Facile synthesis of novel heterocyclic compounds based on pyridine moiety with pharmaceutical activities

Article abstract of DOI:10.1002/jhet.3881

A novel run of fused heterocyclic derivatives containing pyridine moieties has been disclosed by allowing 2-amino-4-phenyl-6-(phenyl amino)pyridine-3,5-dicarbonitrile 1 to undergo annulation reactions with different reagents. Most of synthesized compounds have moderate to strong antitumor activity against HePG-2 and MCF-7. Moreover, MOE 2014.09 software was used to run the computational studies to support the biological activity results. The assigned structures for all the newly prepared derivatives were ascertained on the basis of elemental analyses and spectral data.

Full text of DOI:10.1002/jhet.3881

Received: 27 September 2019
DOI: 10.1002/jhet.3881
Revised: 13 December 2019
Accepted: 16 December 2019
A R T I C L E
Facile synthesis of novel heterocyclic compounds based on
pyridine moiety with pharmaceutical activities
Naglaa F. H. Mahmoud
| Ahmed El-Sewedy
Chemistry Department, Faculty of Science
Ain Shams University, Cairo, Egypt
Abstract
A novel run of fused heterocyclic derivatives containing pyridine moieties has
been disclosed by allowing 2-amino-4-phenyl-6-(phenyl amino)pyridine-3,-
5-dicarbonitrile 1 to undergo annulation reactions with different reagents.
Most of synthesized compounds have moderate to strong antitumor activity
against HePG-2 and MCF-7. Moreover, MOE 2014.09 software was used to run
the computational studies to support the biological activity results. The
assigned structures for all the newly prepared derivatives were ascertained on
the basis of elemental analyses and spectral data.
Correspondence
Naglaa F. H. Mahmoud, Chemistry
Department, Faculty of Science Ain
Shams University, Abbassia, Cairo 11566,
Egypt.
Email: naglaa.fawzy@yahoo.com
K E Y W O R D S
anticancer, azepan, molecular docking, o-aminonitrile pyridine, pyrazolo pyrimidine
1 | INTRODUCTION
2 | RESULTS AND DISCUSSION
Pyridine moieties are familiar substructures in numerous
The starting compound 2-amino-4-phenyl-6-(phenylamino)
pyridine-3, 5-dicarbonitrile 1 was prepared by the reaction
of benzaldehyde, malononitrile, and aniline without cata-
lyst and solvent free [22]. A novel series of heterocyclic com-
pounds containing pyridine moieties has been disclosed by
allowing 2-amino-4-phenyl-6-(phenylamino)pyridine-3, 5-
dicarbonitrile 1 to undergo annulation reactions with dif-
ferent reagents.
Initially, 2-amino-3-cyano pyridine derivative 1 under-
went thermal cycloaddition with formamide to afford
4-imino-5-phenyl-7-(phenylamino)-3, 4-di-hydropyrido[2,3-d]
pyrimidine-6-carbonitrile 2. The structural elucidation of
2 was inferred from its IR and elemental microanalysis. In
particular, its IR showed characteristic stretching bands at
3310, 3186, and 2208 cm−1 due to the presence of NH2, NH,
and CN, respectively. The mass spectrum exhibited the
molecular ion peak at m/z 338 (M + ˙, 12%) (Scheme 1).
Moreover, the cyclocondensation of 2-amino-
3-cyano pyridine derivative 1 with formic acid yielded
[1–3]
natural pharmaceuticals and functional materials
.
Polysubstituted pyridines possess important biological
and pharmacological behavior and could be used as
possible agrochemicals, for example as herbicides [4]. In
addition, the molecules containing pyridine moiety are
used as nonlinear optical materials [5], electrical mate-
rials [6], and chelating agents in metal ligand chemistry
[7]. Among them, 2-amino-3-cyanopyridines are known
as IKK-β inhibitors [8]. They have been identified to
[9]
possess biological behavior such as antimicrobial
,
antiviral [10], antibacterial [11], antifungal [12], antitumor
[13–18], anti-inflammatory [19], as well as antihyperten-
sive properties [20]. Besides, they are important and use-
ful intermediates in preparing a variety of heterocyclic
compounds [12,21]. In extension of our previous work
[22–27], 2-amino-4-phenyl-6-(phenylamino) pyridine-3,-
5-dicarbonitrile will be utilized as a substrate for the
synthesis of different heterocyclic derivatives, and their
pharmaceutical behavior as anticancer agent will be
studied.
4-oxo-5-phenyl-7-(phenylamino)-3,
4-di-hydropyrido
[2,3-d]pyrimidine-6-carbonitrile 3 which showed a new
J Heterocycl Chem. 2019;1–14.
wileyonlinelibrary.com/journal/jhet
© 2019 John Wiley & Sons, Ltd.
1

2
MAHMOUD AND EL-SEWEDY
SCHEME 1
Cyclocondensation of 1 with
formamide, formic acid, and triethyl
orthoformate
FIGURE 1 Graphical correlation between
tested compounds and their IC50 against Hep G-
2 and MCF-7
absorption band in the IR spectrum at 1676 cm−1 of
(C O) (Scheme 1).
1670 cm−1 (C O). Mass spectrum showed the molecular
in peak at m/z 385 (M+˙, 1%). The IR spectrum of com-
pound 5 showed absorption bands at 3424 cm−1 (OH),
3286, 3233 cm−1 (NH2), 3146 cm−1 (NH), and 1722 cm−1
(C O) and disappearance of any band related to cyano
group (Scheme 1).
Formation of pyrido pyrimidine thione and dithione
derivatives by reaction of 2-amino-3-cyano pyridine
derivative 1 with phenyl isothiocyanate and/or carbon
disulphide was carried out to afford pyrido pyrimidine
On the other hand, reaction of 2-amino-3-cyano pyri-
dine derivative 1 with triethyl orthoformate afforded
ethyl-N-(3-carbamoyl-5-cyano-4-phenyl-6-(phenylamino)
pyridin-2-yl) formimidate 4 which in turn underwent
refluxing with hydrazine hydrate in alcoholic solution to
afford pyridopyrimidine carboxylic acid derivative 5. The
IR spectrum of compound 4 showed broad absorption
bands at 3456 cm−1 (NH2, NH), 2225 cm−1 (CN), and

MAHMOUD AND EL-SEWEDY
3
thione derivative 6 and pyrido pyrimidine dithione deriv-
ative 7, respectively. H-NMR showed disappearance of
NH2 groups. Meanwhile, the IR spectrum showed new
absorption bands related to (NH) groups at 3207 and
3218 cm−1, respectively.
a cyclized intermediate. Ultimate hydrolysis and elimination
of ammonia afforded the anticipated pyrido oxazine deriva-
tive 10. The IR spectrum of compound 10 showed absorp-
tions bands at 3341 cm−1 (NH), 2225 cm−1 (CN), 1744 cm−1
1
1
(C O), while its H-NMR showed a D2O-exchangeable sig-
The treatment of dithioxo-pyrido pyrimidine deriva-
tive 7 with oxalyl chloride in dry benzene gave pyrido
thiazolo pyrimidine oxoacetyl chloride derivative 8. The
IR spectrum of compound 8 showed new absorption
bands related to (4 C O) at 1773, 1750, 1727, and
nal at 10.21 ppm due to NH proton (Scheme 3).
Ammonolysis of pyridoxazine-6-carbonitrile 10 by
boiling with formamide gave 4-oxo-2,5-diphenyl-
7-(phenylamino)-3,4-di-hydropyrido [2,3-d] pyrimidine-
6-carbonitrile 11. The reaction took place via nucleophilic
attack of amino group on carbonyl carbon atom followed
by amino intramolecular nucleophilic cyclization.
Finally, a dehydration followed by the release of formic
acid molecule was able to afford 11. The structure of 11
was confirmed by the IR spectrum which exhibited
strong absorption bands at 3305 cm−1 (2NH), 2220 cm−1
(CN), and 1667 cm−1 (C O), respectively. Mass spectrum
showed m/z 415 (M+˙, 29%) (Scheme 3).
1
1690 cm−1 while H-NMR showed the disappearance of
NH2 and NH signals.
The acid hydrolysis of dithioxo-pyrido pyrimidine
derivative 7 with acetic acid gave the di- thioxo pyrido
pyrimidine carboxylic acid derivative 9 where its IR spec-
trum showed peaks corresponding to (OH) group at
3444 cm−1 and a peak at 1716 cm−1 corresponding to
(C O). Furthermore, mass spectrum showed the molecu-
lar ion peak at m/z 406 (M+˙, 3%) (Scheme 2).
The strategy for construction for oxazinone scaffold was
emanated from allowing 1 to undergo benzoylation upon
treatment with benzoyl chloride to afford 4-oxo-2,5-diphenyl-
7-(phenylamino)-4H-pyrido [2,3-d] [1,3] oxazine-6-carbonitrile
10. The reaction took place via nucleophilic attack of the
amino group on the electron deficient carbonyl group
followed by releasing of a hydrogen chloride mole to produce
Hydrazinolysis of pyridoxazine-6-carbonitrile 10 was
achieved when it refluxed with hydrazine hydrate in
butanol
to
afford,
3-amino-4-oxo-2,5-diphenyl-
7-(phenylamino)-3,4-dihydro pyrido [2,3-d]pyrimidine-
6-carbonitrile 12. The IR spectrum of compound 12
showed broad absorption bands at 3415, 3178 cm−1 (NH2,
NH), 2228 cm−1 (CN), and 1673 cm−1 (C O). Mass spec-
trum showed m/z 429 (M+˙ −1, 7%) (Scheme 3).
SCHEME 2 Formation of
pyridopyrimidine thione and
dithione derivatives

4
MAHMOUD AND EL-SEWEDY
SCHEME 3 Reactions of
derivative 10 with formamide,
hydrazine hydrate, and o-phenylene
diamine
The electrophilicity of the lactonic carbonyl group of
compound 10 was studied by nucleophilic reaction with
broad singlet bands of NH proton at δ 9.13 ppm and NH2
protons at δ 4.47 ppm. All IR spectra of compounds 15, 16,
and 17 showed new absorption bands for the carbonyl
group at 1719, 1690, and 1730 cm1, respectively (Scheme 4).
Treatment of 2-amino-3-cyano pyridine derivative
1 with chloro acetylchloride in dry benzene yielded
2-chloro-N-(4-phenyl-6-(phenylamino) pyridin-2-yl) acet-
amide 18. IR of compound 18 showed strong absorption
bands at 3267, 3206 cm−1 (NH), and 1673 cm−1 (C O)
and disappearance of any cyano group. The 1H-NMR
spectrum showed exchangeable broad singlet bands of
2NH protons at δ 10.29 and 9.10 ppm and a peak at
4.27 ppm for the methylene protons (Scheme 5).
o-phenylene diamine to yield 1,6-diphenyl-3-(phenylamino)
[4,5]
benzo
imidazo [1,2-c] pyrido [3,2-e] pyrimidine-
2-carboxamide 13, which was formed via ring opening of
the oxazine ring by an amino group followed by ring clo-
sure and then dehydration with the other amino group and
hydrolysis of cyano group to carboxamide. The IR spectrum
of compound 13 showed the appearance of strong absorp-
tion bands at 3430, 3313 cm−1 (NH2), 3172 cm−1(NH), and
1685 cm−1 (C O) and disappearance of any bands related
1
to cyano groups. H-NMR of compound 13 showed D2O-
exchangeable signals at 9.17 and 3.41 ppm due to NH and
NH2 protons. Mass spectrum showed m/z 508 (M+˙ +2, 6%)
(Scheme 3).
A new fused pyridotriazine 19 was obtained by the
treatment of 2-amino-3-cyano pyridine derivative 1 with
sodium nitrite in the presence of hydrochloric acid. One
of the cyano groups was involved in the formation of tri-
azine ring, while the other cyano group underwent acid-
catalyzed hydrolysis functionalized into a carboxylic
group followed by decarboxylation. Compound 19 was
confirmed by the IR spectrum which showed the disap-
pearance of cyano group and the absorption band at
Reactions of 2-amino-3-cyano pyridine derivative
1 with active methylenes such as malononitrile, ethyl
acetoacetate, ethyl cyanoacetate, and ethyl chloroacetate
afforded 2,4-diamino-5-phenyl-7-(phenylamino)-1,8-naph-
thyridine-3,6-dicarbonitrile 14, ethyl-4-amino-6-cyano-
2-methyl-5-phenyl-7-(phenylamino)-1,8-naphthyridine-3
-carboxylate 15, 4-imino-2-oxo-5-phenyl-7-(phenylamino)-
1,2,3,4-tetrahydro-1,8-naphthyridine-3, 6-dicarbonitrile 16,
and ethyl-3-amino-5-cyano-4-phenyl-6-(phenylamino)-1H-
pyrrolo[2,3-b]pyridine-2-carboxylate 17, respectively. The
1H-NMR spectrum of compound 14 showed exchangeable
1
3265 cm−1 of NH. The H-NMR spectrum showed a sig-
nal at 9.68 ppm for NH proton (Scheme 5).
2-Amino-3-cyano pyridine derivative 1 was allowed to
react with p-toluene sulphonylchloride in pyridine/acetic

MAHMOUD AND EL-SEWEDY
5
SCHEME 4 Reactions of 2-amino-3-cyano pyridine derivative 1 with different active methylenes
and 9.87 corresponding to 2NH groups besides a signal at
2.26 ppm corresponding to methyl protons. The mass spec-
trum of 20 exhibited the molecular ion peak at m/z
465 (M+˙, 6%) (Scheme 5).
Furthermore, reaction of 2-amino-3-cyano pyridine
derivative 1 with p-nitro benzaldehyde, 1,6-dibromohexane
afforded 2-([4-nitrobenzylidene]amino)-4-phenyl-6-(pheny-
lamino)pyridine-3,5-dicarbonitrile 21 and 2-(azepan-1-yl)-
4-phenyl-6-(phenylamino)pyridine-3,5-dicarbonitrile 22,
respectively. The IR spectra of compounds 21 and 22
showed absorption bands at 3370 and 3294 cm−1
corresponding to NH groups in addition to two peaks at
2211 and 2216 cm−1 corresponding to two cyano groups.
The mass spectra of compounds 21 and 22 exhibited the
molecular ion peaks at m/z 444 (M+˙, 3%) and
392 (M+˙−1, 29%), respectively (Scheme 6).
Reaction of 2-amino-3-cyano pyridine derivative 1 with
acetic anhydride and benzoin yielded N-(3,5-dicyano-
4-phenyl-6-(phenylamino) pyridin-2-yl) acetamide 23 and
2-([2-oxo-1,2-diphenylethyl]amino)-4-phenyl-6-(pheny-
lamino) pyridine-3,5-dicarbonitrile 24, respectively.
The IR spectra of compounds 23 and 24 showed absorption
bands at 1663 and 1677 cm−1, respectively, corresponding
to the amide carbonyl groups. The 1H-NMR-spectra of
compounds 23 and 24 lacked any characteristic bands for
the amino groups (Scheme 6).
SCHEME 5 Reaction of 1 with chloro acetylchloride, sodium
nitrite, and p-toluene sulphonylchloride
Finally, nucleophilic addition on 2-amino-3-cyano
pyridine derivative 1 utilizing sodium azide and o-
anhydride mixture to afford the corresponding N-
(3, 5-dicyano-4-phenyl-6-(phenylamino) pyridin-2-yl)-
4-methyl benzenesulfonamide derivative 20. The structural
feature of compound 20 was proved by the H-NMR spec-
trum where it showed exchangeable broad signals at 10.92
phenylene
2-(phenylamino)-5-(1H-tetrazol-5-yl)nicotinonitrile
and 6-amino-5-(1H-benzo[d]imidazol-2-yl)-4-phenyl-
2-(phenylamino)nicotinonitrile 26, respectively. The mass
spectra of 25 and 26 exhibited the molecular ion peaks at
diamine
afforded
6-amino-4-phenyl-
25
1

6
MAHMOUD AND EL-SEWEDY
SCHEME 6 Reactions of 1 with p-nitro benzaldehyde, dibromohexane, acetic anhydride, and benzoin
TABLE 1 Antiproliferative activities of prepared derivatives
against human tumor cells
In Vitro Cytotoxicity IC50 (μM)
Compounds
HePG-2
MCF-7
DOX
2
4.50 0.3
43.81 2.6
58.43 3.5
48.10 3.1
7.94 0.7
9.58 0.9
13.89 1.1
52.71 3.5
64.38 3.7
77.54 4.2
32.65 2.4
29.42 2.2
6.73 0.5
18.02 1.4
23.93 1.8
71.66 3.9
4.17 0.2
28.58 2.1
49.11 3.3
55.60 3.6
8.49 0.9
11.23 1.1
9.72 1.0
34.15 2.4
57.42 3.6
81.83 4.5
44.26 2.9
39.87 2.7
5.36 0.6
17.10 1.4
20.04 1.7
68.85 3.7
3
4
5
6
7
8
9
SCHEME 7 Nucleophilic addition of sodium azide and o-
phenylene diamine on 1
10
17
18
19
20
21
23
peak m/z 354 (M+˙, 25%) and 402 (M.+, 20%), respectively
(Scheme 7).
2.1 | Anticancer studies
Note: IC50 (μM): 1-10 (very-strong), 11-20 (strong), and 21-50
(moderate).
51-100 (weak) and above-100 (non-cytotoxic). DOX, doxorubicin
Most of the synthesized derivatives were tested for their
anticancer action against two human anticancer cell lines
hepatocellular carcinoma HePG-2 and mammary gland
MCF-7 cell lines. Doxorubicin was used as a standard
anticancer drug for comparison, where IC50 (μM): 1 to
10 (very strong). 11 to 20 (strong). 21 to 50 (moderate).
51 to 100 (weak) and above 100 (noncytotoxic) (Table 1).
The results showed in Table 1 that derivatives 5, 6,
and 19 have very strong cytotoxicity, while derivatives
compounds 2, 4, 17, 18, and 21 exerted moderate cytotox-
icities. Furthermore, derivatives 3, 8, 9, 10, and 23
showed weak cytotoxicities against HePG-2.
The derivatives 5, 7, and 19 have very strong cytotox-
icities, while derivatives 6 and 20 possess strong cytotox-
icities; however, derivatives 2, 3, 8, 17, 18, and 21 exerted
7
and 20 possess strong cytotoxicities; however,

MAHMOUD AND EL-SEWEDY
7
moderate cytotoxicities. Furthermore, derivatives 4, 9, 10,
and 23 showed weak cytotoxicities against MCF-7.
Graphical correlation between tested compounds and
their IC50 against Hep G-2 and MCF-7 is depicted in
(Figure 1).
hydrogen donor interaction with Glu (91) and Asn (135)
and one Pi-H interaction with Gly (16) amino acids of the
target enzyme (Figures 2 and 3), and compound 19 equals
−6.44 E (kcal/mol), showed good affinity with the enzyme
by forming one hydrogen acceptor interaction with Cys
(87) and one Pi-H interaction with Leu (15) amino acids of
the target enzyme (Figures 4 and 5).
2.2 | Molecular docking studies
Molecular docking study of o-amino nitrile pyridine deriva-
tives was performed by Molecular Operating Environment
(MOE) 2014.09 [28–30]. serine/threonine-protein kinasechk1
(2YEX) was downloaded from protein data bank (http://
www. rcsb. org/pdb) and prepared for docking process. The
cocrystalline ligands were re-docked in the active pockets to
validate the docking protocol. The structures of the target
compounds were drawn in Chem Draw Ultra 14.0
(ChemOffice package), and the energy was minimized
using the MMFF94x force field until a root mean-square
deviation (RMSD) of atomic position gradient of (0.01) Kcal
mol-1A-1. MMFF94x was reported as the efficient force
field for minimizing ligand-protein complexes. The docking
algorithm was done by MOE-DOCK default which uses a
flexible, rigid technique for posing the molecule inside the
cavity. All rotatable bonds of ligands are allowed to undergo
free rotation to explore the conformational space inside the
rigid receptor binding site.
3 | EXPERIMENTAL
All melting points were measured on a Gallenkamp electric
melting point apparatus uncorrected. The infrared spectra
were recorded in potassium bromide disks on a Pye-Unicam
SP-3-300 and Shimdazu FT IR 8101 PC infrared spectropho-
1
tometers. The H-NMR spectrum was recorded at a Varian
Mercury VX-300 MHz and 13C-NMR (75 MHz), using TMS as
internal standard in deuterated chloroform (CDCl3) or deuter-
ated dimethylsulphoxide (DMSO-d6). Chemical shifts are
measured in ppm. The mass spectra were recorded on a
Shimadzu GCMS-QP-1000EX mass spectrometer at 70 eV.
Elemental analysis was carried out at the Micro analytical cen-
ter of Ain Shams University. All the reactions and the purity
of the new compounds were followed and checked by TLC.
3.1 | 2-Amino-4-phenyl-6-(phenylamino)
The MOE 2014.09 package software was used to ana-
lyze all binding energies and docking poses between com-
pounds 5 and 19 and the enzyme serine/threonine-protein
kinasechk1(2Yex) to evaluate the affinity of compounds
according to its binding energy with the enzyme. The total
binding energy of compound 5 equals −6.11 E (kcal/mol)
showed good affinity with the enzyme by forming two
pyridine-3,5-dicarbonitrile (1)
Fusion of benzaldehyde (0.01 mol, 1.06 mL), malononitrile
(0.02 mol, 1.32 mL), and aniline (0.01 mol, 0.93 mL) in sand
bath for 3 hours at 160ꢀC to 200ꢀC. After cooling, the product
was recrystallized from ethanol to give 1. Yield (90%); yellow
powder; mp. 250ꢀC to 252ꢀC. Anal. calcd,: C19H13N5
FIGURE 2 Two-dimensional
representations for the interactions between
compound 5 and enzyme pocket amino acids

8
MAHMOUD AND EL-SEWEDY
FIGURE 3 Three-dimensional
representations for the interactions between
compound 5 and enzyme pocket amino acids
FIGURE 4 Two-dimensional
representations for the interactions between
compound 19 and enzyme pocket amino acids
FIGURE 5 Three-dimensional
representations for the interactions between
compound 19 and enzyme pocket amino acids
(311.1): C, 73.30; H, 4.21; N, 22.49. Found: C, 73.35; H, 4.14; N,
22.51. FT-IR (KBr) (cm−1): 3314, 3225 (NH2), 3055 (NH), 2208
(CN), 1630 (C N). 13C-NMR (DMSO-d6), δ ppm, 165.3, 161.2,
155.6, 138.0, 136.3, 129.7 (2), 129.4 (3), 127.3 (2), 117.8 (2),
122.5, 113.4 (2), 87.7 (2). 1H-NMR (DMSO-d6): δH (ppm): 9.10
(br.s., 1H, NH, D2O exchangeable), 7.64 (br.s., 2H, NH2, D2O
exchangeable), 7.63 to 7.05 (m, 10H, ArH). MS, m/z (%):
310 (M+˙−1, 100%), 207 (20%), 77(10%).
3.2 | 4-Imino-5-phenyl-7-(phenylamino)-
3,4-dihydropyrido[2,3-d]pyrimidine-
6-carbonitrile (2)
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g)
and formamide (20 mL) was heated under refluxed for
3 hours. The solid that deposited after distilling the
excess solvent was collected, washed, dried, and

MAHMOUD AND EL-SEWEDY
9
recrystallized from petroleum ether 80ꢀC to 100ꢀC to
give 2. Yield (45%), mp > 300ꢀC. Anal. calcd. for
C20H14N6 (338): C, 70.99; H, 4.17; N, 24.84. Found: C,
71.24; H, 4.56; N, 24.20. FT-IR (KBr) (cm−1): 3310, 3186
(NH2, NH), 2208 (CN), 1631 (C N), 1602 (C C). 13C-
NMR (DMSO-d6), δ ppm, 157.3, 157.0, 152.6, 152.2,
151.0, 136.3, 133.0, 129.7 (2), 129.4 (3), 127.3 (2), 117.8
3.5 | (3-Amino-4-imino-5-phenyl-
7-(phenylamino)-3,4-dihydropyrido[2,3-d]
pyrimidin-6-yl)(l1-oxidanyl)methanone (5)
To a solution of 4 (0.01 mol, 3.85 g) in (20 mL) ethanol,
hydrazine hydrate (0.02 mol, 1 mL) was added, and the
reaction mixture was heated under reflux for
30 minutes. A solid product was formed, filtered, and
recrystallized from ethanol to give 5. Yield (20%), mp
100ꢀC to 102ꢀC. Anal. calcd. for C20H15N6O2 (371): C,
64.68; H, 4.07; N, 22.63. Found: C, 65.08; H, 4.46; N,
22.24. FT-IR (KBr) (cm−1): broad band centered at 3424
(OH), 3286, 3233, and 3146 (NH2, NH), 1722 (C O),
1
(2), 122.5, 113.4, 105.2, 87.7. H-NMR (DMSO-d6): δH
(ppm): 10.10 (br.s., 1H, NH, D2O exchangeable), 8.41(s,
1H, N CH-N), 7.01 (br.s., 2H, NH2, D2O exchangeable),
7.75 to 7.02 (m, 10H, ArH). MS, m/z (%): 338 (M+˙,
12%), 268.85(15%), 233.2 (61.7%), 231.54 (22%),
44.16 (100%).
1
and 1609 (C C). H-NMR (DMSO-d6): δH (ppm): 12.56
(br.s., 1H, OH, D2O exchangeable), 10.57 (br.s., 1H,
NH, D2O exchangeable), 10.10 (br.s., 1H, NH, D2O
exchangeable), 8.41(s, 1H, N CH-N), 5.41 (br.s., 2H,
NH2, D2O exchangeable), 7.75 to 7.02 (m, 10H, ArH).
MS, m/z (%): 355 (M+˙ -NH2, 12%), 310 (100%),
272 (40%), 244 (11%), and 216 (22%).
3.3 | 4-Oxo-5-phenyl-7-(phenylamino)-
3,4-dihydropyrido[2,3-d]pyrimidine-
6-carbonitrile (3)
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
formic acid (20 mL) was heated under reflux for 6 hours.
The precipitate was filtered off after cooling, and formic
acid was evaporated, washed, dried, and then rec-
rystallized from benzene to give 3. Yield (20%), mp
120ꢀC to 122ꢀC. Anal. calcd. for C20H13N5O (339): C,
70.79; H, 3.86; N, 20.64. Found: C, 70.37; H, 3.28; N,
20.99. FT-IR (KBr) (cm−1): 3322, 3205 (2NH), 2215
3.6 | 4-Imino-3,5-diphenyl-
7-(phenylamino)-2-thioxo-
1,2,3,4-tetrahydropyrido [2,3-d]pyrimidine-
6-carbonitrile (6)
1
(CN), 1676 (C O), 1635 (C N), 1606 (C C). H-NMR
An equimolar mixture of pyridine derivative 1 (0.01 mol,
3.11 g) and phenyl isothiocyanate (0.01 mol, 1.19 mL) in
pyridine (30 mL) was heated under reflux for 5 hours.
The resulting precipitate was formed after distilling the
excess pyridine, dried, and recrystallized from benzene to
give 6. Yield (35%), mp 108ꢀC to 110ꢀC. Anal. calcd. for
C26H18N6S (446): C, 69.94; H, 4.06; N, 18.82. Found: C,
69.56; H, 4.55; N, 18.43. FT-IR (KBr) (cm−1): 3321, 3207
(NH), 2210 (CN), 1624 (C N), and 1597 (C C). 1H-NMR
(DMSO-d6): δH (ppm) 12.18 (br.s., 1H, NH, D2O
exchangeable), 10.57 (br.s., 1H, NH, D2O exchangeable),
9.77 (br.s., 1H, NH, D2O exchangeable), and 7.55 to 7.08
(m, 15H, Ar-H). MS, m/z (%): 369 (M+˙−ph, 7%), 264
(100%), 236(100%), 208(37%), and 235(27%).
(DMSO-d6): δH (ppm) 12.18 (br.s., 1H, NH, D2O
exchangeable), 9.44 (br.s., 1H, NH, D2O exchangeable),
8.94 (s, 1H, CH), 8.27 to 7.12 (m, 10H, Ar-H).
3.4 | Ethyl-N-(3-carbamoyl-5-cyano-
4-phenyl-6-(phenylamino)pyridin-2-yl)
formimidate (4)
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) in
(10 mL) triethyl orthoformate was heated under reflux
for 2 hours. The solid that deposited after concentra-
tion of the reaction mixture was collected and rec-
rystallized from benzene to give 4. Yield (30%), mp
60ꢀC to 62ꢀC. Anal. calcd. for C22H19N5O2 (385): C,
68.56; H, 4.97; N, 18.17. Found: C, 68.17; H, 4.49; N,
18.66. FT-IR (KBr) (cm−1): broad band centered at 3456
(NH2, NH), 2225 (CN), 1670 (C O), and 1600 (C C).
1H-NMR (DMSO-d6): δH (ppm) 10.14 (br.s., 1H, NH,
D2O exchangeable), 8.77 (s, 1H, N CH), 8.24 to 7.03
(m, 10H, Ar-H), 7.17 (br.s., 2H, NH2, D2O exchange-
able), 3.42 (q, 2H, CH2CH3), 1.27 (t, 3H, CH2CH3). MS,
m/z (%): 385 (M+˙, 1%), 310 (12%), 295 (100%),
238 (15%), and 165 (4%).
3.7 | 5-Phenyl-7-(phenylamino)-
2,4-dithioxo-1,2,3,4-tetrahydropyrido[2,3-d]
pyrimidine-6-carbo nitrile (7)
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g)
and excess of carbon disulphide was added dropwise,
and alcoholic sodium hydroxide (20 mL) was heated in
water bath for 6 hours. The solid that deposited after
distilling the excess solvent was collected and

10
MAHMOUD AND EL-SEWEDY
recrystallized from benzene to give 7. Yield (60%), mp
160ꢀC to 162ꢀC. Anal. calcd. for C20H13N5S2 (387): C,
62.00; H, 3.38; N, 18.07. Found: C, 62.42; H, 3.01; N,
18.58. FT-IR (KBr) (cm−1): 3321, 3218, 3120 (NH), 2225
406 (M+˙, 3%), 369 (100%), 271 (19%), 207 (13%), and
127 (88%).
1
(CN), 1623 (C N), 1585 (C C). H-NMR (DMSO-d6):
3.10 | 4-Oxo-2,5-diphenyl-
δH (ppm) 13.31 (br.s.,1H, NH, D2O exchangeable), 10.24
(br.s.,1H, NH, D2O exchangeable), 9.75 (br.s., 1H, NH,
D2O exchangeable), 7.55 to 7.08 (m, 10H, Ar-H). MS,
m/z (%): 355 (M+˙ -S, 16%), 264(60%), 236(100%), 207
(33%), and 180(21%).
7-(phenylamino)-4H-pyrido [2,3-d] [1,3]
oxazine-6-carbonitrile (10)
A solution of pyridine derivative 1 (0.01 mol, 3.11 g)
in (20 mL) benzoyl chloride was stirred and heated
under reflux for 3 hours. The solid product that sepa-
rated out after cooling, washed, dried, and rec-
rystallized from petroleum 80ꢀC to 100ꢀC to give 10.
Yield (40%), mp 138ꢀC to 140ꢀC. Anal. calcd. for
C26H16N4O2 (416): C, 74.99; H, 3.90; N, 13.45.
Found: C, 74.42; H, 4.23; N, 13.04. FT-IR (KBr)
(cm−1): 3341 (NH), 2225(CN), 1744 (C O), and 1655
(C N). 1H-NMR (DMSO-d6): δH (ppm) 10.21 (br.s.,
1H, NH, D2O exchangeable), 7.94 to 7.06 (m, 15H, Ar-
H). MS, m/z (%): 264 (M+˙ −2 ph, 68%), 236 (100%),
208 (21%), 180 (15%), and 165 (12%).
3.8 | 2-((3-Cyano-8,9-dioxo-4-phenyl-
5-thioxo-8,9-dihydro-5H-pyrido[3,2-e]
thiazolo[3,2-a]pyrimi din-2-yl)(phenyl)
amino)-2-oxoacetyl chloride (8)
An equimolar mixture of 7 (0.01 mol, 3.87 g) and oxalyl
chloride (0.01 mol, 1.26 mL) in (30 mL) dry benzene
was heated under reflux for 6 hours. Most of the solvent
was distilled off and left to cool. The solid product that
deposited was collected, washed, dried, and rec-
rystallized from petroleum ether 100ꢀC to 120ꢀC to give
8. Yield (40%), mp 120ꢀC to 122ꢀC. Anal. calcd. for
C24H10N5O4S2Cl (531.5): C, 54.19; H, 1.89; N, 13.17.FT-
IR (KBr) (cm−1): 2226 (CN), 1773, 1750, 1727, 1690
(4 C O), 1647 (C N), and 1591 (C C). 13C-NMR
3.11 | 4-Oxo-2,5-diphenyl-
7-(phenylamino)-3,4-dihydropyrido[2,3-d]
pyrimidine-6-carbonitrile (11)
(DMSO-d6),
δ
ppm, 221.3, 178.2, 172.6, 166.2,
A solution of 10 (0.01 mol, 4.16 g) in formamide (15 mL)
was heated under reflux for 4 hours. Most of the solvent
was distilled off and left to cool. The solid product that
deposited was collected, washed, dried, and recrystallized
from ethanol to give 11. Yield (35%), mp 172ꢀC to 174ꢀC.
Anal. calcd. for C26H17N5O (415): C, 75.17; H, 4.12; N,
16.86. Found: C, 75.59; H, 4.53; N, 16.35. FT-IR (KBr)
(cm−1): 3305 (2NH), 2220 (CN), 1667 (C O). MS, m/z
(%): 415 (M+˙, 29%), 338 (74%), 316 (24%), 281 (23%), and
207 (22%).
162.4158.7, 158.1, 157.8, 153.1, 138.6, 136.3, 129.7(2),
129.4(3), 128.9(2), 127.3 (2), 113.4, 110.7, and 87.7. H-
NMR (DMSO-d6): δH (ppm) 7.57 to 7.40 (m, 10H, Ar-H).
MS, m/z (%): 282 (67%), 194 (42%), 136 (100%),
119 (27%), and 77 (50%).
1
3.9 | 5-Phenyl-7-(phenylamino)-
2,4-dithioxo-1,2,3,4-tetrahydropyrido[2,3-d]
pyrimidine-6-carboxylic acid (9)
A solution of 7 (0.01 mol, 3.87 g) in acetic acid (20 mL)
was heated under reflux for 3 hours. The precipitated
solid product formed after cooling was collected by fil-
tration, washed, dried, and recrystallized from acetic
acid to give 9. Yield (70%), mp 133ꢀC to 135ꢀC. Anal.
calcd. for C20H14N4O2S2 (406): C, 59.10; H, 3.47; N,
13.78. Found: C, 59.49; H, 3.05; N, 13.39. FT-IR (KBr)
(cm−1): 3449 (OH), 3216, 3172, 3126 (3NH), 1716
(C O), 1649 (C N). 1H-NMR (DMSO-d6): δH (ppm)
14.34 (br.s.,1H, NH, D2O exchangeable), 13.31 (br.s.,1H,
NH, D2O exchangeable), 12.74 (br.s.,1H, OH, D2O
exchangeable), 10.51 (br.s., 1H, NH, D2O exchange-
able), 7.75 to 7.08 (m, 10H, Ar-H). MS, m/z (%):
3.12 | 3-Amino-4-oxo-2,5-diphenyl-
7-(phenylamino)-3,4-dihydropyrido [2,3-d]
pyrimidine-6-carbonitrile (12)
A solution of 10 (0.01 mol, 4.16 g) in butanol (20 mL)
was heated under reflux with hydrazine hydrate
(0.02 mol, 1 mL) for 6 hours. The reaction mixture was
allowed to cool, and the precipitated product was filtered,
dried, and recrystallized from ethanol to give 12. Yield
(20%), mp 80ꢀC to 82ꢀC. Anal. calcd. for C26H18N6O
(430): C, 72.55; H, 4.21; N, 19.52. Found: C, 71.93; H,
4.60; N, 19.75. FT-IR (KBr) (cm−1): broad band centered
at 3415 (NH2), 3178 (NH), 2228 (CN), 1673(C O). MS,

MAHMOUD AND EL-SEWEDY
11
m/z (%): 429 (M+˙ −1, 7%), 338 (100%), 324 (18%),
316 (40%), and 299 (12%).
to cool, and then poured onto ice/water. The formed pre-
cipitate was filtered, dried, and recrystallized from petro-
leum ether 60ꢀC to 80ꢀC to give 15. A solid formed was
washed by ethanol. Yield (30%), mp > 300ꢀC. Anal. calcd.
for C25H21N5O2 (423): C, 70.91; H, 5.00; N, 16.54.
Found: C, 70.44; H, 4.52; N, 16.09. FT-IR (KBr) (cm−1):
band centered at 3417 (NH2, NH), 2212 (CN), 1719
3.13 | 1,6-Diphenyl-3-(phenylamino)
benzo[4,5]imidazo[1,2-c]pyrido[3,2-e]
pyrimidine-2-carboxamide (13)
1
(C O), 1632 (C N), 1591 (C C). H-NMR (DMSO-d6):
A mixture of compound 10 (0.01 mol, 4.16 g) and o-
phenylenediamine (0.01 mol, 1.08 g) was fused at 120ꢀC
for 20 minutes. A white solid was obtained, then washed
and recrystallized from benzene to give 13. Yield (25%),
mp 98ꢀC to 100ꢀC. Anal. calcd. for C32H22N6O (506): C,
75.87; H, 4.38; N, 16.59. Found: C, 76.42; H, 3.96; N,
16.46.FT-IR (KBr) (cm−1): broad band centered at 3430,
3313 (NH2), 3172 (NH), 1685 (C O), 1653 (C N), and
1621 (C C). 13C-NMR (DMSO-d6), δ ppm, 166.3, 165.2,
164.6, 156.2, 151.4, 149.7, 148.1, 143.8, 141.1, 138.6, 135.3,
131.1, 129.7(2), 129.4(5), 127.9 (2), 127.7 (2), 123.0 (2),
δH (ppm) 9.10 (s, 1H, NH, D2O exchangeable), 7.05 to
7.65 (m, 10, Ar-H, br.s., 2H, NH2, D2O exchangeable),
4.39 to 4.44 (q, 2H, CH2CH3), 2.27 (s, 3H, CH3), 1.31 to
1.34 (t, 3H, CH2CH3). MS, m/z (%): 389 (M+˙-C2H5, 4%),
341 (28%), 264 (71%), 198 (87%), 184 (40%), and
77 (100%).
3.16 | 4-Imino-2-oxo-5-phenyl-
7-(phenylamino)-1,2,3,4-tetrahydro-
1,8-naphthyridine-3,6-dicarbonitrile (16)
1
122.5, 120.2, 118.4, 117.5 (2), 112.4, and 112.0. H-NMR
(DMSO-d6): δH (ppm) 9.17 (br.s., 1H, NH, D2O exchange-
able), 7.94 to 6.33 (m, 19H, Ar-H), 3.41 (br.s., 2H, NH2,
D2O exchangeable). MS, m/z (%): 508 (M+˙ +2, 6%),
295 (14%), 223 (90%), 194 (46%), and 179 (100%).
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
ethyl cyanoacetate (10 mL) was heated under reflux for
6 hours. The reaction mixture was concentrated, allowed
to cool, and then poured onto ice/water. The formed pre-
cipitate was filtered, dried, and recrystallized from etha-
nol to give 16. Yield (20%), mp 138ꢀC to 144ꢀC. Anal.
calcd. for C22H14N6O (378): C, 69.83; H, 3.73; N, 22.21.
Found: C, 69.51; H, 4.02; N, 22.53. FT-IR (KBr) (cm−1):
broad band centered at 3347, 3216 (3NH), 2207 (CN),
3.14 | 2,4-Diamino-5-phenyl-
7-(phenylamino)-1,8-naphthyridine-
3,6-dicarbonitrile (14)
1
1690 (C O), and 1632 (C N). H-NMR (DMSO-d6): δH
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
malononitrile (0.01 mol, 0.66 g) in ethanol (20 mL) was
heated under reflux in the presence of few drops of tri-
ethylamine. For 48 hours, the reaction mixture was con-
centrated, allowed to cool, and then poured onto
ice/water. The formed precipitate was filtered, dried, and
recrystallized from petroleum ether 60ꢀC to 80ꢀC to give
14. Yield (20%), mp 206ꢀC to 208ꢀC. Anal. calcd. for
C22H15N7 (377): C, 70.01; H, 4.01; N, 25.98. Found: C,
69.78; H, 4.62; N, 25.60. FT-IR (KBr) (cm−1): band cen-
tered at 3465, 3323 (NH2), 3220 (NH), 2226 (CN), 1623
(ppm) 10.21 (br.s., 1H, NH, D2O exchangeable), 9.10 (br.
s., 1H, NH, D2O exchangeable), 8.81 (br.s., 1H, NH, D2O
exchangeable), 7.70 to 7.03 (m, 10H, Ar-H), 3.72 (s, 1H,
CH). MS, m/z (%): 379 (M+˙ + 1, 4%), 342 (61%),
310 (100%), 281 (20%), and 207 (22%).
3.17 | Ethyl-3-amino-5-cyano-4-phenyl-
6-(phenylamino)-1H-pyrrolo [2,3-b]
pyridine-2-carboxylate (17)
1
(C N), and 1585 (C C). H-NMR (DMSO-d6): δH (ppm)
9.13 (br.s., 1H, NH, D2O exchangeable), 7.08 to 7.95 (m,
10H, Ar-H), 4.47 (br.s., 2H, NH2, D2O exchangeable).
A solution of pyridine derivative 1 (0.01 mol, 3.11 g) in
pyridine (20 mL) was heated under reflux with ethyl
chloroacetate (0.01 mol, 1.22 mL) for 6 hours. The reac-
tion mixture was poured on ice/water. The precipitated
solid was collected, washed, and recrystallized from ben-
zene to give 17. Yield (60%), mp 210ꢀC to 212ꢀC. Anal.
calcd. for C23H19N5O2 (397): C, 69.51; H, 4.82; N, 17.62.
Found: C, 69.99; H, 5.25; N, 18.00. FT-IR (KBr) (cm−1):
band centered at 3463, 3322 (NH2), 3218 (NH), 2226
3.15 | Ethyl-4-amino-6-cyano-2-methyl-5-
phenyl-7-(phenylamino)1,8naphthyridine
−3-carboxylate (15)
1
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
ethyl acetoacetate (10 mL) was heated under reflux for
6 hours. The reaction mixture was concentrated, allowed
(CN), 1730 (C O), 1624 (C N), and 1586 (C C). H-
NMR (DMSO-d6): δH (ppm) 9.10 (br.s, 1H, NH, D2O
exchangeable), 7.93 (br.s, 1H, NH, D2O exchangeable),

12
MAHMOUD AND EL-SEWEDY
7.55 to 7.47 (m, 12H, Ar-H), 7.34 (br.s, 1H, NH2, D2O
exchangeable), 4.45 to 4.39 (q, 2H, CH2CH3), 1.35 to 1.31
(t, 3H, CH2CH3). MS, m/z (%):397 (M+˙, 6%), 369.1 (7%),
264 (100%), 208 (21%), and 77 (11%).
s., 1H, NH, D2O exchangeable), 7.61 to 6.99 (m, 14H, Ar-
H), 2.26 (s, 3H, CH3). MS, m/z (%):465 (M+˙, 6%),
295 (29%), 247 (21%), 91 (70%), and 77 (15%).
3.21 | 2-([4-Nitrobenzylidene]amino)-
4-phenyl-6-(phenylamino)pyridine-
3,5-dicarbonitrile (21)
3.18 | 2-Chloro-N-(4-phenyl-
6-(phenylamino)pyridin-2-yl)
acetamide (18)
To a solution of pyridine derivative 1 (0.01 mol, 3.11 g) in
(10 mL) butanol, p-nitro benzaldehyde (0.01 mol, 1.5 g)
was added, and the reaction mixture was heated under
reflux for 18 hours. The reaction mixture was concen-
trated and left to cool. The solid product that separated out
was filtered off, dried, and recrystallized from benzene:
ethanol to give 21. Yield (30%), mp 180ꢀC to 182ꢀC. Anal.
calcd. for C26H16N6O2 (444): C, 70.26; H, 3.63; N, 18.91.
Found: C, 70.72; H, 3.10; N, 19.32. FT-IR (KBr) (cm−1):
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
chloro acetyl chloride (0.01 mol, 1.36 g) was refluxed for
3 hours with stirring. The solid that deposited and rec-
rystallized from petroleum ether 60ꢀC to 80ꢀC. Yield (40%),
mp 118ꢀC to 120ꢀC. Anal. calcd. for C19H16ClN3O
(337.81): C, 67.56; H, 4.77; N, 12.44. Found: C, 67.09; H,
4.32; N, 12.95.FT-IR (KBr) 3267, 3206 (NH), 1673 (C O).
(cm−1): 1H-NMR (DMSO-d6): δH (ppm) 10.29 (br.s, 1H, NH,
D2O exchangeable), 9.10 (br.s, 1H, NH, D2O exchangeable),
7.61 to 7.09 (m, 12H, Ar-H), and 4.27 (s, 2H, CH2Cl).
1
3370 (NH), 2211(CN), 1605 (C C). H-NMR (DMSO-d6):
δH (ppm) 9.82 (br.s., 1H, NH, D2O exchangeable), 8.17 to
6.44 (m, 15H, 14Ar-H and 1H, N CH). MS, m/z (%):444
(M+˙, 3%), 290 (100%), 233 (%), 207 (%), and 94 (%).
3.19 | 4-Chloro-N, 5-diphenylpyrido[2,
3-d][1,2,3]triazin-7-amine (19)
3.22 | 2-(Azepan-1-yl)-4-phenyl-
6-(phenylamino)pyridine-
3,5-dicarbonitrile (22)
A solution of pyridine derivative 1 (0.01 mol, 3.11 g) in
hydrochloric acid (10 mL) was cooled to 0ꢀC in an ice bath,
and an aqueous solution of sodium nitrite (0.8 g) in 10 mL
water was added simultaneously with stirring. The precipi-
tated solid formed was collected by filtration, washed, and rec-
rystallized from petroleum 60ꢀC to 80ꢀC to give 19. Yield
(70%), mp 100ꢀC to 102ꢀC. Anal. calcd. for C18H12ClN5
(333.5): C, 64.77; H, 3.62; N, 20.98. Found: C, 64.35; H, 3.98; N,
20.54. FT-IR (KBr) (cm−1): broad band centered at 3265 (NH),
To a solution pyridine derivative 1 (0.01 mol, 3.11 g) in
(10 mL) butanol, dibromo hexane (0.01 mol, 2.41 g) was
added, and the reaction mixture was heated under reflux
for 20 hours. The reaction mixture was concentrated and
left to cool. The solid product that separated out was fil-
tered off, dried, and recrystallized from petroleum ether
80ꢀC to 100ꢀC to give 22. Yield (40%), mp 112ꢀC to
114ꢀC. Anal. calcd. for C25H23N5 (393): C, 76.31; H,
5.89; N, 17.80. Found: C, 75.82; H, 6.14; N, 18.04. FT-IR
(KBr) (cm−1): broad band centered at 3294 (NH), 2216
(CN). 13C-NMR (DMSO-d6), δ ppm, 167.3, 161.2, 155.6,
138.0, 136.3, 129.7 (2), 129.4 (3), 127.3 (2), 117.8 (2),
122.5, 113.4 (2), 87.7 (2), 54.5(2), 29.1(2), 26.3(2). 1H-
NMR (DMSO-d6): δH (ppm) 10.21 (br.s., 1H, NH, D2O
exchangeable), 7.70 to 7.03 (m, 10H, Ar-H), 3.45 to 1.51
(m, 12H, hexane- H). MS, m/z (%):392 (M+˙−1, 29%),
299 (64.5%), 207 (14%), 93 (4%), and 77 (26%).
1
1630 (C N). H-NMR (DMSO-d6): δH (ppm) 9.68 (br.s, 1H,
NH, D2O exchangeable), 7.74 to 7.04 (m, 11H, Ar-H).
3.20 | N-(3,5-dicyano-4-phenyl-
6-(phenylamino)pyridin-2-yl)-
4-methylbenzene sulfonamide (20)
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
p-toluene sulphonylchloride (0.01 mol, 1.89 g) in a mix-
ture of pyridine and acetic anhydride (4:20 mL), respec-
tively, was heated under reflux for 6 h. The reaction
mixture was concentrated, filtered off, dried, and rec-
rystallized from benzene to give 20. Yield (20%), mp
190ꢀC to 192ꢀC. Anal. calcd. for C26H19N5O2S (465.53): C,
67.08; H, 4.11; N, 15.04. Found: C, 67.46; H, 4.40; N,
14.65. FT-IR (KBr) (cm−1): broad band centered at 3443
(NH), 2221(CN), 1631(C N). 1H-NMR (DMSO-d6): δH
(ppm) 10.92 (br.s., 1H, NH, D2O exchangeable), 9.87 (br.
3.23 | N-(3,5-dicyano-4-phenyl-
6-(phenylamino)pyridin-2-yl)
acetamide (23)
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
freshly distilled acetic anhydride (10 mL) was heated

MAHMOUD AND EL-SEWEDY
13
under reflux for 3 hours. The solid that deposited after
distilling the excess solvent and poured on ice/water was
collected and recrystallized from benzene to give 23.
Yield (60%), mp 100ꢀC to 102ꢀC. FT-IR (KBr) (cm−1):
broad band centered at 3295, 3260 (NH), 2211(CN), 1663
(C O), 1622 (C N). H-NMR (DMSO-d6): δH (ppm) 9.87
(br.s, 2H, 2NH, D2O exchangeable), 7.55 to 6.97 (m, 10H,
Ar-H), 2.01 (s, 3H, COCH3).
4.51; N, 20.88. Found: C, 74.30; H, 4.66; N, 21.04. FT-IR
(KBr) (cm−1): 3385, 3363 (NH2), 3289, 3193 (2NH), 2207
(CN), 1632 (C N), 1591 (C C). H-NMR (DMSO-d6): δH
(ppm) 11.79 (br.s., 1H, NH, D2O exchangeable), 10.18 (br.
s., 1H, NH, D2O exchangeable), 7.54 to 6.33 (m, 14H, Ar-
H), 4.95 (br.s., 2H, NH2). MS, m/z (%): 402 (M˙+, 20%),
269 (17%), 213 (24%), 157 (96%), and 77 (4%).
1
1
4 | CONCLUSION
3.24 | 2-([2-Oxo-1,2-diphenylethyl]
amino)-4-phenyl-6-(phenylamino)pyridine-
3,5-dicarbonitrile (24)
2-Amino-3-cyano pyridine derivative was utilized as a
scaffold to synthesize different heterocyclic systems. In
addition, the molecular docking study of those 2-amino-
3-cyanopyridine derivatives was performed by the MOE
2014.09. Finally, in vitro growth inhibitory activity of the
newly synthesized compounds was investigated against
two carcinoma cell lines, a mammary gland carcinome
cell line (MCF-7) and a human hepatocellular carcinoma
cell line (HePG-2) using doxorubicin as an anticancer
standard drug under the same condition. Some of the
tested showed remarkable activities as antitumor agents.
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
benzoin (0.01 mol, 2.12 g) in dry benzene (20 mL) was
heated under reflux for 15 hours. The solid that deposited
after concentration of the reaction mixture was collected
and recrystallized from petroleum ether 60ꢀC to 80ꢀC to
give 24. Yield (40%), mp 78ꢀC to 80ꢀC. Anal. calcd. for
C33H22N5O (505): C, 78.40; H, 4.59; N, 13.85. Found: C,
78.82; H, 5.10; N, 13.27. FT-IR (KBr) (cm−1): 3316, 3186
(NH), 2213(CN), 1677(C O), 1659 (C N), 1593(C C).
MS, m/z (%):506 (M+˙ +1, 43%), 505 (M˙+,13%),
310 (100%), 207 (20%), 93 (4%), and 77 (52%).
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ORCID
3.25 | 6-Amino-4-phenyl-
2-(phenylamino)-5-(1H-tetrazol-5-yl)
nicotinonitrile (25)
Naglaa F. H. Mahmoud https://orcid.org/0000-0002-
6655-5741
REFERENCES
A solution of pyridine derivative 1 (0.01 mol, 3.11 g) in DMF
(10 mL), sodium azide (0.01 mol, 0.65 g), and ammonium
chloride (0.01 mol, 0.53 g) was added. The reaction mixture
was heated under reflux for 7 hours and let to cool, and
DMF was evaporated. The precipitated solid formed rec-
rystallized from petroleum 60ꢀC to 80ꢀC to give 25. Yield
(40%), mp 120ꢀC to 122ꢀC. Anal. calcd. for C19H14N8
(354): C, 64.40; H, 3.98; N, 31.62. Found: C, 64.02; H, 4.56; N,
31.42. FT-IR (KBr) (cm−1): 3463 to 3319 (NH2, NH), 2226
(CN), 1624 (C N), 1586 (C C). MS, m/z (%): 354 (M+˙,
25%), 310 (100%), 207 (22%), 93 (4%), and 77 (62%).
[1] G. Jones, in Comprehensive Heterocyclic Chemistry II, Vol. 5
(Eds: A. R. Katritzky, C. W. Rees, E. F. V. Scriven,
A. McKillop), Pergamon, Oxford 1996.
[2] G. D. Henry, Tetrahedron 2004, 60, 6043–61.
[3] J. P. Michael, Nat. Prod. Rep. 2005, 22, 627.
[4] C. Temple, G. A. Rener Jr.., W. R. Waud, P. E. Noker, J. Med.
Chem. 1992, 35, 3686–90.
[5] H. Wang, R. Helgeson, B. Ma, F. Wudl, J. Org. Chem. 2000, 65,
5862–7.
[6] T. Kanbara, T. Kushida, N. Saito, I. Kuwajima, K. Kubota,
T. Yamamoto, Chem. Lett. 1992, 21, 583–6.
[7] T. J. Meyer, Acc. Chem. Res. 1989, 22, 163–70.
[8] T. Murata, M. Shimada, S. Sakakibara, T. Yoshino, H. Kadono,
T. Masuda, M. Shimazaki, T. Shintani, K. Fuchikami,
K. Sakai, H. Inbe, K. Takeshita, T. Niki, M. Umeda,
K. B. Bacon, K. B. Ziegelbauer, T. B. Lowinger, Bioorg. Med.
Chem. Lett. 2003, 13, 913.
3.26 | 6-Amino-5-(1H-benzo[d]imidazol-
2-yl)-4-phenyl(phenylamino)
nicotinonitrile (26)
[9] Mungra, D. C.; Patel, M. P.; Patel, R. G., ARKIVOC 2009,
xiv, 64.
[10] Hammam, A. G.; EI-Hafez, N. A. A.; Midura, W. H.;
Mikolajczyk, M.; Z. Naturforsch., B., J. Chem. Sci. 2000,
55, 417.
[11] S. G. Konda, V. T. Khedkar, B. S. Dawane, J. Chem. Pharm.
Res. 2010, 2, 187.
A mixture of pyridine derivative 1 (0.01 mol, 3.11 g) and
o-phenylenediamine (0.01 mol, 3.11 g) was fused for
20 minutes. The formed solid was crystallized from Petro-
leum ether 60ꢀC to 80ꢀC to give 26. Yield (20%), mp 84ꢀC
to 86ꢀC. Anal. calcd. for C25H18N6 (402): C, 74.61; H,

14
MAHMOUD AND EL-SEWEDY
[12] A. R. Gholap, K. S. Toti, F. Shirazi, R. Kumari, M. K. Bhat,
M. V. Deshpande, K. V. Srinivasan, Bioorg. Med. Chem. 2007,
15, 6705–15.
[22] N. F. H. Mahmoud, A. El-Sewedy, J. Chem 2018, 2018,
7958739.
[23] N. F. H. Mahmoud, E. A. Ghareeb, J. Heterocyclic chem. 2019,
56, 81–91.
[13] F. Zhang, Y. Zhao, L. Sun, L. Ding, Y. Gu, P. Gong, Eur.
J. Med. Chem. 2011, 46, 3149–57.
[24] N. F. H. Mahmoud, E. A. El-Bordany, G. A. Elsayed, J. Chem.
[14] S. M. Gomha, Z. A. Muhammad, M. R. Abdel-aziz,
H. M. Abdel-aziz, H. M. Gaber, M. M. Elaasser, J. Heterocycl.
Chem. 2018, 55, 530–6.
2017, 2017, 5373049.
[25] N. F. H. Mahmoud, M. A. El-Saghier, J. Heterocyclic Chem.
2019, 56, 1820–4.
[15] M. A. Abdallah, S. M. Gomha, M. A. Morad, M. M. Elaasser,
[26] N. F. H. Mahmoud, G. A. Elsayed, M. F. Ismail, J. Heterocyclic
J. Heterocycl. Chem. 2017, 54, 1242–51.
[16] I. Abbas, S. M. Gomha, M. M. Elaasser, M. Bauomi, Turk.
J. Chem. 2015, 39, 334–46.
Chem. 2018, 55, 465–74.
[27] G. A. Elsayed, N. F. H. Mahmoud, S. A. Rizk, Curr. Org. Syn.
2018, 15, 413.
[17] F. M. Abdelrazek, S. M. Gomha, A. H. Abdelrahman, P. Metz,
M. A. Sayed, Lett. Drug Des. Discov. 2017, 14, 752.
[18] S. M. Gomha, F. M. Abdelrazek, A. H. Abdelrahman, P. Metz,
J. Heterocycl. Chem. 2018, 55, 1729–37.
[19] T. Murata, M. Shimada, S. Sakakibara, T. Yoshino, T. Masuda,
T. Shintani, H. Sato, Y. Koriyama, K. Fukushima, N. Nunami,
M. Yamauchi, K. Fuchikami, H. Komura, A. Watanabe,
K. B. Ziegelbauer, K. B. Bacon, T. B. Lowinger, Bioorg. Med.
Chem. Lett. 2004, 14, 4019–22.
[28] M. Sharma, P. M. S. Chauhan, Future Med. Chem. 2012, 4,
1335–65.
[29] A. Daina, V. Zoete, Chem. Med. Chem. 2016, 11, 1117–21.
[30] C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Adv.
Drug Deliv. Rev. 2001, 46, 3 The article was originally publi-
shed in Adv. Drug Deliv. Rev. 23 (1997) 3–25.
How to cite this article: Mahmoud NFH, El-
Sewedy A. Facile synthesis of novel heterocyclic
compounds based on pyridine moiety with
pharmaceutical activities. J Heterocycl Chem. 2019;
1–14. https://doi.org/10.1002/jhet.3881
[20] J. J. Baldwin, E. L. Engelhardt, R. Hirschmann,
G. S. Ponticello, J. G. Atkinson, B. K. Wasson, C. S. Sweet,
A. Scriabine, J. Med. Chem. 1980, 23, 65–70.
[21] B. C. H. May, J. A. Zorn, J. Witkop, J. Sherrill, A. C. Wallace,
G. Legname, S. B. Prusiner, F. E. Cohen, J. Med. Chem. 2007,
50, 65–73.