Synthesis, characterization, antimicrobial activities, anticancer of some new pyridines from 2, 3-dihydro-2-oxo-4-phenyl-6-(thien-2-yl) pyridine-3-carbonitrile

Article abstract of DOI:10.1080/00397911.2020.1849726

2,3-Dihydro-2-oxo-4-phenyl-6-(thien-2-yl)pyridine-3-carbonitrile (4) was synthesized via reaction of four compounds (benzaldehyde, 2-acetylthiophene, ethyl cyanoacetate and ammonium acetate) in one step reaction. 2-((Hydrazinocarbonyl)methyloxy)-4-phenyl-

Full text of DOI:10.1080/00397911.2020.1849726

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis, characterization, antimicrobial
activities, anticancer of some new pyridines
from 2, 3-dihydro-2-oxo-4-phenyl-6-(thien-2-yl)
pyridine-3-carbonitrile
Safaa I. Elewa, Abdou O. Abdelhamid, Ahmed A. Hamed & Eman Mansour
To cite this article: Safaa I. Elewa, Abdou O. Abdelhamid, Ahmed A. Hamed & Eman Mansour
(2021) Synthesis, characterization, antimicrobial activities, anticancer of some new pyridines from
2, 3-dihydro-2-oxo-4-phenyl-6-(thien-2-yl) pyridine-3-carbonitrile, Synthetic Communications, 51:1,
151-161, DOI: 10.1080/00397911.2020.1849726
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2021, VOL. 51, NO. 1, 151–161
https://doi.org/10.1080/00397911.2020.1849726
Synthesis, characterization, antimicrobial activities,
anticancer of some new pyridines from 2, 3-dihydro-2-oxo-
4-phenyl-6-(thien-2-yl) pyridine-3-carbonitrile
Safaa I. Elewaa, Abdou O. Abdelhamidb , Ahmed A. Hamedc , and
Eman Mansoura
aDepartment of Chemistry, Faculty of Women for Arts, Science and Education, Ain Shams University,
b
c
Cairo, Egypt; Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt; Microbial
Chemistry Department, National Research Centre, Dokki, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 2 September 2020
2,3-Dihydro-2-oxo-4-phenyl-6-(thien-2-yl)pyridine-3-carbonitrile (4) was
synthesized via reaction of four compounds (benzaldehyde, 2-acetylth-
iophene, ethyl cyanoacetate and ammonium acetate) in one step
reaction. 2-((Hydrazinocarbonyl)methyloxy)-4-phenyl-6-(2-thienyl)pyri-
dine-3-carbonitrile was obtained by reaction of 5 with hydrazine
hydrate. Schiff’s bases, pyrazole derivatives, urea derivatives, and car-
bamates were also synthesized. Based on the spectral facts and elem-
ental analysis, structures of the newly synthesized compounds were
elucidated. Also, the new compounds were evaluated for their antibac-
terial and antitumor activities.
KEYWORDS
Anticancer activity;
antimicrobial; pyrazoles;
Schiff’s bases;
thiophene; urea
GRAPHICAL ABSTRACT
CN
H
CN
N
N
O
N
Ar
O
S
O
N
O
O
CN
OH
S
O
NH
N
S
CN
O
H
NH
N
N
N
O
S
O
CONTACT Safaa I. Elewa
Safaa_elewa@yahoo.com; Safaa.elewa@women.asu.edu.eg
Department of Chemistry,
Faculty of Women for Arts, Science and Education, Ain Shams University, Cairo, P.O. Box 11566, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

152
S. I. ELEWA ET AL.
Introduction
Breast cancer is a complex disease that comprises heterogeneous tumors associated with
distinctive histological patterns and different clinical characteristics.[1] An estimated 1.7
million women will be diagnosed with breast cancer in 2020, a 26% increase from
current levels.[2] Approximately 30% of the women diagnosed with early-stage disease
subsequently progress to metastatic breast cancer (MBC), for which few therapeutic reg-
imens exist.[3] Despite the advances in therapeutic modalities, MBC remains incurable,
with an estimated survival rate of about 23% over 5 years.[4] Chemotherapy resistance is
also a consistent obstacle in the management of breast cancer, where many of the ini-
tially responsive tumors relapse and develop resistance to diverse chemotherapeutic
agents.[5] Consequently, new agents with low susceptibility to common drug resistance
mechanisms are urgently needed for the management and treatment of various forms of
breast cancer.
Pyridine derivatives are very essential chemical compounds with the tremendous bio-
logical applications. In medicinal applications, these compounds share a necessary part.
The activities of pyridine derivatives vary from moderate to excellent against a number
of biological targets such as anti-microbial, anti-viral, antioxidant, anti-diabetic,
anticancer activities, antimalarial agents, and anti-amoebic agents.[6–26] With altering
substituents on the pyridine nucleus, the biological targets differ from microbial dis-
eased to viral problems and a variety of cancerous cells. These derivatives target
exclusive biological problems by interacting with enzymes, proteins and DNA. From the
above facts, and our interest in designing new heterocyclic compounds that have
pharmaceutical properties.[27–34]
Results and discussion
Pyridine-3-carbonitrile derivative (4) was synthesized by the condensation reaction of a
mixture of benzaldehyde (1), 2-acetylthiophene (2), and ethyl cyanoacetate (3) in boiling
ethanol in presence of ammonium acetate. 2-((ethoxycarbonyl)methyloxy)-4-phenyl-6-(2-
thienyl)pyridine-3-carbonitrile (5) was obtained by the reaction of 4 with ethyl chloroace-
tate in ethanol. Compound 5 reacted with sodium ethoxide in boiling ethanol afforded
one isolable product (6) according to TLC. The IR of the product revealed bands at (KBr,
ꢀ, cmꢀ1): 3109, 3092 (CH), 2217 (CN), 1584 (C¼C), 1445 (CH2), 1355 (CH3). H1-NMR
spectra of the synthesized compound (6) revealed a triplet-quartet pattern of ethyl protons
at 1.46–1.50 and 4.55–4.61 ppm and singlet signal at 7.06 for pyridine H. Meanwhile, the
reaction of compound 5 with hydrazine hydrate gave pyridine-3-carbonitrilederivative (8).
Schiff’s bases (9a–d) were obtained from reaction of compound 5 with the appropriate
benzaldehyde,4-methoxybenzaldehyde,4-methylbenzaldehyde and 4-chlorobenzaldehyde in
ethanol, respectively, in the presence of a few drops of acetic acid (Scheme 1).The struc-
tures of 8 and 9a–d were established on the foundation of elemental analysis and spectral
results (cf. Section “Experimental”).
Also, thienylpyridine-3-carbonitrile derivative 10 was synthesized by the reaction of 8
with indoline-2,3-dione in methanol and the presence of catalytic amounts of acetic
acid (Scheme 2).

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Scheme 1. 2-Ethoxy-4-phenyl-6-(thien-2-yl)nicotinonitrile.
Treatment of compound 8 with the appropriate benzene sulfonyl chloride and p-tolu-
ene sulfonyl chloride in pyridine at room temperature afforded compound (11) and
(12), respectively.
Thienylpyridine-3-carbonitrile 13 and nicotinonitrile derivatives 14 were obtained
via the reaction of compound 8 with appropriate acetylacetone, ethyl acetoacetate in
ethanol/glacial acetic acid mixture (30 mL) (2:1) (cf. Scheme
“Experimental”).
2 and Section
Furthermore, Compound 8 was reacted with nitrous acid to give nicotinonitrile
derivative 15. Based on the elemental analysis, spectral records, and chemical transform-
ation, the structure of 15 was confirmed. Thus, compound 15 can be transformed into
urea derivatives, 16–18, and 19 from the suitable aromatic amines, or anthranilic acid
(or methyl anthrarnelate) in boiling dry dioxane, respectively. Pyridine-3-carbonitrile
derivative 20 can also be formed by boiling phenol in dry benzene with azido 15
(Scheme 3).

154
S. I. ELEWA ET AL.
O
CN
O
CN
O
N
N
N
N
N
N
S
O
S
O
14
13
iv
v
ii-iii
vi
CN
O
CN
H
N
O
CN
O
N3
S
N
N
O
N
H
N
O
CONHNH2
S
O
S
O
S
X
8
15
11,12
i
X=H
X=CH3
i -indoline-2,3-dione/AcOH
ii = PhSO2Cl / EtOH
iii = 4-CH3 PhSO2Cl / EtOH
iv = Acetylacetone
v = Ethyla cetoacetate
vi = NaNO2/ AcOH
CN
H
N
NH
N
O
N
O
S
O
10
Scheme 2. Synthesis of pyrazole and azide.
Scheme 3. Synthesis of urea, quinoxaline and carbamate derivatives.

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155
Antimicrobial activity
Recently, Antimicrobial resistance becomes one of the biggest threats to humanity.[40] It can
affect any person at any age, in any country. Antimicrobial resistance usually happens when
humans misuse antibiotics and several pathogenic infections, such as tuberculosis, gonor-
rhea, pneumonia, and salmonellosis—are becoming harder to treat as the antibiotics used to
treat them become less effective. In our effort to evaluate the inhibitory activities of the syn-
thesized compounds, the antibacterial potential against S. aureus, B. subtilis, E. coli, and P.
aruginosa were measured. Compounds 11 and 15 displayed a pronounced antibacterial
activity against Gram-positive S. aureus with 59.54% and 55.84% of inhibition respectively,
followed by compounds 9a, 10, 13, 18, 20. While compounds 9b and 9c showed a mild to
moderate inhibitory activity against Gram-positive B. subtilis with % of inhibition ranged
from 45.09% to 48.01%. Both compounds 9a and 9c showed potent to moderate inhibitory
activity against Gram-negative E. coli with inhibition ratio of 64.81% and 64.61%, followed
by 15, 18b, and 11. Compound 13 showed moderate antibacterial activity against Gram-
negative P. aruginosa with an inhibition ratio 53.10% (Figure 1).
Antibiofilm activity
Bacterial biofilm formation has been found to play a critical role in the persistence of
bacterial infections[36,37] This phenomenon helps bacteria to maintain their attachment
on living or no living surface in close proximity to each other.[38] Thus, biofilms are
recognized as a remarkable source of bacterial infectious diseases such as peridontitis,
osteomyelitis, dental caries, otitis media.[39] The antibiofilm activity of the synthesized
compounds has been measured against four clinical microbes (P. aeruginosa, S. aureus,
B. subꢀlis
p. aerginosa
120
100
80
60
40
20
0
120
100
80
60
40
20
0
compounds
compounds
E. coli
S. aureus
120
100
80
60
40
20
0
120
100
80
60
40
20
0
compounds
compounds
Figure 1. Antibacterial activity as % of inhibition (4, 5, 8, 9a, 9 b, 9c, 9d, 10, 11, 12, 13, 15, 16, 17,
18, 19 and 20) against different bacterial strains.

156
S. I. ELEWA ET AL.
B. subꢀlis
P.aruginosa
100
80
60
40
20
0
100
80
60
40
20
0
4
5
8 9a 9b 9c 10 11 12 13 15 16 17 18 19 20
compounds
4
5
8 9a 9b 9c 10 11 12 13 15 16 17 18 19 20
compouds
E.coli
S. aureus
100
80
60
40
20
0
100
80
60
40
20
0
4
5
8 9a 9b 9c 10 11 12 13 15 16 17 18 19 20
compounds
4
5
8 9a 9b 9c 10 11 12 13 15 16 17 18 19 20
compouds
Figure 2. Anti-biofilm activity of compounds (4, 5, 8, 9a, 9 b, 9c, 9d, 10, 11, 12, 13, 15, 16, 17, 18,
19 and 20) on different strains of microorganisms.
E. coli and B. subtilis) (Figure 2). Compounds 15 and 11 reduced the biofilm formation
of the strain S. aureus up to 57.61% and 59.84%, respectively followed by compounds 4,
13, 10, 9a with inhibition ratio ranged from 47.23% to 50.33%. While in the case of B.
subtilis biofilm inhibition, only three compounds 15, 9c, 11 showed a moderate to low
biofilm inhibition activity 41.19%, 44.46% and 40.56%. On the other hand, compounds
9a, 9c, 11 displayed a potent anti-biofilm activity with inhibition ratio 78.75, 73.67, and
72.78%, followed by compounds 8, 10, 15, 20, 18 with inhibition activity ranged from
61.49 to 67.70. P. aruginosa was more susceptible bacteria to the synthesized com-
pounds. While, compounds 4, 5, 8, 13, 10, 20, 18, 19, and 9a showed biofilm inhibitory
activity ranged from 60.29 to 68.14%, followed by compounds 15, 16, 17, 9d, 9b and 9c
with inhibition ratio ranged from 42.17 to 59.13 (Figure 2).
In vitro cytotoxicity
As there is a matching correlation between the antimicrobial activity of the synthesized
compounds and their cytotoxicity. Three compounds 15, 9a, and 9c were accordingly
selected based on antimicrobial and anti-biofilm results to investigate their efficiency as anti-
cancer agents. So, they were studied against liver (HePG-2), breast (MCF-7), colon (HCT-
116) cancer cell lines, in comparison with doxorubicin as a reference control. Accordingly,
compounds 9c, 9a and 15 showed moderate cytotoxic activity against HCT116 and
MCF7cell lines (IC50: 23.09–39.70 mg/mL), meanwhile, compound 15 showed a strong cyto-
toxicity (IC50:19.85 mg/mL) against HePG-2 followed by 9a and 9c with (Table 1).
Structure activity relationship
Recent reports demonstrated that the antibacterial mechanism of action generally
involves regulation or inhibition of enzymes responsible for the cell wall biosynthesis,

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Table 1.
In vitro cytotoxicity IC50 (mg/ml)a
Comp.
WI38
HCT116
HePG-2
MCF7
DOX
15
9a
6.72 0.5
56.16 3.5
39.26 2.5
45.89 2.9
5.23 0.3
29.17 1.9
25.39 0.8
34.10 2.3
4.50 0.2
19.85 1.4
36.84 0.6
28.76 2.1
4.17 0.2
23.09 2.3
30.48 1.0
39.70 2.9
9c
aIC50 (mg/ml): 1–10 (very strong); 11–20 (strong); 21–50 (moderate); 51–100 (weak) and above 100 (non-cytotoxic)
DOX: Doxorubicin.
protein synthesis, nucleic acid metabolism and repair and disruption of membrane
structure.[40] The obtained biological activity results (antibacterial, anti-biofilm, and
anticancer) declared that, compounds 15, 11, 9c, 9d and 9a displayed pronounced anti-
bacterial, and anti-biofilm activity. On the other hand, three compounds 15, 9a, and 9d
showed anti-proliferative activity toward liver (HePG-2), breast (MCF-7), colon (HCT-
116) cancer cell lines. Based on the structure of the active compounds, the activity have
resulted from the presence of thiophene group in combination with azide group in
compound 15, cyanide group in compound 11, methoxy group in compound 9c, chlor-
ine element in compound 9d and benzene ring in compound 9a. These results con-
firmed that the presence of chemical groups such as (azide, methoxy, cyanide, benzene)
and chlorine element may increase the activity of the synthesized compounds.
Conclusion
In our work, new pyridine-3-carbonitile derivatives were synthesized, and their struc-
tures were confirmed by different spectral data, also it was found that they are useful as
a key precursor for the synthesis of different heterocyclic derivatives which have an
interesting anti-proliferative activity such as Schiff’s bases, azide, urea, quiazoline , and
carbamate derivatives. Most of the synthesized compounds were investigated for their
anticancer activity. The anticancer effects of some compounds showed moderate cyto-
toxic activity against HCT116 and MCF7cell lines, meanwhile, others showed strong
cytotoxicity against HePG-2, in addition it was also compared with the standard anti-
cancer drug doxorubicin.
Experimental
All melting points have been measured by the use of Reichert Thermovar equip-ment
and are uncorrected. Listed yields are of isolated compounds. The IR spectra for the
KBr disk was registered on a Perkin-Elmer spectrometer model 1720 FTIR.1H-NMR
and 13C-NMR spectra have been reported on a BrukerAC-400 or DPX-400 spectrometer
in CDCl3 and (CD3)2SO solutions and chemical shifts are expressed in ppm units using
tetramethylsilane as an internal reference and the J coupling constants are given in Hz.
Once TLC followed the progress of the reactions using aluminum silica gel plates 60
with a Shimadzu GCMS–QP–1000 EX mass spectrometer in EI (70 eV) model F245.
Elemental analyses were performed at the University of Cairo Microanalytical Center.

158
S. I. ELEWA ET AL.
The Biological Activity of the compounds was carried out at National Research Center
(NRC), Tahrir Street, Dokki, Cairo, Egypt.
2-Oxo-4-phenyl-6-(thienyl-2-yl)-1,2-dihydropyridine-3-carbonitrile (4)
A mixture of benzaldehyde 1 (1.06 g, 1.02 mL, 0.01 mol), 2-acetylthiophene 2 (1.26 g,
1.08 mL, 0.01 mol), ethyl cyanoacetate 3 (1.13 g, 1.09 mL, 0.01 mol) and ammonium acet-
ate (7.71 g, 0.1 mol) in ethanol (50 mL) refluxed for 1 h. Filtered, treated with cold etha-
nol (50 mL), the precipitate was dried and crystallized with ethanol. Yield: 90%,
yellowish-green crystal, m.p.: 340 ꢀ 342 ꢁC. IR (KBr, ꢀ, cmꢀ1): 3453 (NH), 2216 (CN),
1
1635 (C ¼ O); H NMR (DMSO-d6, d ppm), 7.08 (s, 1H, pyridinone-H-5) 7.27–7.22
(dd, J ¼ 4 Hz, J ¼ 12 Hz, 1H, thienyl H-4), 7.58–7.68 (m, 3H, thienyl and ArH),
7.69–7.71 (d, 2H, J ¼ 8 Hz, ArH ), 8.06–8.08 (d, 2H, J ¼ 8 Hz, ArH), 12.77 (s, 1H, NH);
13C NMR (DMSO-d6, dppm): 39.37, 39.58, 39.79, 40.00, 40.20, 40.42, 40.62, 42.00,
116.73, 128.68, 129.29, 129.44, 130.04, 130.71, 132.92, 136.42; Anal. For C16H10N2OS
(278.33), calcd (%): C, 69.04; H, 3.62; N, 10.06; Found: C, 69.29; H, 3.41; N, 9.86.
2-((Ethoxycarbonyl)methyloxy)-4-phenyl-6-(2-thienyl)pyridine-3-carbonitrile (5)
A mixture of 4 (2.78 g, 0.01 mol), ethyl chloroacetate (1.22 g, 1.06 mL 0.01 mol) and
anhydrous potassium carbonate (4.5 g, 0.04 mol) in DMF (30 mL) was stirred at room
temperature for 20 h. The reaction mixture was poured onto ice-cold water and
the reaction left in a fridge for overnight. The resulting solid was filtered, washed with
water, dried and recrystallized from ethanol (50 mL).Yield: 75%, paje crystal, m.p.:
1
130–132 ꢁC. IR (KBr, ꢀ, cmꢀ1): 2218 (CN), 1751 (CO), 1586 (C¼N). H NMR (DMSO-
d6, d ppm): 1.26 (t, 3H, J ¼ 4 Hz, CH3), 4.23–4.25 (q, 2H, J ¼ 8 Hz, CH2), 5.11 (s, 2H,
CH2), 7.27–7.22 (dd, 1H, J ¼ 4, Hz, J ¼ 12 Hz, thienyl H-4), 7.22–7.31 (m, 3H, thienyl
and ArH), 7.61 (s, 1H, pyridinone-H-5), 7.71–7.73 (d, 2H, J ¼ 8 Hz, ArH), 8.06–8.08
(d, 2H, J ¼ 8 Hz, ArH); MS, m/z (%): 365 (Mþ1, 20.53), 364 (Mþ, 78.48), 291 (100), 279
(10.60), 261 (36.38), 190 (18.14), 127.20 (3.86), 102 (3.98), 77 (15.79); Anal. for
C20H16N2O3 S (364.42), calcd (%): C, 65.92; H, 4.43; N, 7.69, S, 8.80; Found: C, 65.56;
H, 4.50; N, 7.99, S, 8.72.
2-Ethoxy-4-phenyl-6-(thien-2-yl)nicotinonitrile (6)
In absolute ethanol (25 mL) a mixture of 5 (0.364 g, 0.001 mol) and sodium ethoxide
(0.68 g sodium) was heated under reflux for 12 h, the reaction mixture was cooled up.
The solid was obtained and crystallized from ethanol (50 mL) to give colorless needles
m.p. 90–92 ꢁC. IR (KBr, ꢀ, cmꢀ1): 3109, 3092 (CH), 28,217 (CN), 1584 (C ¼ C), 1445
(CH2), 1355 (CH3). 1H NMR (CDCl3, d) showed signals at ¼ 1.46–1.50 (t, 3H,
CH3CH2O), 4.55–4.61(q, 2H, CH3CH2O), 7.06 (s, 1H, pyridine H-5),7.20–7.25 (m, 3H,
thienyl and ArH), 7.26–7.30 (dd, 1H, J ¼ 4, Hz, J ¼ 12 Hz, thienyl H-4), 7.73–7.75
(d, 2H, J ¼ 8 Hz, ArH), 7.94–7.96 (d, 2H, J ¼ 8 Hz, ArH), Anal. for C18H14N2OS
(306.38), calcd (%): C, 70.56; H, 4.61; N, 9.14; S, 10.47; Found: C, 70.64; H, 4.55; N,
9.00; S, 10.38.

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2-((Hydrazinocarbonyl)methyloxy)-4-phenyl-6-(2-thienyl)pyridine-3-carbonitrile (8)
The hydrazine hydrate (5 g, 4.9 mL, 0.1 mol) was added once to a suspension of 5
(3.64 g, 0.01 mol) in absolute ethanol (50 mL). The mixture was heated under reflux for
6 h and cooled at room temperature. The precipitate was filtered, dried and crystallized
from ethanol (50 mL). Yield: 68%, pale yellow needles, m.p.: 228–230 ꢁC. IR (KBr, ꢀ,
1
cmꢀ1): 3329–3105 (NH2, NH), 2222 (CN), 1678 (CO), H NMR (DMSO-d6, d ppm):
5.09 (s, 2H, CH2), 5.37 (s, br., 2H , NH2, exchangeable), 7.08 (s, 1H, pyridinone-H-5),
7.26–7.30 (dd, J ¼ 4,12 Hz, 1H, thienyl H-4), 7.60–7.62 (m, 3H, thienyl and ArH),
7.71–7.73 (d, 2H, J ¼ 8 Hz, ArH), 8.06–8.08 (d, 2H, J ¼ 8 Hz, ArH), 9.35 (s, 1H, NH
exchangeable); 13C NMR (DMSO-d6, dppm): 39.37, 39.58, 39.79, 40.00, 40.20, 40.41,
40.42, 42.00, 116.73(2 C), 128.68, 129.29(2 C), 129.44, 130.04, 130.71, 132.92, 136.42;MS
m/z (%): 352 (1.26 Mþ2), 351 (4.17, Mþ1), 350 (17.23, Mþ), 320 (16.99), 319 (75.16),
292 (14.47), 291 (59.76), 280 (22.09), 279 (100), 278 (71.43), 262 (10.08); Anal. for
C18H14N4O2S (350.40), calcd (%): C, 61.70; H, 4.03; N, 15.99; S, 9.15; Found: C, 61.56;
H, 4.11; N, 16.05; S, 9.20.
Funding
This study was supported by Faculty of Women’s for Arts, Science and Education, Ain
Shams University.
ORCID
Abdou O. Abdelhamid
Ahmed A. Hamed
http://orcid.org/0000-0002-5380-7727
http://orcid.org/0000-0002-9997-9284
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