Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl)pyrido[2,3-d]pyrimidine derivatives as promising anticancer and antibacterial agents

Article abstract of DOI:10.1016/j.bmcl.2016.04.038

A series of novel 1,2,3-triazole/isoxazole functionalized pyrido[2,3-d]pyrimidine derivatives 6a-c, 7a-h and 8a-e were prepared in series of synthetic steps. All the compounds screened for the anticancer activity against four human cancer cell lines using

Full text of DOI:10.1016/j.bmcl.2016.04.038

Accepted Manuscript
Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl) pyrido
[2,3-d]pyrimidine derivatives as promising anticancer and antibacterial agents
R. Naresh Kumar, G. Jitender Dev, N. Ravikumar, D. Krishna Swaroop, B.
Debanjan, G. Bharath, B. Narsaiah, S. Nishant Jain, A. Gangagni Rao
PII:
S0960-894X(16)30411-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.04.038
BMCL 23800
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 November 2015
4 April 2016
15 April 2016
Please cite this article as: Naresh Kumar, R., Jitender Dev, G., Ravikumar, N., Krishna Swaroop, D., Debanjan, B.,
Bharath, G., Narsaiah, B., Nishant Jain, S., Gangagni Rao, A., Synthesis of novel triazole/isoxazole functionalized
7-(trifluoromethyl) pyrido [2,3-d]pyrimidine derivatives as promising anticancer and antibacterial agents,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.04.038
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Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl) pyrido[2,3-d]pyrimidine
derivatives as promising anticancer and antibacterial agents
R. Naresh Kumara,d, G. Jitender Dev,a,d N. Ravikumar,a D. Krishna Swaroop,a,d B. Debanjan,b G. Bharath,c B.
Narsaiah,a,d  S. Nishant Jainb and A. Gangagni Rao.c

Bioorganic & Medicinal Chemistry Letters
Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl) pyrido
[2,3-d]pyrimidine derivatives as promising anticancer and antibacterial agents
R. Naresh Kumar,a,d G. Jitender Dev,a,d N. Ravikumar,a D. Krishna Swaroop,a,d B. Debanjan,b G. Bharath,c
B. Narsaiah,a,d S. Nishant Jainb and A. Gangagni Rao.c
aFluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, India.
bMedicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, India..
cBioengineering & Environmental Science, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
dAcademy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of novel 1,2,3-triazole/isoxazole functionalized pyrido[2,3-d]pyrimidine derivatives 6a-c,
7a-h and 8a-e were prepared in series of synthetic steps. All the compounds screened for the
anticancer activity against four human cancer cell lines using Nocodazole as standard. Compounds
7d and 7h showed highest activity against PANC-1 (pancreatic cancer) and A549 (lung cancer) cell
lines respectively and more than standard. All the compounds also screened for antibacterial activity
using Rifampicin and Ciprofloxacin as standards and identified promising compounds further
evaluated for minimum inhibitory concentration to validate the data.
Key words:
Pyrido[2,3-d]pyrimidine
Triazole
Isoxazole
Anticancer
1,3-Dipolar cycloaddition
Sharpless conditions
The design and development of new antiproliferative drugs with
improved efficacy and minimal side effects is a major challenge in modern
drug discovery because of multidrug resistant in tumor cells. Eventhough the
field of clinical research related to cancer therapy advances, major
malignancies cancer still second leading cause of death in developing and
developed countries.1 The main drawback of these cytotoxic drugs is that,
they do not discriminate between cancer cell and normal cell types and are
accompanied by toxic side effects that are often cumulative and dose
limiting.2 Recent literature review reveals that, reactions involving hetero
atoms such as 1,3-dipolar cycloaddition, provides rapid access to a wide
variety of interesting five and six-membered heterocycles and they offer an
advantage in design of antiproliferative agents as they mimic many
biomolecules. They have also found wide applications in medicinal
chemistry. Among all the six membered heterocycles, pyrido[2,3-d]
pyrimidines are fused 6,6-bicyclic heterocycles consisting of a pyridine ring
fused to a pyrimidine. The scaffold system is
present in a number of biologically active compounds and synthesis of these
compounds has markedly increased in the literature. Pyrido[2,3-
d]pyrimidines are also great interest due to their broad spectrum of biological
activity such as antifolate,3 antibacterial,4 growth regulator,5 antipyretic,6
analgesic,7 antihistaminic,8 PDE4 inhibitor,9 adenosine kinase inhibitor,10
tyrosine kinase inhibitor,11 and diuretic,12,13 activities, Especially these
derivatives were reported to exhibit antitumor14 activity, which may be
attributed to inhibition of cyclin dependent kinase,15,16 check point kinase17 or
mammalian target of rapamycin.18
On the other side, recently various five membered heterocycles like
1,2,3-triazole/isoxazole derivatives attracted attention due to their diverse
pharmaceutical properties. Many compounds possessing 1,2,3-triazole
fragment afford huge biological activities.19 Discovery of copper (I) as an
efficient and regiospecific catalyst for the transformation of 1,4-disubstitued
1,2,3-triazoles by Hüisgen [3+2] cycloaddition between alkynes and organic
azides. Compounds with 1,2,3-triazole could actively participate in hydrogen
bonding and dipole-dipole interactions due to their strong dipole moments;
———
 Corresponding author. Tel.: +91-40-27193185; fax: +91-40-27160387 ; e-mail: narsaiah@iict.res.in

besides, it is extremely hard to be hydrolyzed and keeps stable in oxidative or
reductive conditions.20 The 1,2,3-triazoles showed significant antiproliferative
against a wide variety of human cancer cell lines, including those that are
multidrug resistant.21 Several compounds with 1,2,3-triazoles moiety, have
occupied an important position in medicinal chemistry22 owing to its
chemotherapeutic effect such as cytostatic,23 antiviral,24 antibacterial25 or
antifungal,26 antitubercular,27 antineoplasm28 activities. Moreover, the
isoxazole core structure constitutes one of the most five-membered promising
nitrogen-oxygen containing heterocyclic systems29 and they have attracted
considerable attention in the field of medicinal chemistry by showing various
biological properties viz., antidiabetic, analgesic, antiarrhythmic, anti-
inflammatory, antifungal and antiviral.30-33
ratio of N/O-propargylated is 1:2, for phenyl 1:3 and it is attributed to steric
hindrance of substitution at C-2 position.
In this view, the research effort has been initiated towards the
investigation of the antitumor properties containing both pyrido[2,3-
d]pyrimidine and 1,2,3-triazole/isoxazole pharmacophores in a compact
system. The diverse biological activity of these compounds encouraged and
prompted us to synthesise the novel series of various 1,2,3-triazole/isoxazole
functionalized pyrido[2,3-d]pyrimidine hybrid molecules by conjugation with
O-CH2 or N-CH2 linker to explore new opportunities for structure
optimization and diverse range of mechanisms for a potent anticancer
activity. All the derivatives were subjected to anticancer activity against four
human cancer cell lines such as MDA MB-231(breast), PANC 1(pancreatic),
A549 (lung) and HeLa (cervical), and also screened for antibacterial activity.
Most of the compounds were identified as more potent.
Scheme 2. Synthetic pathways for compounds 6a-c and 7a-h
Synthesis of the target compounds 6a-c, 7a-h and 8a-e was successfully
achieved as illustrated in Scheme 1, 2 and 3. The dry HCl gas was passed
through ethyl cyano acetate in ethanol and diethyl ether (2:1) continuosly for
2 to 3 hours resulted ethyl 3-amino-3-ethoxyacrylate. Compound ethyl 3-
amino-3-ethoxyacrylate and ammonium acetate were taken in absolute
ethanol and followed by addition of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one to
form ethyl 2-amino-6-(trifluoromethyl)nicotinate 135. Compounds 2a-c were
obtained on reaction of compound 1 with different alkyl or aryl acid chlorides
Scheme 3. Synthetic pathways for compounds 8a-e
Table 1. Synthesis of triazole/isoxazole functionalized
pyridopyrimidin derivatives 6a-c, 7a-h and 8a-e
o
at 60-120 C. Further, compound 1 or 2a-c was taken in formamide, heated
upto 140-150 oC resulted 2-substituted-7-(trifluoromethyl)pyrido[2,3-
d]pyrimidin-4(3H)-one 3a-d. Compounds 3a-d reacted individually with
propargyl bromide in acetone using potassium carbonate as base. Compound
3a and 3b form exclusively N-propargylated compounds 3-(prop-2-yn-1-yl)-
7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one 4a and 2-ethyl-3-(prop-
2-yn-1-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-
S. No. Compd
R
R1
Yield (%) m.p. (°C)
1
2
H
H
4-ClC6H4
4-BrC6H4
65
60
68
80
88
76
89
87
76
86
88
76
89
65
90
76
163-165
157-159
109-110
243-245
180-182
250-252
79-81
6a
6b
6c
7a
7b
7c
7d
7e
7f
3
C6H5
C2H5
C6H5
H
C10H7 (1-napthyl)
CH2CONHC6H5
4-NO2C6H4
4
5
6
4-NO2C6H4
7
C2H5
C2H5
2-Furan
C6H5
C2H5
C6H5
C6H5
C6H5
C6H5
C6H5
n-C10H21
8
n-C8H17
100-101
124-126
180-182
128-130
151-153
161-163
171-173
210-212
204-206
9
n-C10H21
10
11
12
13
14
15
16
n-CH2CH2C6F13
n-CH2CH2C6F13
CH2CONHC6H5
n-C10H21
7g
7h
8a
8b
8c
8d
8e
Scheme 1. Synthetic pathways for 4a-d and 5a-b
n-C8H17
4(3H)-one 4b respectively while compound 3c and 3d form two regioisomers
such as N-propargylated compounds 4c, 4d respectively and O-propargylated
compounds 5c, 5d respectively in definite proportions. If R = furyl group, the
n-CH2CH2C6F13
3,4,5-(OCH3)3C6H2

1
The structures of product were established based on H NMR data in which
triazole and isoxazole rings respectively helps in interaction with receptors,
7a and 8a have the amide (CONH) functional group on triazole ring which
helps in formation of hydrogen bonding expecting more activity and the
presence of electron with drawing NO2 group in compound 7c may helps to
increase the activity. All other compounds showed moderate to high activity,
which have no co-relation and independent of substituents present either on
C-2 or on triazole ring.
the signal for N-CH2 appeared in the range of δ 4.56 to 5.26 ppm, whereas O-
CH2 signal appeared in the range δ 5.35 to 5.40 ppm. For alkyl substitution
resulted exclusively N-propargylated derivatives 4a-b. Compound 4a or 4d
and triethylamine were taken in dry DCM and the reaction mixture was
cooled to 0 oC then addition of aqueous sodium hypochlorite followed by aryl
aldoxime yielded 2-substituted-3-((3-arylisoxazol-5-yl)methyl)-7-(trifluoro
methyl) pyrido[2,3-d]pyrimidin-4(3H)-one 6a-c. Compounds 4a-d (N-
propargylated) or 5d (O-propargylated), different alkyl azides/substituted aryl
azides/2-azido-N-substituted aryl acetamides, catalytic amount of copper
iodide (CuI) were taken in dry tetrahydrofuran at room temperature under
Sharpless conditions by 1,3-dipolar cycloaddition to give in good to excellent
yield of 1,4-disubstituted 1,2,3-triazole functionalized pyridopyrimidine
derivatives 7a-h and 8a-e. The synthetic sequence of products is drawn in a
Scheme 1, 2 and 3. Products are tabulated in Table 1.
The 16 newly synthesized target compounds were evaluated for their
antibacterial activity against three gram negative bacteria like Escherichia
coli, Klebsiella pneumonia, Pseudomonas aeruginosa and three gram positive
bacteria like Bacillus licheniformis, Streptococcus pneumonia and
Staphylococcus aureus. Agar-diffusion method was used for the
determination of the preliminary antibacterial activity. Rifampicin and
ciprofloxacin were used as reference drugs.
Table 3. Antimicrobial activity of triazole/isoxazole functionalized
pyridopyrimidin derivatives 6a-c, 7a-h and 8a-e
Compounds 6a-c, 7a-h and 8a-e were screened against four human
cancer cell lines such as All the compounds showed high activity MDA MB-
231 (breast cancer), PANC1 (pancreatic cancer), A549 (lung cancer) and
HeLa (cervical cancer) using Nocodazole as standard. against all cell lines at
<10 µM concentration. Compound 7d (GI50 0.02 μM) against PANC1 and 7h
(GI50 0.03 μM) against A549 showed highest activity and more than standard.
This is attributed to the presence of ethyl group on C-2 position and long
chain alkyl/perfluoroalkyl chain on triazole ring. Similarly compounds 7c
(GI50 0.14 μM), 8e (GI50 0.24 μM) against MDA MB-231, 6c (GI50 0.14 μM),
7a (GI50 0.32 μM) against PANC1, 7a (GI50 0.30 μM), 7f (GI50 0.20 μM) and
8a (GI50 0.14 μM) against A549 also showed high activity at <0.35 µM
concentration.
Zone of inhibition (mm)
Gram negative (-ve)
bacteria
Gram positive (+ve)
bacteria
Test
compound
E.ca
K.pb
19
07
-
P.ac
B.ld
S.pe
28
06
16
26
25
23
S.af
7d
7e
8b
25
07
-
16
07
-
21
08
08
21
24
24
15
09
10
22
25
25
8c
08
27
23
0.8
27
22
0.7
29
25
Rifampicin
Ciprofloxacin
Table 2. Anticancer activity of triazole/isoxazole functionalized
pyridopyrimidin derivatives 6a -c, 7a-h and 8a-e
- =No activity
aEscherichia col, ibKlebsiella
pneumonia, cPseudomonas aeruginosa,
dBacillus licheniformis, eStreptococcus pneumonia, fStaphylococcus aureus
GI50 values in μM
S.No
Compnd
Table 4. Minimum inhibitory concentration (MIC) of selected
compounds 7d and 8c
MDA MB-231
0.87 ± 0.03
0.71 ± 0.02
1.01 ± 0.04
1.70 ± 0.06
1.24 ± 0.06
0.14 ± 0.01
2.21 ± 0.08
1.34 ± 0.05
1.10 ± 0.04
9.89 ± 0.09
2.83 ± 0.05
0.65 ± 0.01
1.05 ± 0.05
0.57 ± 0.01
0.52 ± 0.02
0.24 ± 0.01
PANC1
A549
HeLa
1
2
7.08 ± 0.09
1.16 ± 0.04
0.14 ± 0.01
0.32 ± 0.01
2.55 ± 0.04
1.89 ± 0.04
0.02 ± 0.01
3.28 ± 0.05
3.18 ± 0.05
2.95 ± 0.04
0.73 ± 0.01
4.5 ± 0.07
1.09 ± 0.04 0.84 ± 0.03
3.81 ± 0.08 1.24 ± 0.04
3.14 ± 0.07 0.91 ± 0.03
5.26 ± 0.07 0.86 ± 0.02
0.77 ± 0.02 0.86 ± 0.02
0.30 ± 0.01 0.89 ± 0.03
0.86 ± 0.03 0.81 ± 0.02
2.87 ± 0.05 1.27 ± 0.04
0.20 ± 0.01 0.87 ± 0.03
0.52 ± 0.02 0.87 ± 0.02
0.03 ± 0.01 0.93 ± 0.03
0.14 ± 0.01 0.89 ± 0.03
2.31 ± 0.05 1.04 ± 0.04
5.33 ± 0.08 0.95 ± 0.03
1.91 ± 0.05 1.20 ± 0.04
4.05 ± 0.06 0.89 ± 0.03
6a
6b
6c
7a
7b
7c
7d
7e
7f
MIC(µg/ml)
3
Gram negative(-ve)
bacteria
Gram positive (+ve)
bacteria
4
Test
compound
5
E.ca
K.pb
P.ac
B.ld
S.pe
S.af
6
25
-
25
12.5
-
12.5
25
12.5
12.5
12.5
7d
8c
7
8
-
12.5
12.5
9
12.5
12.5
12.5
12.5
12.5
Ciprofloxacin
10
11
12
13
14
15
16
7g
7h
8a
8b
8c
8d
8e
- =No activity
aEscherichia col, ibKlebsiella
pneumonia, cPseudomonas aeruginosa,
dBacillus licheniformis, eStreptococcus pneumonia, fStaphylococcus aureus
0.49 ± 0.02
2.66 ± 0.06
2.99 ± 0.07
0.82 ± 0.03
The results were recorded for each tested compound in diameter of
inhibition of zones of bacterial growth around the disks in mm. The minimum
inhibitory concentration (MIC) measurement was also determined for
significant growth inhibition.36 The inhibition zone diameters values and MIC
(µg/ml) values are revealed in Table 3 & 4, respectively. The results revealed
that only 8b, 8c, 7d, 7e compounds displayed variable inhibitory effects on
the growth of the tested Gram-positive and Gram-negative bacterial strains.
The compound 7d showed good activity against Gram-positive and gram
Nocodazole
0.042 ± 0.001 0.029 ± 0.003 0.08 ± 0.001 0.063 ± 0.002
Structure verses activity revealed that, by changing the substitution on C-2
carbon and triazole or isoxazole ring observed difference in activities.
Compounds 6c and 7f were showing the long chain alkyl (SP3) group on

negative bacteria (inhibitory zone ≥20 mm). The compound 8c showed good
activity against Gram-positive bacteria (inhibitory zone ≥20 mm). The other
compounds 8b, 7e compounds exhibited moderate activity against tested
bacterial strains. The MIC values of compounds 8c, 7d showed moderate to
good activity (50-12.50 µg/ml) against gram-negative strains, with respect to
reference drug. Structure verses activity revealed that, the presence of ethyl
group or phenyl group on C-2 position and long chain alkyl (SP3) group on
triazole ring in compounds 7d, 7e, 8b and 8c helps to increase the inhibition
of bacterial growth.
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Acknowledgements
Authors are thankful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, India for the financial assistance in the form of
XII five year plan project DITSF code;CSC-0204. Authors (R. Naresh
Kumar, G. Jitender Dev, N. Ravikumar, D. Krishna Swaroop, B. Debanjan
and G. Bharath) are also thankful to CSIR for providing financial assistance
in the form of Research Fellowship and contingency grant.
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