4.90, 1H,
Ar─H), 7.78 (dd, J = 3.78, 1H, Ar─H), 7.88 (s, 1H,
Ar─H); 13C NMR (CDCl3, 75 MHz): 12.4, 43.8, 120.6,
124.0, 126.0, 126.5, 128.2, 129.2, 130.4, 130.9, 133.7,
136.2, 140.1, 143.0, 145.3, 147.2, 160.9; MS (ESI): m/z
[(M + H)+]: 450. Anal. Calcd for C17H9F6N3OS2: C,
45.44; H, 2.02; N, 9.35%. Found: C, 45.45; H, 2.04; N,
[12] Gangjee, A.; Zeng, Y.; McGuire, J. J.; Mehraein, F.; Kisliuk,
R. L. J Med Chem 2004, 47, 6893.
[13] Gangjee, A.; Zeng, Y.; McGuire, J. J.; Kisliuk, R. L. J Med
Chem 2005, 48, 5329.
[14] Janeba, Z.; Balzarini, J.; Andrei, G.; Snoeck, R.; De Clercq, E.;
Robins, M. J. J Med Chem 2005, 48, 4690.
9.36%.
3-Propyl-7-(thiophen-2-yl)-2,9-bis(trifluoromethyl)
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (5o).
Whitish solid; mp 212–214°C; IR (KBr, cmꢀ1): 1678
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. Racha, B. Vadla, K. Peddolla, and S. Betala
Vol 000
[15] Furukawa, S.; Takada, M.; Castle, R. N. J Heterocyclic Chem
1981, 18, 581.
[24] Narsaiah, B.; Shivaprasad, A.; Venkataratnam, R. V. J Fluor
Chem 1994, 69, 139.
[16] Leevers, S. L.; Vanhaesebroeck, B.; Waterfield, M. D. Curr
Opin Cell Biol 1999, 11, 219.
[25] Klebe, G.; Abraham, U.; Mietzner, T. J Med Chem 1994, 37,
4130.
[17] Lawlor, M. A.; Alessi, D. R. J. Cell Sci 2001, 114, 2903.
[18] Vanhaesebroeck, B.;. S. J.; Leevers, K.; Ahmadi, J.; Timms,
R.; Katso, P. C.; Driscoll, R.; Woscholski, P. J.; Parker, M. D. Rev
Biochem 2001, 70, 535.
[26] Abdel-Rahman, E.; Abdul, E.; Bakhite Etify, A.; Al-Taifi, E.
A. J Chem Res 2005, 2005, 461.
[27] Mosmann, T. J Immunol Methods 1983, 65, 55.
[19] Cantley, L. C. Science 2002, 296, 1655.
[20] Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J Org
Chem 1988, 53, 2406.
SUPPORTING INFORMATION
[21] Filler, R. Stud Org Chem 1993, 48, 362.
[22] Chae, J.; Konno, T.; Ishihara, T.; Yamanaka, H. Chem Lett
2004, 33, 314.
[23] Santhosh Kumar, G.; Poornachandra, Y.; Gunda, S. K.;
Ratnakar Reddy, K.; Mohmed, J.; Shaik, K.; Ganesh Kumar, C.; Narsaiah,
B. Bioorg Med Chem Lett 2018, 28, 2328.
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet