Efficient synthesis and In Silico study of some novel pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.3901

A novel series of 1,5-dihydropyrido-triazolo-pyrimidine derivatives were prepared by cyclocondensation of 2-thioxo-pyrido[2,3-d]pyrimidines (prepared from reaction of chalcone with 6-aminothiouracil) with a variety of hydrazonoyl chlorides. Based on spect

Full text of DOI:10.1002/jhet.3901

Received: 6 September 2019
DOI: 10.1002/jhet.3901
Revised: 16 December 2019
Accepted: 30 December 2019
A R T I C L E
Efficient synthesis and In Silico study of some novel
pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives
1
,2
1,3
4
Fathy M. Abdelrazek
| Sobhi M. Gomha
| Hassan M. Abdel-aziz
|
1,5
2
1
Mohamed S. Farghaly
| Peter Metz | Ahmed Abdel-Shafy
1
Chemistry Department, Faculty of
Abstract
Science, Cairo University, Giza, Egypt
2
A novel series of 1,5-dihydropyrido-triazolo-pyrimidine derivatives were pre-
pared by cyclocondensation of 2-thioxo-pyrido[2,3-d]pyrimidines (prepared
from reaction of chalcone with 6-aminothiouracil) with a variety of
hydrazonoyl chlorides. Based on spectroscopic evidence and their chemical
syntheses, the structures of the newly prepared compounds were elucidated.
Designated compounds are forced for molecular docking by using MOE
Fakultat Chemie und Lebensmittel
chemie, TU-Dresden, Dresden, Germany
3
Chemistry Department, Faculty of
Science, Islamic University in Almadinah
Almonawara, Almadinah Almonawara,
Saudi Arabia
4
Chemistry Department, Faculty of
Science, Bani Suef University, Bani Suef,
Egypt
2
014.010 Package software; one of in silico study tools. Synthesized compounds
are targeting Human Cyclin-defendant Kinase 2 (CK2) PDB ID (1PXO.Protein
data bank) due to its important role in controlling the human cell cycle and
also for meiosis.
5
Science & Technology Center of
Excellence, Ministry of Military
Production, Cairo, Egypt
Correspondence
Sobhi M. Gomha, Chemistry Department,
Faculty of Science, Cairo University, Giza
12613, Egypt.
Email: s.m.gomha@gmail.com
1
| INTRODUCTION
(CDKs) are serine/threonine kinases that control the pro-
liferation of eukaryotic cells. Due to their crucial role in
In continuation of our studies dealing with the utility of
hydrazonoyl halides for synthesis of various bridgehead
the regulation of the cell division cycle, CDKs have
emerged as important therapeutic targets in anticancer
drug research. Azolopyrimidine derivatives such as
triazolo-pyrimidines, pyrazolo-pyrimidines and pyrrolo-
pyrimidines were shown to potently inhibit cyclin-
[1–5]
nitrogen polyheterocycles,
substituted pyrido[2,3-d]
pyrimidines have a broad variety of physiological charac-
[
6]
teristics, including anti-inflammatory, analgesic,
[7]
[8]
[29–31]
antibacterial,
antitumoral,
and antileishmanial
agents. They also act as dihydrofolate reductase inhibi-
dependent kinase 2 (CDK2) (Figure 1).
[9]
In these last two decades, we have launched a pro-
gram designed to create new easy, synthetic paths to het-
erocyclic systems that are functionally replaced, using
[
10]
tors and tyrosine kinase inhibitors.
Some drugs,
tranquilizing
antiallergic
[11]
including antiasthmatic pemirolast,
[12]
[13]
pirenperoazne,
Barmastine,
antiulcerative agents,
inexpensive laboratory materials with anticipated
[
14]
[32–42]
also have the pyrido[1,2-a]pyrimidine
bioactivities.
Under our program, some new
skeleton. Therefore, the synthesis of such ring systems
has been very interesting in view of their potent biologi-
pyridine-fused aza heterocyclic compounds have to be
evaluated for biological activity. It was expected that
combining a triazole ring with a pyridine and/or a pyrim-
idine ring in one system could lead to improved biologi-
cal activity. Thus, we targeted pyrido-triazolo-pyrimidine
[15–23]
cal and pharmacological activities.
The tricyclic
pyrido[2,3-d][1,2,4]triazolo [4,3-a]pyrimidin-5-ones are
pharmacological scaffold that represent a wide range of
[24–28]
biological activities.
Cyclin-dependent kinases
derivatives
bearing
an
ethoxy-carbonyl
group.
J Heterocyclic Chem. 2020;1–11.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
ABDELRAZEK ET AL.
FIGURE 1 Different examples of CDK2 and target
compounds 15
O
N
HN
N
HN
O
N
N
N
N
N
N
H2NO2S
N
N
N
HO
N
N
N
H
N
H
OH
H
Roscovitine
Dinaciclib
NU6102
SO NH
2
2
N
HN
Ph
N
O
N
R
HN
N
N
N
N
N
N
EtOOC
N
N
N
O
N
Br
N
Ar`
N
HN
Ar
Target
pyridotriazolopyrimidines
Triazolopyrimidinesshowedgoodactivity
towardsCDK2
1
5a,e,fand15l
tautomers 7a,b, which in role undergo an autooxidation
to afford the final isolable pyrido[2,3-d]pyrimidine prod-
ucts 8a,b, respectively. The presence of the ester triplet
1
and quartet signals in the H NMR spectra of 8a and 8b
as well as the MS and the elemental analyses confirmed
their structures.
Compounds 8a,b have been reacted with various
hydrazonoyl chlorides 12 to give the pyrido[2,3-d][1,2,4]
triazolo[4,3-a]pyrimidine derivatives 15a-q. The reaction
is presumed to continue through S-alkylation with
removal of HCl to afford intermediates 13 that undergo
Smiles rearrangement to afford the thiohydrazide inter-
SCHEME 1 Synthesis of chalcone derivatives 3a,b
Functionally substituted chalcones derived from ethyl
acetoacetate 1 seemed suitable starting materials to fulfill
this objective. To prevent the active methylene of 1 from
interfering in the condensation reaction, it was manda-
tory to block it through coupling with diazonium salts.
mediates 14 that lose H S to afford the final products
(Scheme 3).
2
3 | MOLECULAR DOCKING
Designated compounds are forced for molecular docking
by using MOE2014.010 Package software one of in silico
study tools. The synthesized compounds are targeting
Human Cyclin-defendant Kinase 2 (CK2) PDB ID (1PXO.
Protein data bank) due to its important role in controlling
of the human cell cycle and also for meiosis.
2
| RESULTS AND DISCUSSION
Ethyl acetoacetate 1 was coupled with two substituted
benzene diazonium chlorides to give the aryl hydrazones
2
a,b. These latter compounds were allowed to condense
with benzaldehyde and sodium hydroxide to give the
chalcones 3a,b, respectively (Scheme 1).
The pyrido[2,3-d]pyrimidine derivatives 8a,b were
prepared from reaction of chalcones 3a,b with the
Synthesized compounds prepared for modeling by
adding hydrogen and forced to energy minimization also
targeted protein prepared for docking by protein optimi-
zation process and minimization of energy in order to
meet all the residues involved in the active protein site.
All four synthesized compounds and the protein's
6
1
-aminothiouracil 4, rather than their position isomers
0a,b, which would have been readily cyclized into the
triazaphenalene derivatives 11a,b (Scheme 2). The reac-
native
inhibitor
(4-(2-amino-4-methyl-thiazol-5-yl)-
tion presumably occurs according to the procedure
pyrimidin-2-yl]-(3-nitro-phenyl)-amine) reveal various
binding energies. Compound 15a showing total binding
energies (−12.5) Kcal/mol by making three pi-hydrogen
interaction with Ile 10 with binding energies (−1.1, −1.0)
Kcal/mol, with Gly 13 with binding energy (−0.7) Kcal/
[43]
reported by Quiroga et al
via the condensation of the
amino group of 4 with the carbonyl group of 3a,b to
afford the intermediates 5a,b that in situ undergo
electrocyclization to afford the intermediates 6a,b or their

ABDELRAZEK ET AL.
3
Ar
SCHEME 2 Synthesis of 2-thioxo-
pyrido[2,3-d]pyrimidines 8a,b
O
NH
N
Ar
NH
N
O
COOEt
NH
O
O
O
O
HN
a,b
N
H
S
NH
N
EtO
Ph
Ph
N
N
H
S
Ph
N
N
H
S
N
9
10a,b
11a,b
HN
Ar
O
NH
Ph
N
O
O
O
H2N
N
H
S
NH
EtO
Ph
4
EtOOC
HN
N
H
S
N
AcOH
HN
N
5a,b
3a,b
Ar
Ar
Ar = a, Ph; i, 3,5-(Me2)C6H3
Ph
O
Ph
O
H
Auto-oxidation
NH
NH
EtOOC
EtOOC
N
H
N
H
S
N
N
H
S
N
N
HN
Ar
HN
Ar
6
a,b
7
a,b
Ph
N
O
NH
EtOOC
HN
N
H
S
N
8
a,b
Ar
Ar = a, Ph; b, 3,5-(Me2)C6H3
SCHEME 3 Synthesis of
1
,5-dihydropyrido-triazolo-pyrimidine
derivatives (15a-q)
mol, Hydrogen donor interaction with Glu 162 with bind-
ing energy −7.6 Kcal/mol and hydrogen acceptor interac-
tion with Glu 12 with binding energy −2.1 Kcal/mo
On the other side, compound 15e shows strong affin-
ity to the (ck2) enzyme with a total binding energy equal
to −13.6 Kcal/mol by expressing to pi-hydrogen interac-
tions with Ile 10 with binding energies (−0.9, −0.9) Kcal/
(Figure 2).

4
ABDELRAZEK ET AL.
FIGURE 2 Compund 15a fitted into the
active binding site of (ck2) enzyme
FIGURE 3 Compund 15e fitted into the
active binding site of (ck2) enzyme
mol, hydrogen donor interaction with Glu 162 with −9.7
Kcal/mol binding energy, and hydrogen acceptor interac-
tion with −2.1 Kcal/mol binding energy with Glu
binding energies which equal −13.1 Kcal/mol. Com-
pound 15l makes two pi-hydrogen interactions with
Ile 10 with binding energies (−1.0, −1.0) Kcal/mol,
hydrogen donor interaction with Glu 162 with −9.7
Kcal/mol binding energy, and hydrogen acceptor
interaction with Glu12 with −1.4 Kcal/mol binding
energy (Figure 5).
1
2 (Figure 3).
While total binding energies of compound 15f reveal-
ing a weak affinity to the (ck2) enzyme giving −0.9 Kcal/
mol by making pi-hydrogen interaction with Val
1
8 (Figure 4).
From the above studies, compound 15f revealing the
lowest affinity to the (ck2) enzyme compared to the three
others compounds (15a, 15e, and 15f) (Figure 6), which
Finally the potency of compound 15l as inhibitor
to the (ck2) enzyme was explained by the total

ABDELRAZEK ET AL.
5
FIGURE 4 Compund 15f fitted into the
active binding site of (ck2) enzyme
FIGURE 5 Compund 15l fitted into the
active binding site of (ck2) enzyme
emphasize the position of substituents (pharmacophores)
affecting strongly on the potency of the candidate drug
by affecting the fitting of the drug into the active binding
site of the targeted enzyme.
4 | EXPERIMENTAL
Electrothermal IA-9000 apparatus was used for recording
all melting points of new derivatives. After preparation of

6
ABDELRAZEK ET AL.
−
1
(
2C=O), 1603 (C=N) cm ; δ = 1.21 (t, J = 7.3 Hz, 3H,
H
CH ), 4.15 (q, J = 7.3 Hz, 2H, CH ), 6.84 (d, J = 15.8 Hz,
3
2
1H, CH=CH), 6.87 to 7.51 (m, 10H, Ar-H), 7.88 (d,
J = 15.8 Hz, 1H, CH=CH), 11.42 (s, 1H, NH) ppm; MS,
+
m/z (%) 322 (M , 29). Anal. Calcd. For C H N O
19
18
2
3
(
5
322.36): C, 70.79; H, 5.63; N, 8.69. Found: C, 70.68; H,
.60; N, 8.49%.
4
.3 | Ethyl 2-(2-[3,5-dimethylphenyl]
hydrazono)-3-oxo-5-phenylpent-
-enoate (3b)
4
ꢀ
ꢀ
Yellow solid (2.76 g; 79% yield), mp168 C to 188 C
(
(
EtOH); νmax = 3421 (NH), 3024, 2918 (CH), 1729, 1692
−
1
2C=O), 1613 (C=N) cm ; δ = 1.23 (t, J = 7.3 Hz,
H
FIGURE 6 Graph showing the different binding energies of
the four compounds and the native inhibitor (Nat.Inh)
3
H, CH ), 2.25 (s, 3H, CH ), 2.36 (s, 3H, CH ), 4.22 (q,
3 3 3
J = 7.3 Hz, 2H, CH ), 6.24 (d, J = 15.8 Hz, 1H,
2
CH=CH), 6.54 to 7.24 (m, 8H, Ar-H), 7.27 (d,
KBr discs of the new synthesized fused cycloheptane deriva-
tives, IR-spectra were determined using Raman spectrome-
ter (Nexus 670 FT-IRFT). NMR spectra were acquired on a
J = 15.8 Hz, 1H, CH=CH), 11.50 (s, 1H, NH) ppm; MS,
+
m/z (%) 350 (M , 27). Anal. Calcd. For C H N O
21
22
2
3
(350.41): C, 71.98; H, 6.33; N, 7.99. Found: C, 71.78; H,
6.12; N, 7.80%.
1
Bruker Avance 400 instrument at 400 MHz for H NMR in
DMSO-d solutions, using residual solvent signals as inter-
6
nal standards. Also, measuring of elemental analyzes were
carried out on Elementar vario-LIII C-H-N-S analyzer. The
mass spectra were measured on MS Spectrometer (GCMS-
QP 1000EX Shimadzu Gas Chromatography). TLC using
aluminum sheets were utilized to monitor the progress and
purity of the products, and all spots were disclosed by
exposure to UV lamp. Ethyl 3-oxo-2-(2-phenylhydrazono)-
4.4 | Synthesis of ethyl 2-(4-oxo-5-aryl-
2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d]
pyrimidin-7-yl)-2-(2-phenylhydrazono)
acetates 8a,b
Chalcones 2a or 2b (10 mmol) were refluxed for 12 hours
with 6-aminothiouracil 4 (1.43 g, 10 mmol) in 30 mL of
AcOH. The obtained product after evaporation was fil-
tered and recrystallized from dioxane to give the respec-
tive thiones 8a,b.
[44]
butanoate derivatives 2a and 2b and 6-amino-2-thioxo-2,-
[
45]
3
1
-dihydropyrimidin-4(1H)-one
hydrazonoyl chlorides
[46]
2a-k were prepared as described in the literature.
4.1 | Synthesis of chalcones 3a and 3b
4.5 | Ethyl 2-(2-phenylhydrazono)-
To an ethanolic solution of each of ethyl 3-oxo-
-(2-phenylhydrazono)-butanoate derivatives 2a or 2b
10 mmol) and benzaldehyde (1.06 g, 10 mmol), an aque-
2-(1,2,3,4-tetrahydro-4-oxo-5-phenyl-
2-thioxopyrido[2,3 d]pyrimidin-7-yl)
acetate (8a)
2
(
ous sodium hydroxide solution (50%, 10 mL) was slowly
ꢀ
ꢀ
ꢀ
added with stirring at 25 C for 4 to 6 hours as indicated
Brown solid (3.34 g; 75% yield), mp 239 C to 241 C (diox-
by TLC. The reaction mixture was poured into ice-cold
water, and the product that separated was filtered, dried,
and crystallized from ethanol to give chalcones 5a-d,
respectively.
ane); νmax = 3423 to 3320 (3NH), 3043, 2921 (CH), 1726,
−
1
1650 (2C=O), 1605 (C=N) cm ; δ = 1.21 (t, 3H, CH ),
H
3
4.27 (q, 2H, CH ), 6.35 (s, 1H, NH), 6.85 to 8.04 (m, 11H,
2
13
Ar-H), 11.27, 11.59 (2s, 2H, 2NH) ppm; C NMR
(
DMSO-d6): δ 14.44 (CH ), 62.73 (CH ), 114.58, 115.58,
3 2
123.48, 127.06, 128.05, 128.59, 130.40, 132.48, 133.39,
4
2
.2 | Ethyl 3-oxo-5-phenyl-
-(2-phenylhydrazono)pent-4-enoate (3a)
139.06, 139.16, 142.95, 143.10, 150.76, 159.81(Ar–C and
C=N), 165.03 (C=O), 178.39 (C=S) ppm; MS, m/z (%)
+
4
45 (M , 54). Anal. Calcd. For C H N O S (445.49): C,
23
19 5 3
ꢀ
ꢀ
Yellow solid (2.6 g; 82% yield), mp 200 C to 202 C
62.01; H, 4.30; N, 15.72. Found: C, 61.90; H,
4.18; N, 15.60%.
(EtOH); νmax = 3462 (NH), 3069, 2929 (CH), 1729, 1654

ABDELRAZEK ET AL.
7
4
.6 | Ethyl 2-(2-[3,5-dimethylphenyl]
67.24; H, 4.41; N, 17.15. Found: C, 67.15; H,
4.33; N, 17.06%.
hydrazono)-2-(1,2,3,4-tetrahydro-4-oxo-
5
7
-phenyl-2-thioxopyrido[2,3-d]pyrimidin-
-yl)acetate (8b)
4
.9 | Ethyl 2-(3-acetyl-5-oxo-6-phenyl-
ꢀ
ꢀ
Brown solid (3.78 g; 80% yield), mp 220 C to 222 C (diox-
ane); νmax = 3423 to 3320 (3NH), 3043, 2921 (CH), 1726,
1-[p-tolyl]-1,5-dihydropyrido[2,3-d][1,2,4]
triazolo[4,3-a]pyrimidin-8-yl)-
2-(2-phenylhydrazono)acetate (15b)
−
1
1
2
6
650 (2C=O), 1605 (C=N) cm ; δ = 1.22 (t, 3H, CH ),
.25 (s, 3H, CH ), 2.36 (s, 3H, CH ), 4.22 (q, 2H, CH ),
.38 (s, 1H, NH), 6.53 to 7.50 (m, 8H, Ar–H), 7.58 (s, 1H,
H
3
3
3
2
ꢀ
ꢀ
Brown solid (4.45 g; 76% yield), mp 185 C to 187 C (diox-
ane); νmax = 3375 (NH), 3090, 2923 (CH), 1729, 1689,
1662 (3C=O), 1594 (C=N) cm ; δ = 1.27 (t, 3H, CH ),
2.27 (s, 3H, CH ), 2.34 (s, 3H, CH ), 4.31 (q, 2H, CH ),
3 3 2
pyridine 5-H), 11.20 & 11.48 (2s, 2H, 2NH); MS, m/z (%)
+
−1
4
6
4
73 (M , 54). Anal. Calcd. For C H N O S (473.55): C,
3.41; H, 4.90; N, 14.79. Found C, 63.33; H,
.75; N, 14.67%.
25
23
5
3
H
3
7.16 to 7.98 (m, 14H, Ar–H), 8.40 (s, 1H, pyridine-H7),
+
11.53 (s, 1H, NH) ppm; MS, m/z (%) 585 (M , 60). Anal.
Calcd. For C H N O (585.61): C, 67.68; H, 4.65; N,
33
27 7 4
4
.7 | Synthesis of 1,5-dihydropyrido
16.74. Found: C, 67.55; H, 4.46; N, 16.80%.
[
2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-
3
-carboxylate derivatives (15a-q)
.7.1 | General procedure
4
.10 | Ethyl 2-(3-acetyl-
1-[4-chlorophenyl]-5-oxo-6-phenyl-
,5-dihydropyrido[2,3-d][1,2,4]triazolo
4
1
Triethylamine (1 mL, 10 mmol) has been added to a
mixture of thione 8a or 8b (10 mmol) and
hydrazonoyl halides 12a-k (10 mmol) in 10 mL diox-
ane. The reaction mixture was refluxed for 5 to
[4,3-a]pyrimidin-8-yl)-
2-(2-phenylhydrazono)acetate (15c)
ꢀ
ꢀ
Brown solid (4.48 g; 74% yield), mp 190 C to 192 C (diox-
1
0 hours. Evaporate solvent, filter the formed solid,
ane); νmax = 3405 (NH), 3040, 2921 (CH), 1729, 1710,
1660 (3C=O), 1597 (C=N) cm ; δ = 1.27 (t, 3H, CH ),
H 3
−
1
washed with methanol, dried, and recrystallized from
the proper solvent to give the products 15a-q, respec-
tively. Compounds 15a-q and their analytical con-
stants are listed below.
2.38 (s, 3H, CH ), 4.25 (q, 2H, CH ), 7.18 to 8.08 (m, 14H,
3
2
Ar–H), 8.43 (s, 1H, pyridine-H7), 11.58 (s, 1H, NH) ppm;
MS, m/z (%) 605 & 607 (M− & M , 60). Anal. Calcd. for
1
+1
C H ClN O (606.03): C, 63.42; H, 3.99; N, 16.18.
32
24
7 4
Found: C, 63.31; H, 3.82; N, 16.08%.
4
1
.8 | Ethyl 2-(3-acetyl-5-oxo-1,6-diphenyl-
,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]
pyrimidin-8-yl)-2-(2-phenylhydrazono)
acetate (15a)
4.11 | Ethyl 2-(3-acetyl-
1-(3-chlorophenyl)-5-oxo-6-phenyl-
1
,5-dihydropyrido[2,3-d][1,2,4]triazolo
ꢀ
ꢀ
Brown solid (4.45 g; 78% yield), mp 175 C to 177 C (diox-
[4,3-a]pyrimidin-8-yl)-
2-(2-phenylhydrazono)acetate (15d)
ane); νmax = 3377 (NH), 3059, 2922 (CH), 1726, 1693,
667 (3C=O), 1598 (C=N) cm ; δ = 1.27 (t, 3H, CH ),
H 3
.38 (s, 3H, CH ), 4.27 (q, 2H, CH ), 7.09 to 8.10 (m, 15H,
−
1
1
2
ꢀ
ꢀ
Brown solid, (4.79 g; 79% yield); mp 200 C to 202 C
3
2
Ar–H), 8.46 (s, 1H, pyridine-H7), 11.90 (s, 1H, NH) ppm;
(dioxane); νmax = 3388 (NH), 3065, 2923 (CH), 1725,
13
−1
C NMR (DMSO-d6): δ 12.07, 24.06 (CH ), 61.43 (CH ),
1684, 1663 (3C=O), 1591 (C=N) cm ; δ = 1.27 (t, 3H,
3
2
H
1
1
1
11.52, 112.06, 114.34, 114.52, 116.22, 123.76, 124.11,
25.82, 127.91, 128.28, 129.38, 129.59, 136.30, 137.13,
41.47, 142.69, 143.38, 146.28, 156.13, 156.62 (Ar–C and
CH ), 2.37 (s, 3H, CH ), 4.23 (q, 2H, CH ), 7.09 to 8.13
3
3
2
(m, 14H, Ar-H), 8.40 (s, 1H, pyridine-H7), 11.55 (s, 1H,
NH) ppm; MS m/z (%): 605 & 607 (M− & M , 15). Anal.
1
+1
C=N), 162.85, 175.91, 195.57(C=O) ppm; MS, m/z (%)
5
Calcd. for C H ClN O (606.03): C, 63.42; H, 3.99; N,
32
24
7 4
+
71 (M , 31). Anal. Calcd. For C H N O (571.59): C,
16.18. Found: C, 63.33; H, 3.85; N, 16.02%.
32
25 7 4

8
ABDELRAZEK ET AL.
4
1
1
.12 | Ethyl 2-(3-acetyl-
-(4-bromophenyl)-5-oxo-6-phenyl-
,5-dihydropyrido[2,3-d][1,2,4]triazolo
66.33; H, 4.75; N, 15.93. Found: C, 66.38; H,
4.72; N, 15.80%.
[
4,3-a]pyrimidin-8-yl)-
2
-(2-phenylhydrazono)acetate (15e)
4.15 | Ethyl 8-(2-ethoxy-2-oxo-
1
-(2-phenylhydrazono)ethyl)-5-oxo-
ꢀ
ꢀ
Brown solid, (5.2 g; 80% yield); mp 205 C to 207 C (diox-
ane); νmax = 3397 (NH), 3048, 2922 (CH), 1723, 1679,
6-phenyl-1-(m-tolyl)-1,5-dihydropyrido
[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-
3-carboxylate (15h)
−
1
1
2
662 (3C=O), 1596 (C=N) cm ; δ = 1.26 (t, 3H, CH ),
H 3
.38 (s, 3H, CH ), 4.19 (q, 2H, CH ), 7.19 to 7.97 (m, 14H,
3
2
ꢀ
ꢀ
Ar-H), 8.39 (s, 1H, pyridine-H7), 11.57 (s, 1H, NH) ppm;
MS m/z (%): 649 & 651 (M & M , 13). Anal. Calcd. for
C H BrN O (650.48): C, 59.09; H, 3.72; N, 15.07.
Brown solid (4.6 g; 75% yield); mp 163 C to 165 C (diox-
−
1
+1
ane); νmax = 3384 (NH), 3059, 2923 (CH), 1748, 1724,
−
1
1675 (3C=O), 1594 (C=N) cm ; δ = 1.25 (t, 3H, CH ),
H 3
32
24
7
4
Found: C, 58.95; H, 3.66; N, 14.92%.
1.27 (t, 3H, CH ), 2.38 (s, 3H, CH ), 4.38 (q, 2H, CH ),
3 3 2
4
1
.41 (q, 2H, CH ), 7.19 to 7.98 (m, 14H, Ar–H), 8.28 (s,
2
H, pyridine-H7), 11.22 (s, 1H, NH) ppm; MS m/z (%):
+
4
1
1
.13 | Ethyl 8-(2-ethoxy-2-oxo-
-(2-phenylhydrazono)ethyl)-5-oxo-
,6-diphenyl-1,5-dihydropyrido [2,3-d][1,2,4]
615 (M , 20). Anal. Calcd. for C H N O (615.64): C,
34
29 7 5
66.33; H, 4.75; N, 15.93. Found: C, 66.21; H,
4.65; N, 15.87%.
triazolo[4,3-a]pyrimidine-
-carboxylate (15f)
3
4
.16 | Ethyl 1-(4-chlorophenyl)-
ꢀ
ꢀ
Brown solid (4.75 g; 79% yield); mp 170 C to 172 C (diox-
8-(2-ethoxy-2-oxo-1-(2-phenylhydrazono)
ethyl)-5-oxo-6-phenyl-1,5-dihydropyrido
[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-
3-carboxylate (15i)
ane); νmax = 3386 (NH), 3050, 2916 (CH), 1748, 1724,
−
1
1
1
7
1
1
1
1
1
1
660 (3C=O), 1586 (C=N) cm ; δ = 1.21 (t, 3H, CH ),
H 3
.27 (t, 3H, CH ), 4.35 (q, 2H, CH ), 4.38 (q, 2H, CH ),
.02 to 8.08 (m, 15H, Ar-H), 8.28 (s, 1H, pyridine-H7),
1.24 (s, 1H, NH) ppm; C-NMR (DMSO-d6): δ 13.16,
3.67 (CH ), 62.38, 62.73 (CH ), 101.29, 111.59, 111.74,
14.63, 116.22, 125.52, 126.53, 127.66, 130.26, 136.42,
38.30, 138.58, 139.80, 139.89, 142.36, 146.18, 150.26,
56.42, 158.36, 159.89, (Ar–C and C=N), 165.68, 167.66,
75.60 (C=O) ppm; MS m/z (%): 601 (M , 19). Anal.
Calcd. for C H N O (601.61): C, 65.88; H, 4.52; N,
3
2
2
13
ꢀ
ꢀ
Brown solid (4.77 g; 75% yield); mp 155 C to 157 C (diox-
ane); νmax = 3392 (NH), 3061, 2927 (CH), 1748, 1725,
1678 (3C=O), 1598 (C=N) cm ; δ = 1.27 (t, 3H, CH ),
H 3
1.37 (t, 3H, CH ), 4.35 (q, 2H, CH ), 4.38 (q, 2H, CH ),
7.22 to 8.09 (m, 14H, Ar–H), 8.34 (s, 1H, pyridine-H7),
11.32 (s, 1H, NH) ppm; MS m/z (%): 635 & 637 (M
M , 13). Anal. Calcd. for C H ClN O (636.06): C,
33 26 7 5
3
2
−
1
3
2
2
+
−1
&
+1
33
27
7
5
1
6.30. Found: C, 65.78; H, 4.45; N, 16.21%.
62.31; H, 4.12; N, 15.41. Found C, 62.22; H,
.01; N, 15.33%.
4
4
1
6
.14 | Ethyl 8-(2-ethoxy-2-oxo-
-(2-phenylhydrazono)ethyl)-5-oxo-
-phenyl-1-(p-tolyl)-1,5-dihydropyrido
4.17 | Ethyl 8-(2-ethoxy-2-oxo-
1-(2-phenylhydrazono)ethyl)-
1-(4-nitrophenyl)-5-oxo-6-phenyl-
1,5-dihydropyrido[2,3-d][1,2,4]triazolo[4,3-a]
pyrimidine-3-carboxylate (15j)
[
3
2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-
-carboxylate (15g)
ꢀ
ꢀ
Brown solid, (4.5 g; 74% yield); mp 140 C to 142 C (diox-
ane); νmax = 3388 (NH), 3069, 2922 (CH), 1744, 1722,
ꢀ
ꢀ
Brown solid (4.7 g; 73% yield); mp 165 C to 167 C (diox-
−
1
1
1
4
1
6
673 (3C=O), 1591 (C=N) cm ; δ = 1.27 (t, 3H, CH ),
.38 (t, 3H, CH ), 2.32 (s, 3H, CH ), 4.35 (q, 2H, CH ),
.37 (q, 2H, CH ), 7.13 to 7.97 (m, 14H, Ar–H), 8.31 (s,
H, pyridine-H7), 11.22 (s, 1H, NH) ppm; MS m/z (%):
ane); νmax = 3403 (NH), 3055, 2923 (CH), 1749, 1729,
H
3
−
1
1680 (3C=O), 1592 (C=N) cm ; δ = 1.25 (t, 3H, CH ),
H 3
3
3
2
1.40 (t, 3H, CH ), 4.35 (q, 2H, CH ), 4.39 (q, 2H, CH ),
3 2 2
7.19 to 8.16 (m, 14H, Ar-H), 8.38 (s, 1H, pyridine-H7),
11.55 (s, 1H, NH) ppm; MS m/z (%): 646 (M , 61). Anal.
2
+
+
15 (M , 32). Anal. Calcd. for C H N O (615.64): C,
34
29 7 5

ABDELRAZEK ET AL.
9
Calcd. for C H N O (646.61): C, 61.30; H, 4.05; N,
(613.67): C, 68.50; H, 5.09; N, 15.98. Found C, 68.39; H,
4.98; N, 15.89%.
33
26 8 7
1
7.33. Found C, 61.21; H, 3.92; N, 17.21%.
4
8
.18 | Ethyl 1-(2,4-dichlorophenyl)-
-(2-ethoxy-2-oxo-1-(2-phenylhydrazono)
4.21 | Ethyl 2-(3-acetyl-
1-(4-chlorophenyl)-5-oxo-6-phenyl-
1,5-dihydropyrido[2,3-d][1,2,4]triazolo
[4,3-a]pyrimidin-8-yl)-
2-(2-[3,5-dimethylphenyl]hydrazono)
acetate (15n)
ethyl)-5-oxo-6-phenyl-1,5-dihydropyrido
2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-
-carboxylate (15k)
[
3
ꢀ
ꢀ
Brown solid (4.6 g; 69% yield); mp 155 C to 157 C (diox-
ane); νmax = 3398 (NH), 3045, 2928 (CH), 1749, 1724,
ꢀ
ꢀ
Brown solid (4.37 g; 69% yield); mp 250 C to 252 C (diox-
−
1
1
1
7
1
650 (3C=O), 1591 (C=N) cm ; δ = 1.18 (t, 3H, CH ),
.22 (t, 3H, CH ), 4.26 (q, 2H, CH ), 4.29 (q, 2H, CH ),
.05 to 7.98 (m, 13H, Ar–H), 8.25 (s, 1H, pyridine-H7),
1.36 (s, 1H, NH) ppm; MS m/z (%): 669 & 671 (M
ane); νmax = 3374 (NH), 3060, 2919 (CH), 1726, 1685,
H
3
−
1
1669 (3C=O), 1589 (C=N) cm ; δ = 1.25 (t, 3H, CH ),
H 3
3
2
2
2.28 (s, 3H, CH ), 2.30 (s, 3H, CH ), 2.36 (s, 3H, CH ),
3 3 3
−1
&
4.15 (q, 2H, CH ), 6.85 to 7.65 (m, 12H, Ar–H), 8.19 (s,
2
+
1
M , 46). Anal. Calcd. for C H Cl N O (670.5): C,
1H, pyridine-H7), 11.58 (s, 1H, NH) ppm; MS m/z (%):
33
25
2 7 5
633 & 635 (M− & M , 16). Anal. Calcd. for
1
+1
5
3
9.11; H, 3.76; N, 14.62. Found C, 59.00; H,
.66; N, 14.55%.
C H ClN O (634.08): C, 64.40; H, 4.45;N, 15.46.
34
28
7 4
Found C, 64.39; H, 4.34;N, 15.36%.
4
1
.19 | Ethyl 2-(3-acetyl-5-oxo-
,6-diphenyl-1,5-dihydropyrido[2,3-d][1,2,4]
4.22 | Ethyl 8-(1-(2-[3,5-dimethylphenyl]
hydrazono)-2-ethoxy-2-oxoethyl)-5-oxo-
1,6-diphenyl-1,5-dihydropyrido[2,3-d][1,2,4]
triazolo[4,3-a]pyrimidine-
triazolo[4,3-a]pyrimidin-8-yl)-
-(2-[3,5-dimethylphenyl]hydrazono)
acetate (15l)
2
3-carboxylate (15o)
ꢀ
ꢀ
Brown solid (4.7 g; 79% yield); mp 184 C to 186 C (diox-
ꢀ
ꢀ
ane); νmax = 3308 (NH), 3024, 2919 (CH), 1720, 1673,
Brown solid (4.5 g; 72% yield); mp 125 C to 127 C (diox-
−
1
1
2
4
1
5
6
4
665 (3C=O), 1588 (C=N) cm ; δ = 1.24 (t, 3H, CH ),
ane); νmax = 3417 (NH), 3058, 2920 (CH), 1741, 1719, 1651
(3C=O), 1605 (C=N) cm ; δ = 1.26 (t, 3H, CH ), 1.39 (t,
H 3
3H, CH ), 2.26 (s, 3H, CH ), 2.32 (s, 3H, CH ), 4.28 (q, 2H,
3 3 3
CH ), 4.32 (q, 2H, CH ), 6.67 to 7.59 (m, 13H, Ar–H), 8.38
(s, 1H, pyridine-H7), 11.24 (s, 1H, NH) ppm; MS m/z (%):
H
3
−1
.28 (s, 3H, CH ), 2.36 (s, 3H, CH ), 2.41 (s, 3H, CH ),
3
3
3
.27 (q, 2H, CH ), 7.06 to 7.65 (m, 13H, Ar–H), 8.10 (s,
2
H, pyridine-H7), 11.55 (s, 1H, NH) ppm; MS m/z (%):
2
2
+
99 (M , 21). Anal. Calcd. for C H N O (599.64): C,
34
29 7 4
+
8.10; H, 4.87; N, 16.35;. Found C, 67.97; H,
.78; N, 16.22%.
629 (M , 38). Anal. Calcd. for C H N O (629.66): C,
3
5 31 7 5
66.76; H, 4.96; N, 15.57. Found C, 66.67; H, 4.82; N, 15.45%.
4
1
.20 | Ethyl 2-(3-acetyl-5-oxo-6-phenyl-
-(p-tolyl)-1,5-dihydropyrido[2,3-d][1,2,4]
4.23 | Ethyl 8-(1-(2-[3,5-dimethylphenyl]
hydrazono)-2-ethoxy-2-oxoethyl)-5-oxo-
6-phenyl-1-(p-tolyl)-1,5-dihydropyrido
[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-
3-carboxylate (15p)
triazolo[4,3-a]pyrimidin-8-yl)-
-(2-[3,5-dimethylphenyl]hydrazono)
acetate (15m)
2
ꢀ
ꢀ
ꢀ
ꢀ
Brown solid (4.17 g; 68% yield); mp 185 C to 187 C (diox-
Brown solid (4.95 g; 77% yield); mp 195 C to 197 C (diox-
ane); νmax = 3330 (NH), 3050, 2918 (CH), 1718, 1671,
ane); νmax = 3396 (NH), 3043, 2920 (CH), 1743, 1719,
−
1
−1
1
2
2
664 (3C=O), 1588 (C=N) cm ; δ = 1.23 (t, 3H, CH ),
1653 (3C=O), 1602 (C=N) cm ; δ = 1.26 (t, 3H, CH ),
H
3
H
3
.27 (s, 3H, CH ), 2.30 (s, 3H, CH ), 2.35 (s, 3H, CH ),
1.31 (t, 3H, CH ), 2.26 (s, 3H, CH ), 2.31 (s, 3H, CH ),
3 3 3
2.36 (s, 3H, CH ), 4.28 (q, 2H, CH ), 4.40 (q, 2H, CH ),
3 2 2
3
3
3
.40 (s, 3H, CH ), 4.25 (q, 2H, CH ), 6.94 to 7.58 (m, 12H,
3
2
Ar-H), 8.17 (s, 1H, Pyridine-H7), 11.52 (s, 1H, NH) ppm;
6.67 to 7.58 (m, 12H, Ar-H), 8.35 (s, 1H, pyridine-H7),
11.55 (s, 1H, NH) ppm; MS m/z (%): 643 (M , 19). Anal.
+
+
MS m/z (%): 613 (M , 20). Anal. Calcd. for C H N O
35
31
7
4

10
ABDELRAZEK ET AL.
Calcd. for C H N O (643.69): C, 67.17; H, 5.17; N,
Hassan M. Abdel-aziz https://orcid.org/0000-0002-
36
33 7 5
1
5.23. Found C, 67.03; H, 5.05; N, 15.12%.
3440-2927
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8
2
1
.24 | Ethyl 1-(4-chlorophenyl)-
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[
5
| CONCLUSION
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Fathy M. Abdelrazek https://orcid.org/0000-0003-1179-
[
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Sobhi M. Gomha https://orcid.org/0000-0002-7739-
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[
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[
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Abdel-Shafy A. Efficient synthesis and In Silico
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