3-Aminothieno[2,3-b]pyridine-2-carboxylate: Effective precursor for microwave-assisted three components synthesis of new pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one hybrids

Article abstract of DOI:10.1002/jhet.4313

In this study, ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate was taken as a versatile precursor for the one-pot three-component synthesis of related fused pyrimidine hybrids. The tandem protocol involved the reaction of 3-aminothieno[2,3-b]pyridine, di

Full text of DOI:10.1002/jhet.4313

Received: 2 March 2021
DOI: 10.1002/jhet.4313
Revised: 15 May 2021
Accepted: 27 May 2021
A R T I C L E
3-Aminothieno[2,3-b]pyridine-2-carboxylate: Effective
precursor for microwave-assisted three components
synthesis of new pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4
(3H)-one hybrids
Mohamed A. Mohamed Teleb | Ahmed E. M. Mekky
| Sherif M. H. Sanad
Chemistry Department, Faculty of
Abstract
Science, Cairo University, Giza, Egypt
In this study, ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate was taken as a
versatile precursor for the one-pot three-component synthesis of related fused
pyrimidine hybrids. The tandem protocol involved the reaction of
Correspondence
Ahmed E. M. Mekky, Chemistry
Department, Faculty of Science, Cairo
University, Giza 12613, Egypt.
Email: ataher2211@yahoo.com
3-aminothieno[2,3-b]pyridine,
dimethylformamide-dimethylacetal,
and
amines. The reaction afforded a new series of the target pyrimidine hybrids,
linked to different arene units, in good to excellent yields. The prior reaction
was evaluated in different solvents under traditional heating or microwave
irradiation. Moreover, the influence of reaction temperature was also exam-
ined. The optimal conditions were obtained under microwave irradiation in
dioxane at 110ꢀC for 40 to 60 min. Additionally, by repeating the previous tan-
dem reaction using the appropriate amines at reaction times of 20 to 60 min, a
new series of pyrimidine hybrids linked to alkyl, arylthiazole, and benzo[d]thi-
azole units has been prepared in good to excellent yields. Furthermore, the
utility of bis(amines) was examined to conduct the synthesis of new
bis(pyrimidine) hybrids linked to aliphatic cores, in excellent yields, using the
same protocol at 30 min reaction time.
1 | INTRODUCTION
with 5-thia-1,3,6-triaza subunits [26,27]. Because of the wide
range of medicinal and pharmacological applications of the
Many attempts have been made recently to investigate the
biological significance of pyrimidine hybrids. These hybrids
demonstrated promising anticancer [1–3], antioxidant [4,5],
antihypertensive [6,7], antiviral [8,9], antidiabetic [10,11],
antiinflammatory [12–14], anti-ulcer [15], antibacterial [16–18],
anti-influenza [19,20], and antimalarial activities [21,22].
Further, they exhibit powerful inhibitory activity to acetyl-
cholinesterase, carbonic anhydrase [23], cyclooxygenase [24],
and DNA gyrase enzymes [25].
Among the diverse spectrum of pyrimidine deriva-
tives, those hybrids with related fused thienopyridine
play an important role. Hence, pyrido[30,20:4,5]thieno
[3,2-d]pyrimidines can be considered as fluorene analogues
prior hybrids, several publications reported their synthesis
[28–31]. These pyrimidine hybrids displayed the potent
inhibitory activity to mGluR1, which plays a crucial role in
the central sensitization of pain and other functions with
potential implications for neurological and psychiatric con-
ditions [32,33].
Moreover, pyridothienopyrimidines hybrids act as
promising inhibitors of phosphodiesterase IV, a target for
the treatment of asthma and chronic obstructive pulmo-
nary disease [34]. They also act as potent and selective
vascular endothelial growth factor receptor-2/kinase
insert domain receptor kinase enzyme inhibitors [35], as
well as inhibitors of multitarget Ser/Thr kinases [36].
J Heterocyclic Chem. 2021;1–11.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

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MOHAMED TELEB ET AL.
In addition, these hybrids act as good antimicrobial
[37,38], antifungal [39], anticancer [40], and antitumor
agents [41]. Figure 1 represents some potent bioactive
pyridothienopyrimidine hybrids I–III [32,35,38].
2 | RESULTS AND DISCUSSION
The synthesis of pyrimidinone derivatives using
3-aminothieno[2,3-b]pyridine-2-carboxylate I was docu-
mented by Bohm et al. [56] via a three-step synthetic
route (Scheme 1). At first, 3-aminothieno[2,3-b]pyridine-
2-carboxylate I was heated in alcoholic potassium
hydroxide solution to yield the potassium carboxylate II,
which was cyclocondensed with acid anhydrides to give
2-alkyloxazinones III. Next, III was reacted with the pri-
mary amines to give the target pyrimidinones. In the cur-
rent study, we designed a facile synthetic route to
synthesize the target pyrimidinone hybrids utilizing a
three-component one-pot protocol.
To begin our study, ethyl 3-aminothieno[2,3-b]pyri-
dine-2-carboxylate derivative 1 was taken as a synthetic
precursor for the tandem synthesis of related fused
pyrimidine hybrids [57]. The three-component reaction
between 1, dimethylformamide-dimethylacetal (DMF-
DMA) 2 and aniline 3a was conducted as a model reac-
tion to look for the optimal reaction conditions
(Scheme 2) [32,58]. By conducting the prior reaction in
On the other hand, the rapid synthesis of biologically
relevant heterocycles has remained one of the fascinating
tasks for organic and medicinal chemists [42,43]. In recent
years, multicomponent reactions have emerged as efficient
methods for the synthesis of various polyfunctionalized het-
erocyclic hybrids, which involves the transformation of
more than two reactants into the desired products in a one-
pot one-step fashion [44,45]. Simplicity, shorter reaction
time, greater efficiencies, improved atom economy, and
minimizing the production of by-products with the genera-
tion of diverse and complex “drug-like” scaffolds linked to
heterocyclic units are some of the advantages of these reac-
tions [46,47].
In connection with our previous efforts in the mul-
ticomponent synthesis of biologically promising heterocy-
clic hybrids [48–55], we reported herein an efficient
procedure for the synthesis of pyrimidine hybrids with
related thieno[2,3-b]pyridine moiety.
FIGURE 1 Structure of some potent bioactive pyridothienopyrimidine hybrids I–III
SCHEME 1 Previous synthesis of pyrimidinone hybrids
SCHEME 2 Tandem synthesis of pyrimidine hybrid 4a

MOHAMED TELEB ET AL.
3
DMF under either conventional heating for 10 h or
microwave irradiation for 45 min at 160 ꢀC, the desired
pyrimidine hybrid 4a could be isolated in 52% and 64%
yield, respectively (Table 1, entry 1). As a further investi-
gation, we evaluated a series of different solvents includ-
ing polar and nonpolar solvents (Table 1, entries 2–5).
Moreover, the influence of reaction temperature was also
examined (Table 1, entries 5–7). Thus, the microwave
irradiation of the reaction mixture in dioxane as a solvent
at 110ꢀC was proved to be the best reaction conditions,
providing the desired product in 77% yield.
Having determined the optimal conditions, we inves-
tigated the substrate scope of aryl amines 3a–3g [58]. The
results showed that aryl amines with various substituents
could be well tolerated in this tandem cyclization reac-
tion. As shown in Scheme 3, aryl amines 3b–3d bearing
electron-rich substituents (4-Me, 4-OMe, 4-Cl) were suc-
cessfully transformed into the corresponding products
4b–4d in good to excellent yields (82%–88%). Further-
more, aryl amines 3b–3d, linked to electron-deficient
substituents (4-CN, 4-NO2, 4-CO2Et), allowed the forma-
tion of the desired products 4e–4g in moderate yields
(57%–63%). Notably, as observed by thin layer chroma-
tography analyses, the formation of pyrmidines 4b–4d
was conducted at a shorter reaction time (40 min)
compared to the formation of 4f–4g hybrids (60 min).
These results implied that the stronger nucleophilicities
of amines could be beneficial for the transformation. The
structures of the pyrimidine hybrids 4 were established
by considering of their spectral data and elemental ana-
1
lyses. The H-nuclear magnetic resonance (NMR) spec-
trum of 4b, as a representative example, revealed four
singlet signals at δ 2.37, 3.84, 7.84, and 8.02 assigned to p-
CH3, p-OCH3, pyridine-H, and pyrimidine-H protons,
respectively. In addition, it showed a multiple signal in
the range of δ 7.10–8.24 corresponding to the thiophene
and aromatic protons (see Section 4).
The prior tandem protocol was subsequently studied
with a number of heteroaromatic amines to further dem-
onstrate its generality. Conducting the reaction using a
series of 4-arylthiazoles 5a–5e gave the desired pyrimi-
dine hybrids 6a–6e in 77%–84% yields (see Scheme 4 and
Section 4) [59].
The results showed that the reaction could readily
employ a variety of aryl substituents, which are very sig-
nificant functional units in pharmaceutical chemistry for
post-diversification. It should be noted that the electronic
effect and the position of the substituents on the phenyl
rings seemed to affect this reaction somewhat, but not
strongly, and the reactions of aromatic amines with
TABLE 1 Synthesis of pyrimidine
hybrid 4a under either microwave
Thermal heatinga,c
Microwave irradiation b,c
Entry Solvent
Temp. (ꢀC) Time (h) Yield (%) Time (min.)
Yield (%)
irradiation or conventional method
1
2
3
4
5
6
7
DMF
160
120
140
10
12
12
10
10
12
12
52
60
60
60
45
45
60
75
64
Toluene
Xylene
32
36
37
40
Pyridine 120
57
65
Dioxane
Dioxane
Dioxane
110
rt
69
77
Traces
43
Traces
51
70
aThe reactions were heated at reflux.
bThe reactions were irradiated by microwaves of power 300 W at 120ꢀC.
cThe reactions were followed up by thin layer chromatography analyses.
SCHEME 3 Tandem synthesis of 3-arylpyrimidine hybrids 4b–4g

4
MOHAMED TELEB ET AL.
electron-rich substituents produced similar yields to
those with electron-poor substituents. Furthermore, the
desired pyrimidine hybrid 8 linked to benzo[d]thiazole
unit was produced, in a good yield, by repeating the prior
tandem protocol using benzo[d]thiazol-2-amine 7 as a
reactive amine (Scheme 4) [60].
Next, we examined the utility of aliphatic amines in
the formation of the target pyrimidine hybrids. Thus, the
use of methylamine 9a or ethylamine 9b furnished
the synthesis of hybrids 10a and 10b, respectively, in
90%–92% yields (Scheme 5) [61]. In order to improve the
structural diversification of the product library, further
extension of this reaction to different bis(pyrimidine)
hybrids was performed. Thus, the use of bis(amines) 11a
or 11b afforded the desired products in excellent yields
(Scheme 5).
To identify the mechanism of the reaction, some con-
trol experiments were conducted (Scheme 6). Initially,
3-aminothieno[2,3-b]pyridine 1 was treated with DMF-
DMA 2 under the standard conditions for 15 min to pro-
duce the corresponding 3-(([dimethylamino]methylene)
amino)thieno[2,3-b]pyridine 13 in a quantitative yield
(Scheme 6, Experiment A) [62]. Subsequently, the reac-
tion of the compound 13 with aniline 3a under standard
conditions for 30 minutes achieved the generation of the
foreseen product 4a in 78% yield (Scheme 6, Experiment B).
Next, we examined the reaction of DMF-MDA 2 with ani-
line 3a under the optimized reaction conditions for
15 minutes, and the formamidine derivative 14 was
obtained in a quantitative yield (Scheme 6, Experiment
C) [63]. Then, the formamidine derivative 14 was trans-
formed into the target molecule 4a in 75% yield through
SCHEME 4 Tandem synthesis
of pyrimidine hybrids 6 and 8,
linked to 4-arylthiazole or
benzothiazole units
SCHEME 5 Tandem synthesis of 3-alkylpyrimidine hybrids 10 and bis(pyrimidine) hybrids 12

MOHAMED TELEB ET AL.
5
SCHEME 6 Control
experiments
its reaction with 3-aminothieno[2,3-b]pyridine 1 under
the optimized reaction conditions for 30 min (Scheme 6,
Experiment D). On the other hand, when the substrate
1 and the aniline 3a were reacted in standard conditions
for 60 min, compound 15 could not be detected
(Scheme 6, Experiment E). This result suggested that the
compound 15 was not an intermediate in the reaction.
Based on the above experimental results, a tentative
reaction pathway is represented in Scheme 7. First, the
corresponding formamidine intermediates 13 and 14 are
formed via the condensation of DMF-DMA 2 with the
appropriate substrate 1 or 3a, respectively. Subsequently,
two formamidine intermediates would undergo the cross-
imidination followed by the cyclocondensation to give
the desired product 4a through the intermediate 16.
amines under microwave irradiation in dioxane at 110ꢀC
for 20–60 min. This work has demonstrated the construc-
tion of a series of pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one hybrids, linked to different alkyl, arene,
arylthiazole and benzo[d]thiazole units in good to excel-
lent yields.
4 | EXPERIMENTAL
4.1 | Materials
All solvents were acquired from commercial sources and
used as received unless otherwise stated. All other
chemicals were acquired from Merck or Aldrich and used
without further purification. Microwave experiments
were performed using chemistry, electronics and
mechanics Discover apparatus (300 W), utilizing 35 ml
capped glass reaction vessels automated power control
based on temperature feedback. The melting points were
measured on a Stuart melting point apparatus and are
uncorrected. Infrared spectroscopy (IR) spectra were
recorded on a Smart iTR, which is an ultra-high-perfor-
mance, versatile attenuated total reflectance sampling
3 | CONCLUSIONS
We reported herein the development of an efficient one-
pot three-component synthesis of a new series of pyrimi-
dine hybrids with fused thieno[2,3-b]pyridine units. The
tandem protocol involved the reaction of 3-aminothieno
[2,3-b]pyridine, dimethylformamide-dimethylacetal and

6
MOHAMED TELEB ET AL.
SCHEME 7 Suggested
mechanism for the tandem synthesis
of pyrimidine 4a
accessory on the Nicolet iS10 fourier transform infrared
spectroscopy spectrometer. NMR spectra were recorded
on Bruker Avance III 400 MHz spectrophotometer
ethanol, dried and then recrystallized from the proper
solvent.
1
(400 MHz for H and 100 MHz for 13C) using TMS as an
7-(4-Methoxyphenyl)-3-phenyl-9-(thiophen-2-yl)pyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (4a)
internal standard and DMSO-d6 as solvent and chemical
shifts were expressed as δ ppm units. Elemental analyses
were carried out on a EuroVector instrument C, H, N, S
analyzer EA3000 Series.
Pale yellow solid (dioxane/ethanol mixture); Yield 1.80 g,
1
77%; m.p. 210–212ꢀC; IR (υ cmꢁ1): 1665 (CO); H-NMR
(400 MHz, DMSO-d6): δ 3.85 (s, 3H, p-OCH3), 7.08 (d,
J = 8.8 Hz, 2H, ArH), 7.32 (t, J = 4.4 Hz, 1H, thiophene-
H4), 7.43 (d, J = 7.6 Hz, 2H, ArH), 7.54–7.60 (m, 3H,
ArH), 7.82 (s, 1H, pyridine-H), 7.91 (d, J = 2.4 Hz, 1H,
thiophene-H5), 7.94 (d, J = 4.4 Hz, 1H, thiophene-H3),
8.00 (s, 1H, pyrimidine-H), 8.22 (d, J = 8.8 Hz, 2H, ArH);
13C-NMR (100 MHz, DMSO-d6): δ 55.8, 112.3, 114.2,
117.0, 126.4, 126.6, 127.8, 128.5, 128.7, 128.9, 129.4, 129.9,
130.4, 137.4, 137.7, 141.8, 148.2, 154.6, 156.5, 158.4, 158.9,
164.9; Anal. calcd. for C26H17N3O2S2 (467.5): C, 66.79; H,
3.66; N, 8.99; found: C, 67.02; H, 3.43; N, 8.76%.
4.2 | The procedures and spectral data
4.2.1 | General procedure for the synthesis
of pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4
(3H)-one hybrids 4, 6, 8 and 10
A
mixture of ethyl 3-aminothieno[2,3-b]pyridine-
2-carboxylate 1 (5 mmol), DMF-DMA 2 (6 mmol) and
the appropriate of aryl amines 3a–3g, 4-arylthiazoles
5a–5e, benzo[d]thiazol-2-amine 7 or aliphatic amines
9a,b (5 mmol) in dioxane (10 ml) was irradiated by
microwaves with a power of 300 W to reach a reaction
temperature of 110ꢀC under autogenerated pressure
for 20–60 min. The reaction mixture was cooled and
then 2 ml of ethanol was added drop wisely. The prod-
uct was collected by filtration, washed with cold
7-(4-Methoxyphenyl)-9-(thiophen-2-yl)-3-(p-tolyl)pyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (4b)
Pale yellow solid (dioxane/ethanol mixture); Yield 1.97 g,
82%; m.p. 220ꢀC; IR (υ cmꢁ1): 1667 (CO); 1H-NMR
(400 MHz, DMSO-d6): δ 2.37 (s, 3H, p-CH3), 3.84 (s, 3H,
p-OCH3), 7.10 (d, J = 8.8 Hz, 2H, ArH), 7.20 (d,
J = 8.0 Hz, 2H, ArH), 7.32 (t, J = 4.4 Hz, 1H, thiophene-

MOHAMED TELEB ET AL.
7
H4), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.84 (s, 1H, pyridine-
H), 7.92 (d, J = 2.4 Hz, 1H, thiophene-H5), 7.96 (d,
J = 4.4 Hz, 1H, thiophene-H3), 8.02 (s, 1H, pyrimidine-
H), 8.24 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (100 MHz,
DMSO-d6): δ 20.8, 55.7, 112.7, 114.4, 117.2, 125.9, 126.3,
128.4, 128.7, 129.0, 129.7, 130.0, 130.7, 131.2, 135.3, 137.0,
142.1, 148.4, 154.2, 156.8, 158.7, 159.2, 164.4; Anal. calcd.
for C27H19N3O2S2 (481.5): C, 67.34; H, 3.98; N, 8.73;
found: C, 67.59; H, 4.25; N, 8.47%.
1H, thiophene-H5), 7.93 (d, J = 4.4 Hz, 1H, thiophene-
H3), 7.97 (s, 1H, pyrimidine-H), 8.23 (d, J = 8.8 Hz, 2H,
ArH); 13C-NMR (100 MHz, DMSO-d6): δ 55.7, 103.6,
111.4, 114.3, 115.7, 117.1, 123.7, 127.2, 128.4, 128.8, 129.1,
129.7, 130.1, 133.5, 136.4, 138.4, 142.2, 148.0, 154.2, 156.3,
158.9, 159.2, 165.1; Anal. calcd. for C27H16N4O2S2
(492.5): C, 65.84; H, 3.27; N, 11.37; found: C, 66.06; H,
3.02; N, 11.51%.
7-(4-Methoxyphenyl)-3-(4-nitrophenyl)-9-(thiophen-2-yl)
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (4f )
Yellow solid (dioxane); Yield 1.46 g, 57%; m.p. 278–
280ꢀC; IR (υ cmꢁ1): 1669 (CO); 1H-NMR (400 MHz,
DMSO-d6): δ 3.85 (s, 3H, p-OCH3), 7.11 (d, J = 8.8 Hz,
2H, ArH), 7.35 (t, J = 4.4 Hz, 1H, thiophene-H4), 7.81 (s,
1H, pyridine-H), 7.84 (d, J = 8.0 Hz, 2H, ArH), 7.95 (d,
J = 2.4 Hz, 1H, thiophene-H5), 7.98 (d, J = 4.4 Hz, 1H,
thiophene-H3), 8.04 (s, 1H, pyrimidine-H), 8.24 (d,
J = 8.8 Hz, 2H, ArH), 8.30 (d, J = 8.0 Hz, 2H, ArH); 13C-
NMR (100 MHz, DMSO-d6): δ 55.6, 112.8, 114.5, 117.3,
124.3, 125.8, 126.8, 128.4, 128.7, 129.1, 129.9, 130.2, 136.9,
141.4, 141.7, 142.3, 147.6, 153.8, 155.9, 159.2, 159.6, 166.2;
Anal. calcd. for C26H16N4O4S2 (512.5): C, 60.93; H,
3.15; N, 10.93; found: C, 61.21; H, 3.00; N, 10.65%.
3,7-Bis(4-methoxyphenyl)-9-(thiophen-2-yl)pyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (4c)
Yellow solid (dioxane); Yield 2.19 g, 88%; m.p. 254–
257ꢀC; IR (υ cmꢁ1): 1668 (CO); 1H-NMR (400 MHz,
DMSO-d6): δ 3.82 (s, 3H, p-OCH3), 3.85 (s, 3H, p-OCH3),
7.05 (d, J = 8.4 Hz, 2H, ArH), 7.10 (d, J = 8.8 Hz, 2H,
ArH), 7.34 (t, J = 4.4 Hz, 1H, thiophene-H4), 7.38 (d,
J = 8.4 Hz, 2H, ArH), 7.80 (s, 1H, pyridine-H), 7.93 (d,
J = 2.4 Hz, 1H, thiophene-H5), 7.96 (d, J = 4.4 Hz, 1H,
thiophene-H3), 8.01 (s, 1H, pyrimidine-H), 8.20 (d,
J = 8.8 Hz, 2H, ArH); 13C-NMR (100 MHz, DMSO-d6): δ
55.3, 55.7, 112.8, 114.2, 114.9, 117.5, 126.7, 127.0, 128.2,
128.5, 128.8, 129.6, 130.1, 130.8, 136.8, 141.3, 147.6, 153.7,
155.6, 156.2, 158.7, 159.3, 165.2; Anal. calcd. for
C27H19N3O3S2 (497.5): C, 65.17; H, 3.85; N, 8.44;
found: C, 64.90; H, 3.59; N, 8.71%.
Ethyl 4-(7-(4-methoxyphenyl)-4-oxo-9-(thiophen-2-yl)
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)
benzoate (4 g)
3-(4-Chlorophenyl)-7-(4-methoxyphenyl)-9-(thiophen-
2-yl)pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-
one (4d)
Yellow solid (dioxane); Yield 1.70 g, 63%; m.p. 242–
245ꢀC; IR (υ cmꢁ1): 1731, 1667 (2 CO); 1H-NMR
(400 MHz, DMSO-d6): δ 1.39 (t, J = 7.2 Hz, 3H, CH3CH2),
3.85 (s, 3H, p-OCH3), 4.36 (q, J = 7.2 Hz, 2H,
CH3CH2), 7.10 (d, J = 8.8 Hz, 2H, ArH), 7.32 (t,
J = 4.4 Hz, 1H, thiophene-H4), 7.55 (d, J = 8.0 Hz, 2H,
ArH), 7.81 (s, 1H, pyridine-H), 7.92 (d, J = 2.4 Hz, 1H,
thiophene-H5), 7.94 (d, J = 4.4 Hz, 1H, thiophene-H3),
8.04 (s, 1H, pyrimidine-H), 8.09 (d, J = 8.0 Hz, 2H, ArH),
8.26 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (100 MHz,
DMSO-d6): δ 14.1, 55.8, 61.1, 112.5, 114.4, 117.1, 121.5,
123.9, 126.4, 128.5, 128.7, 128.9, 129.6, 129.9, 131.6, 136.5,
138.6, 142.2, 147.7, 154.2, 156.0, 159.1, 159.3, 164.3, 166.4
(CO); Anal. calcd. for C29H21N3O4S2 (539.6): C, 64.55; H,
3.92; N, 7.79; found: C, 64.28; H, 4.13; N, 7.96%.
Pale yellow solid (dioxane); Yield 2.13 g, 85%; m.p. 258–
260ꢀC; IR (υ cmꢁ1): 1669 (CO); 1H-NMR (400 MHz,
DMSO-d6): δ 3.85 (s, 3H, p-OCH3), 7.09 (d, J = 8.8 Hz,
2H, ArH), 7.34 (t, J = 4.4 Hz, 1H, thiophene-H4), 7.45 (d,
J = 8 Hz, 2H, ArH), 7.52 (d, J = 8 Hz, 2H, ArH), 7.85 (s,
1H, pyridine-H), 7.93 (d, J = 2.4 Hz, 1H, thiophene-H5),
7.96 (d, J = 4.4 Hz, 1H, thiophene-H3), 7.99 (s, 1H,
pyrimidine-H), 8.26 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR
(100 MHz, DMSO-d6): δ 55.7, 111.9, 114.5, 117.4, 126.8,
128.4, 128.7, 128.9, 129.0, 129.5, 129.9, 130.4, 132.8, 136.0,
137.1, 142.4, 147.5, 153.9, 155.8, 158.7, 159.5, 165.4; Anal.
calcd. for C26H16ClN3O2S2 (502.0): C, 62.21; H, 3.21; N,
8.37; found: C, 61.95; H, 3.48; N, 8.56%.
4-(7-(4-Methoxyphenyl)-4-oxo-9-(thiophen-2-yl)pyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-3(4H)-yl)
benzonitrile (4e)
7-(4-Methoxyphenyl)-3-(4-phenylthiazol-2-yl)-
9-(thiophen-2-yl)pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6a)
Yellow solid (dioxane); Yield 1.48 g, 60%; m.p. 244–
247ꢀC; IR (υ cmꢁ1): 2224 (CN), 1666 (CO); 1H-NMR
(400 MHz, DMSO-d6): δ 3.86 (s, 3H, p-OCH3), 7.08 (d,
J = 8.8 Hz, 2H, ArH), 7.32 (t, J = 4.4 Hz, 1H, thiophene-
H4), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.72 (d, J = 8.0 Hz,
2H, ArH), 7.83 (s, 1H, pyridine-H), 7.91 (d, J = 2.4 Hz,
Yellow solid (DMF/ethanol mixture); Yield 2.17 g, 79%;
1
m.p. 240ꢀC; IR (υ cmꢁ1): 1669 (CO); H-NMR (400 MHz,
DMSO-d6): δ 3.86 (s, 3H, p-OCH3), 7.10 (d, J = 8.8 Hz,
2H, ArH), 7.34 (t, J = 4.4 Hz, 1H, thiophene-H4), 7.41 (t,
J = 7.6 Hz, 1H, ArH), 7.46 (t, J = 7.6 Hz, 2H, ArH), 7.77
(s, 1H, thiazole-H), 7.84 (s, 1H, pyridine-H), 7.88 (d,

8
MOHAMED TELEB ET AL.
J = 7.6 Hz, 2H, ArH), 7.94 (d, J = 2.4 Hz, 1H, thiophene-
H5), 7.97 (d, J = 4.4 Hz, 1H, thiophene-H3), 8.03 (s, 1H,
pyrimidine-H), 8.24 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR
(100 MHz, DMSO-d6): δ 55.8, 112.2, 112.8, 114.6, 117.3,
126.3, 126.6, 128.2, 128.4, 128.7, 128.9, 129.3, 129.7, 130.2,
133.1, 137.0, 141.4, 147.3, 150.7, 152.4, 154.2, 155.8, 159.2,
160.2, 166.1; Anal. calcd. for C29H18N4O2S3 (550.6): C,
63.25; H, 3.29; N, 10.17; found: C, 62.98; H,
3.54; N, 9.92%.
(400 MHz, DMSO-d6): δ 3.84 (s, 3H, p-OCH3), 7.08 (d,
J = 8.8 Hz, 2H, ArH), 7.32 (t, J = 4.4 Hz, 1H, thiophene-
H4), 7.49 (d, J = 8.0 Hz, 2H, ArH), 7.61 (d, J = 8.0 Hz,
2H, ArH), 7.81 (s, 1H, thiazole-H), 7.85 (s, 1H, pyridine-
H), 7.96 (d, J = 2.4 Hz, 1H, thiophene-H5), 8.00 (d,
J = 4.4 Hz, 1H, thiophene-H3), 8.05 (s, 1H, pyrimidine-
H), 8.17 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (100 MHz,
DMSO-d6): δ 55.7, 112.9, 113.6, 114.4, 116.6, 126.6, 127.6,
128.4, 128.6, 128.9, 129.2, 129.9, 130.4, 132.2, 135.9, 136.9,
142.1, 146.8, 150.9, 152.6, 154.4, 155.6, 159.3, 160.1, 166.4;
Anal. calcd. for C29H17ClN4O2S3 (585.1): C, 59.53; H,
2.93; N, 9.58; found: C, 59.80; H, 3.20; N, 9.32%.
7-(4-Methoxyphenyl)-9-(thiophen-2-yl)-3-(4-(p-tolyl)
thiazol-2-yl)pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4
(3H)-one (6b)
Yellow solid (DMF / ethanol mixture); Yield 2.31 g, 82%;
m.p. 252–254ꢀC; IR (υ cmꢁ1): 1667 (CO); 1H-NMR
(400 MHz, DMSO-d6): δ 2.39 (s, 3H, p-CH3), 3.84 (s, 3H,
p-OCH3), 7.07 (d, J = 8.8 Hz, 2H, ArH), 7.29 (d,
J = 8.0 Hz, 2H, ArH), 7.34 (t, J = 4.4 Hz, 1H, thiophene-
H4), 7.74 (s, 1H, thiazole-H), 7.82 (s, 1H, pyridine-H),
7.85 (d, J = 8.0 Hz, 2H, ArH), 7.95 (d, J = 2.4 Hz, 1H,
thiophene-H5), 7.97 (d, J = 4.4 Hz, 1H, thiophene-H3),
8.06 (s, 1H, pyrimidine-H), 8.22 (d, J = 8.8 Hz, 2H, ArH);
13C-NMR (100 MHz, DMSO-d6): δ 20.4, 55.7, 112.8, 113.0,
114.4, 116.9, 126.0, 126.4, 128.3, 128.6, 128.8, 129.0, 129.8,
130.5, 131.3, 136.7, 139.2, 141.7, 147.4, 151.0, 152.6, 153.8,
155.5, 159.0, 159.9, 165.8; Anal. calcd. for C30H20N4O2S3
(564.7): C, 63.81; H, 3.57; N, 9.92; found: C, 64.05; H,
3.69; N, 10.20%.
7-(4-Methoxyphenyl)-3-(4-(4-nitrophenyl)thiazol-2-yl)-
9-(thiophen-2-yl)pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6e)
Yellow solid (DMF/ethanol mixture); Yield 2.29 g, 77%;
m.p. 284–287ꢀC; IR (υ cmꢁ1): 1667 (CO); 1H-NMR
(400 MHz, DMSO-d6): δ 3.83 (s, 3H, p-OCH3), 7.09 (d,
J = 8.8 Hz, 2H, ArH), 7.33 (t, J = 4.4 Hz, 1H, thiophene-
H4), 7.83 (s, 1H, thiazole-H), 7.86 (s, 1H, pyridine-H),
7.92 (d, J = 2.4 Hz, 1H, thiophene-H5), 7.96 (d,
J = 4.4 Hz, 1H, thiophene-H3), 8.00 (s, 1H, pyrimidine-
H), 8.09 (d, J = 8.0 Hz, 2H, ArH), 8.25 (d, J = 8.8 Hz, 2H,
ArH), 8.30 (d, J = 8.0 Hz, 2H, ArH); 13C-NMR (100 MHz,
DMSO-d6): δ 55.6, 112.6, 113.1, 114.3, 117.0, 123.9, 126.2,
126.6, 128.6, 128.9, 129.2, 129.9, 130.6, 135.9, 137.4, 141.8,
147.6, 148.5, 151.2, 152.9, 154.6, 156.3, 159.4, 159.9, 166.3;
Anal. calcd. for C29H17N5O4S3 (595.6): C, 58.48; H,
2.88; N, 11.76; found: C, 58.21; H, 3.12; N, 11.98%.
7-(4-Methoxyphenyl)-3-(4-(4-methoxyphenyl)thiazol-
2-yl)-9-(thiophen-2-yl)pyrido[30,20:4,5]thieno[3,2-d]
pyrimidin-4(3H)-one (6c)
3-(Benzo[d]thiazol-2-yl)-7-(4-methoxyphenyl)-
9-(thiophen-2-yl)pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (8)
Yellow solid (DMF/ethanol mixture); Yield 2.44 g, 84%;
1
m.p. 272ꢀC; IR (υ cmꢁ1): 1669 (CO); H-NMR (400 MHz,
DMSO-d6): δ 3.82 (s, 3H, p-OCH3), 3.86 (s, 3H, p-OCH3),
7.02 (d, J = 8.0 Hz, 2H, ArH), 7.07 (d, J = 8.8 Hz, 2H,
ArH), 7.33 (t, J = 4.4 Hz, 1H, thiophene-H4), 7.58 (d,
J = 8.0 Hz, 2H, ArH), 7.80 (s, 1H, thiazole-H), 7.86 (s,
1H, pyridine-H), 7.93 (d, J = 2.4 Hz, 1H, thiophene-H5),
7.96 (d, J = 4.4 Hz, 1H, thiophene-H3), 8.02 (s, 1H,
pyrimidine-H), 8.24 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR
(100 MHz, DMSO-d6): δ 55.5, 55.8, 112.9, 113.2, 114.0,
114.6, 117.6, 126.5, 127.0, 128.1, 128.6, 128.8, 129.1, 129.7,
130.2, 136.3, 141.4, 147.0, 151.3, 152.3, 153.9, 156.2, 159.1,
159.4, 159.9, 166.3; Anal. calcd. for C30H20N4O3S3
(580.7): C, 62.05; H, 3.47; N, 9.65; found: C, 61.79; H,
3.62; N, 9.83%.
Pale yellow solid (dioxane); Yield 2.04 g, 78%; m.p. 276–
278ꢀC; IR (υ cmꢁ1): 1668 (CO); 1H-NMR (400 MHz, DMSO-
d6): δ 3.84 (s, 3H, p-OCH3), 7.08 (d, J = 8.8 Hz, 2H, ArH),
7.32 (t, J = 4.4 Hz, 1H, thiophene-H4), 7.37 (t, J = 7.6 Hz,
1H, H60), 7.44 (t, J = 7.6 Hz, 1H, H50), 7.82 (d, J = 7.6 Hz,
1H, H70), 7.85 (s, 1H, pyridine-H), 7.89 (d, J = 7.6 Hz, 1H,
H40), 7.92 (d, J = 2.4 Hz, 1H, thiophene-H5), 7.96 (d,
J = 4.4 Hz, 1H, thiophene-H3), 8.04 (s, 1H, pyrimidine-H),
8.26 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (100 MHz, DMSO-
d6): δ 55.7, 112.7, 114.5, 116.4, 120.5, 120.6, 123.3, 125.8,
126.6, 128.4, 128.7, 129.0, 129.8, 130.3, 132.2, 136.6, 141.8,
148.3, 151.8, 153.5, 154.4, 156.3, 158.1, 159.2, 165.8; Anal.
calcd. for C27H16N4O2S3 (524.6): C, 61.81; H, 3.07; N, 10.68;
found: C, 62.02; H, 2.85; N, 10.42%.
3-(4-(4-Chlorophenyl)thiazol-2-yl)-7-(4-methoxyphenyl)-
9-(thiophen-2-yl)pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (6d)
7-(4-Methoxyphenyl)-3-methyl-9-(thiophen-2-yl)pyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (10a)
Pale yellow solid (dioxane/ethanol mixture); Yield 1.86 g,
Yellow solid (DMF/ethanol mixture); Yield 2.37 g, 81%;
m.p. 274–276ꢀC; IR (υ cmꢁ1): 1666 (CO); 1H-NMR
92%; m.p. 188–190ꢀC; IR (υ cmꢁ1): 1672 (CO); H-NMR
1

MOHAMED TELEB ET AL.
9
(400 MHz, DMSO-d6): δ 3.72 (s, 3H, NCH3), 3.86 (s, 3H,
p-OCH3), 7.10 (d, J = 8.8 Hz, 2H, ArH), 7.35 (t,
J = 4.4 Hz, 1H, thiophene-H4), 7.86 (s, 1H, pyridine-H),
7.95 (d, J = 2.4 Hz, 1H, thiophene-H5), 7.99 (d,
J = 4.4 Hz, 1H, thiophene-H3), 8.11 (s, 1H, pyrimidine-
H), 8.26 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (100 MHz,
DMSO-d6): δ 32.1, 55.8, 113.1, 114.7, 116.8, 126.3, 128.6,
128.8, 129.1, 130.0, 130.5, 136.9, 142.4, 148.6, 154.8, 156.8,
158.7, 159.3, 165.4; Anal. calcd. for C21H15N3O2S2
(405.4): C, 62.20; H, 3.73; N, 10.36; found: C, 61.95; H,
3.99; N, 10.21%.
J = 2.4 Hz, 2H, 2 thiophene-H5), 7.99 (d, J = 4.4 Hz, 2H,
2 thiophene-H3), 8.14 (s, 2H, 2 pyrimidine-H), 8.24 (d,
J = 8.8 Hz, 4H, ArH); 13C-NMR (100 MHz, DMSO-d6): δ
27.2, 43.5, 55.8, 113.2, 114.3, 116.5, 126.3, 128.6, 128.8,
129.0, 129.7, 130.4, 136.9, 142.0, 148.6, 154.3, 155.9, 158.7,
159.3, 165.2; Anal. calcd. for C43H30N6O4S4 (822.9): C,
62.76; H, 3.67; N, 10.21; found: C, 62.99; H,
3.42; N, 9.97%.
3,30-(Butane-1,4-diyl)bis(7-(4-methoxyphenyl)-
9-(thiophen-2-yl)pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one) (12b)
3-Ethyl-7-(4-methoxyphenyl)-9-(thiophen-2-yl)pyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (10b)
Pale yellow solid (dioxane/ethanol mixture); Yield 1.89 g,
Yellow solid (dioxane); Yield 3.77 g, 90%; m.p. 208–
210ꢀC; IR (υ cmꢁ1): 1671 (CO); 1H-NMR (400 MHz,
DMSO-d6): δ 1.70 (t, J = 6.8 Hz, 4H, 2 NCH2CH2), 3.85
(s, 6H, 2 p-OCH3), 4.17 (t, J = 6.8 Hz, 4H, 2 NCH2), 7.09
(d, J = 8.8 Hz, 4H, ArH), 7.34 (t, J = 4.4 Hz, 2H, 2 thio-
phene-H4), 7.83 (s, 2H, 2 pyridine-H), 7.93 (d, J = 2.4 Hz,
2H, 2 thiophene-H5), 7.95 (d, J = 4.4 Hz, 2H, 2 thio-
phene-H3), 8.13 (s, 2H, 2 pyrimidine-H), 8.26 (d,
J = 8.8 Hz, 4H, ArH); 13C-NMR (100 MHz, DMSO-d6): δ
25.9, 45.2, 55.7, 113.5, 114.6, 116.7, 126.6, 128.5, 128.9,
129.2, 129.9, 130.8, 136.6, 141.8, 148.3, 153.9, 155.6, 158.4,
159.2, 164.8; Anal. calcd. for C44H32N6O4S4 (837.0): C,
63.14; H, 3.85; N, 10.04; found: C, 62.87; H,
4.04; N, 9.76%.
1
90%; m.p. 194–196ꢀC; IR (υ cmꢁ1): 1673 (CO); H-NMR
(400 MHz, DMSO-d6): δ 1.34 (t, J = 7.2 Hz, 3H, NCH2CH3),
3.85 (s, 3H, p-OCH3), 4.12 (q, J = 7.2 Hz, 2H, NCH2CH3),
7.08 (d, J = 8.8 Hz, 2H, ArH), 7.32 (t, J = 4.4 Hz, 1H,
thiophene-H4), 7.83 (s, 1H, pyridine-H), 7.94 (d, J = 2.4 Hz,
1H, thiophene-H5), 7.97 (d, J = 4.4 Hz, 1H, thiophene-H3),
8.13 (s, 1H, pyrimidine-H), 8.25 (d, J = 8.8 Hz, 2H, ArH);
13C-NMR (100 MHz, DMSO-d6): δ 13.4, 40.7, 55.7, 112.9,
114.6, 116.9, 126.5, 128.4, 128.7, 129.0, 129.9, 130.7, 136.6,
142.2, 148.3, 154.4, 156.3, 158.2, 159.5, 165.7; Anal. calcd.
for C22H17N3O2S2 (419.5): C, 62.99; H, 4.08; N, 10.02;
found: C, 63.23; H, 3.87; N, 10.28%.
Synthesis of ethyl 3-(([dimethylamino]methylene)
amino)-6-(4-methoxyphenyl)-4-(thiophen-2-yl)thieno
[2,3-b]pyridine-2-carboxylate (13)
4.2.2 | General procedure for the synthesis
of bis(pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4
(3H)-one) hybrids 12
A
mixture of ethyl 3-aminothieno[2,3-b]pyridine-
2-carboxylate 1 (5 mmol) and DMF-DMA 2 (6 mmol) in
dioxane (10 ml) was irradiated by microwaves with a
power of 300 W to reach a reaction temperature of 110ꢀC
under autogenerated pressure for 15 min. The reaction
mixture was cooled and then 2 ml of ethanol was added
drop wisely. The product was collected by filtration,
washed with cold ethanol, dried and then recrystallized
from dioxane/ethanol mixture as yellow solid; Yield
2.21 g, 95%; m.p. 182ꢀC; IR (υ cmꢁ1): 1723 (CO); 1H-
NMR (400 MHz, DMSO-d6): δ 1.32 (t, 3H, J = 7.2 Hz,
CH2CH3), 3.07 (s, 3H, NCH3), 3.17 (s, 3H, NCH3), 3.85 (s,
3H, p-OCH3), 4.26 (q, J = 7.2 Hz, 2H, CH2CH3), 7.08 (d,
J = 8.8 Hz, 2H, ArH), 7.32 (t, J = 4.4 Hz, 1H, thiophene-
H4), 7.41 (s, 1H, CH = N(CH3)2), 7.48 (d, J = 2.4 Hz, 1H,
thiophene-H5), 7.77 (s, 1H, pyridine-H), 7.91 (d,
J = 4.4 Hz, 1H, thiophene-H3), 8.20 (d, J = 8.8 Hz, 2H,
ArH); Anal. calcd. for C24H23N3O3S2 (465.5): C, 61.91; H,
4.98; N, 9.03; found: C, 62.13; H, 5.24; N, 8.77%.
A
mixture of ethyl 3-aminothieno[2,3-b]pyridine-
2-carboxylate 1 (10 mmol), DMF-DMA 2 (12 mmol) and
the appropriate of bis(amines) 11a,b (5 mmol) in dioxane
(10 ml) was irradiated by microwaves with a power of
300 W to reach a reaction temperature of 110ꢀC under
autogenerated pressure for 30 min. The reaction mixture
was cooled and then 2 ml of ethanol was added drop
wisely. The product was collected by filtration, washed
with cold ethanol, dried and then recrystallized from the
proper solvent.
3,30-(Propane-1,3-diyl)bis(7-(4-methoxyphenyl)-
9-(thiophen-2-yl)pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one) (12a)
Yellow solid (dioxane); Yield 3.62 g, 88%; m.p. 212–
215ꢀC; IR (υ cmꢁ1): 1670 (CO); 1H-NMR (400 MHz,
DMSO-d6): δ 1.92 (quint, J = 6.8 Hz, 2H, NCH2CH2),
3.84 (s, 6H, 2 p-OCH3), 4.19 (t, J = 6.8 Hz, 4H, 2 NCH2),
7.07 (d, J = 8.8 Hz, 4H, ArH), 7.33 (t, J = 4.4 Hz, 2H,
2 thiophene-H4), 7.83 (s, 2H, 2 pyridine-H), 7.95 (d,
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are avail-
able in the supplementary material of this article.

10
MOHAMED TELEB ET AL.
[22] S. S. Maurya, S. I. Khan, A. Bahuguna, D. Kumar, D. S. Rawat,
Eur. J. Med. Chem. 2017, 129, 175.
[23] P. Taslimi, A. Sujayev, F. Turkan, E. Garibov, Z. Huyut, V.
ORCID
Ahmed E. M. Mekky https://orcid.org/0000-0002-8226-
010X
Sherif M. H. Sanad https://orcid.org/0000-0002-0186-
6418
_
Farzaliyev, S. Mamedova, I. Gulçin, J. Biochem. Mol. Toxicol.
2018, 32, e22019.
[24] M. A. Abdelgawad, R. B. Bakr, A. A. Azouz, Bioorg. Chem.
2018, 77, 339.
REFERENCES
[25] R. H. Abd El-Aleam, R. F. George, G. S. Hassan, H. M. Abdel-
Rahman, Bioorg. Chem. 2020, 94, 103411.
[26] S. M. H. Sanad, M. A. E. Hawass, A. A. M. Ahmed, M. A. A.
Elneairy, Synth. Commun.. 2018, 48, 1847. https://doi.org/10.
1080/00397911.2018.1468911, 1847.
[1] M. M. Kandeel, H. M. Refaat, A. E. Kassab, I. G. Shahin, T. M.
Abdelghany, Eur. J. Med. Chem. 2015, 90, 620.
[2] L. H. Amin, T. Z. Shawer, A. M. El-Naggar, H. M. El-Sehrawi,
Bioorg. Chem. 2019, 91, 103159.
[27] S. M. H. Sanad, M. A. E. Hawass, A. A. M. Ahmed, M. A. A.
Elneairy, J. Heterocycl. Chem.. 2018, 55, 2823. https://doi.org/
10.1002/jhet.3352, 55, 2823.
[28] S. M. H. Sanad, A. M. Abdel Fattah, F. A. Attaby, M. A. A.
Elneairy, J. Heterocycl. Chem. 2019, 56, 651. https://doi.org/10.
1002/jhet.3444
[29] S. M. H. Sanad, A. M. Abdel Fattah, F. A. Attaby, M. A. A.
Elneairy, J. Heterocycl. Chem.. 2019, 56, 1588. https://doi.org/
10.1002/jhet.3537, 56, 1588.
[30] I. V. Dyachenko, V. D. Dyachenko, P. V. Dorovatovsky, V. N.
Khrustalev, V. G. Nenajdenko, Russ. J. Org. Chem. 2020, 56, 974.
[31] S. N. Sirakanyan, D. Spinelli, A. Geronikaki, A. A.
Hovakimyan, Tetrahedron 2015, 71, 7638.
[32] G. Z. Zheng, P. Bhatia, J. Daanen, T. Kolasa, M. Patel, S.
Latshaw, O. F. El Kouhen, R. Chang, M. E. Uchic, L. Miller,
M. Nakane, S. G. Lehto, M. P. Honore, R. B. Moreland, J. D.
Brioni, A. O. Stewart, J. Med. Chem. 2005, 48, 7374.
[33] D. D. Schoepp, D. E. Jane, J. A. Monn, Neuropharmacology
1999, 38, 1431.
[3] M. Rashid, A. Husain, M. Shaharyar, R. Mishra, A. Hussain,
O. Afzal, Eur. J. Med. Chem. 2014, 83, 630.
[4] N. Revathi, M. Sankarganesh, J. Rajesh, J. D. Raja, J. Fluoresc.
2017, 27, 1801.
[5] I. Kostova, P. Y. Atanasov, Curr. Org. Chem. 2017, 21, 2096.
[6] A. M. Farghaly, O. M. AboulWafa, Y. A. Elshaier, W. A.
Badawi, H. H. Haridy, H. A. Mubarak, Med. Chem. Res. 2019,
28, 360.
[7] H. A. Katouah, H. E. Gaffer, ChemistrySelect 2019, 4, 6250.
[8] A. Okesli, C. Khosla, M. C. Bassik, Curr. Opin. Biotechnol.
2017, 48, 127.
[9] S. Bai, S. Liu, Y. Zhu, Q. Wu, Tetrahedron Lett. 2018, 59, 3179.
[10] S. Shahidpour, F. Panahi, R. Yousefi, M. Nourisefat, M.
Nabipoor, A. Khalafi-Nezhad, Med. Chem. Res. 2015, 24, 3086.
[11] S. V. Hese, R. J. Meshram, R. D. Kamble, P. P. Mogle, K. K.
Patil, S. S. Kamble, R. N. Gacche, B. S. Dawane, Med. Chem.
Res. 2017, 26, 805.
[12] H. u. Rashid, M. A. U. Martines, A. P. Duarte, J. Jorge, S.
Rasool, R. Muhammad, N. Ahmad, M. N. Umar, RSC Adv.
2021, 11, 6060.
[34] J. Taltavull, J. Serrat, J. Gracia, A. Gavalda, M. Andrés, M.
ꢀ
Cordoba, M. Miralpeix, D. Vilella, J. Beleta, H. Ryder, L.
[13] N. Atatreh, A. M. Youssef, M. A. Ghattas, M. Al Sorkhy, S.
Alrawashdeh, K. B. Al-Harbi, I. M. El-Ashmawy, T. I.
Almundarij, A. A. Abdelghani, A. S. Abd-El-Aziz, Bioorg.
Chem. 2019, 86, 393.
Pagès, J. Med. Chem. 2010, 53, 6912.
[35] Y. M. A. Aziz, M. M. Said, H. A. El Shihawy, K. A. Abouzid,
Bioorg. Chem. 2015, 60, 1.
[36] Y. Loidreau, E. Deau, P. Marchand, M. R. Nourrisson, C. Logé,
G. Coadou, N. Loaëc, L. Meijer, T. Besson, Eur. J. Med. Chem.
2015, 92, 124.
[37] S. N. Sirakanyan, D. Spinelli, A. Geronikaki, V. G. Kartsev, E. K.
Hakobyan, A. A. Hovakimyan, Synth. Commun. 2019, 49, 1262.
[38] A. Agarwal, S. Louise-May, J. A. Thanassi, S. D. Podos, J. Cheng,
C. Thoma, C. Liu, J. A. Wiles, D. M. Nelson, A. S. Phadke, B. J.
Bradbury, Bioorg. Med. Chem. Lett. 2007, 17, 2807.
[14] R. B. Bakr, A. A. Azouz, K. R. Abdellatif, J. Enzyme Inhib.
Med. Chem. 2016, 31, 6.
[15] M. Emam, M. A. El Raey, A. E. El-Haddad, S. A. El Awdan,
A. G. M. Rabie, M. A. El-Ansari, M. Sobeh, S. M. Osman, M.
Wink, Molecules 2019, 24, 138.
[16] Y. F. Sui, D. Li, J. Wang, R. R. Y. Bheemanaboina, M. F.
Ansari, L. L. Gan, C. H. Zhou, Bioorg. Med. Chem. Lett. 2020,
30, 126982.
[39] L. Kjellerup, S. Gordon, K. O. Cohrt, W. D. Brown, A. T.
Fuglsang, L. A.-M. Winther, Antimicrob. Agents Chemother.
2017, 61, 1.
[40] Y. Loidreau, M. R. Nourrisson, C. Fruit, C. Corbière, P.
Marchand, T. Besson, Pharmaceuticals 2020, 13, 202.
[41] S. N. Sirakanyan, D. Spinelli, A. Geronikaki, E. K. Hakobyan,
H. Sahakyan, E. Arabyan, H. Zakaryan, L. E. Nersesyan, A. S.
Aharonyan, I. S. Danielyan, R. E. Muradyan, Molecules 2019,
24, 3952.
[42] R. Mishra, A. K. Panday, L. H. Choudhury, J. Pal, R.
Subramanian, A. Verma, Eur. J. Org. Chem. 2017, 2017, 2789.
[43] L. Li, H. Xu, L. Dai, J. Xi, L. Gao, L. Rong, Tetrahedron 2017,
73, 5358.
[17] B. Chandrasekaran, S. Cherukupalli, S. Karunanidhi, A.
Kajee, R. R. Aleti, N. Sayyad, B. Kushwaha, S. R. Merugu,
K. P. Mlisana, R. Karpoormath, J. Mol. Struct. 2019, 1183, 246.
[18] S. M. H. Sanad, A. A. M. Ahmed, A. E. M. Mekky,
J. Heterocycl. Chem. 2020, 57, 590. https://doi.org/10.1002/jhet.
3789, 57, 590.
[19] G. Wang, J. Wan, Y. Hu, X. Wu, M. Prhavc, N. Dyatkina, V. K.
Rajwanshi, D. B. Smith, A. Jekle, A. Kinkade, J. A. Symons, Z.
Jin, J. Deval, Q. Zhang, Y. Tam, S. Chanda, L. Blatt, L.
Beigelman, J. Med. Chem. 2016, 59, 4611.
[20] I. M. Trist, G. Nannetti, C. Tintori, A. L. Fallacara, D.
Deodato, B. Mercorelli, G. Palù, M. Wijtmans, T. Gospodova,
E. Edink, M. Verheij, J. Med. Chem. 2016, 59, 2688.
[21] S. S. Maurya, A. Bahuguna, S. I. Khan, D. Kumar, R. Kholiya,
D. S. Rawat, Eur. J. Med. Chem. 2019, 162, 277.
ꢀ
ꢀ
[44] I. A. Ibarra, A. Islas-Jacome, E. Gonzalez-Zamora, Org. Biomol.
Chem. 2018, 16, 1402.

MOHAMED TELEB ET AL.
11
[45] S. K. Krishnammagari, B. G. Cho, J. T. Kim, Y. T. Jeong, Synth.
Commun. 2018, 48, 2663.
[46] R. C. Cioc, E. Ruijter, R. V. A. Orru, Green Chem. 2014, 16,
2958.
[47] A. Kulkarni, B. Torok, Green Chem. 2010, 12, 875. https://doi.
org/10.1039/C001076F
[48] M. A. M. Teleb, H. M. Hassaneen, I. A. Abdelhamid, F. M.
Saleh, Synth. Commun. 2021, 51, 553. https://doi.org/10.1080/
00397911.2020.1839101
[57] A. E. M. Mekky, S. M. H. Sanad, A. Y. Said, M. A. A. Elneairy,
Synth. Commun. 2020, 50, 2376. https://doi.org/10.1080/
00397911.2020.1778033
[58] M. A. M. Gad-Elkareem, A. M. Abdel-Fattah, M. A. A.
Elneairy, Phosphor. Sulfur Relat. Elem. 2006, 181, 891.
[59] M. Ge Zayda, A. A. Abdel-Rahman, F. A. El-Essawy, ACS
Omega 2020, 5, 6163.
[60] A. Y. Hassan, E. M. Husseiny, J. Heterocycl. Chem. 2019, 56,
2419.
[49] A. E. M. Mekky, M. S. M. Ahmed, S. M. H. Sanad, Z. A.
Abdallah, Synth. Commun. 2021, 51, 1085. https://doi.org/10.
1080/00397911.2020.1867745
[50] S. M. H. Sanad, A. E. M. Mekky, Synth. Commun. 2021, 51,
611. https://doi.org/10.1080/00397911.2020.1846748
[51] S. M. H. Sanad, A. E. M. Mekky, J. Iran. Chem. Soc. 2021, 18,
213. https://doi.org/10.1007/s13738-020-02018-6
[52] A. E. M. Mekky, S. M. H. Sanad, Mendeleev Commun. 2021,
31, 370.
[53] A. E. M. Mekky, S. M. H. Sanad, J. Heterocycl. Chem.. 2020, 57,
4278. https://doi.org/10.1002/jhet.4134, 57, 4278.
[54] A. E. M. Mekky, S. M. H. Sanad, Bioorg. Chem. 2020, 102,
104094. https://doi.org/10.1016/j.bioorg.2020.104094
[55] I. A. Abdelhamid, M. A. E. Hawass, S. M. H. Sanad, A. H. M.
Elwahy, Arkivoc 2021, i, 162. https://doi.org/10.24820/ark.
5550190.p011.404
[61] V. V. Dabaeva, M. R. Bagdasaryan, A. S. Noravyan, Chem. Het-
erocycl. Compd. 2011, 47, 639.
[62] M. A. M. Gad-Elkareem, A. M. Abdel-Fattah, M. A. A.
Elneairy, J. Sulfur Chem. 2011, 32, 273.
[63] D. Toste, J. McNulty, I. W. J. Still, Synth. Commun. 1994, 24, 1617.
SUPPORTING INFORMATION
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in the Supporting Information section at the end of this
article.
How to cite this article: M. A. Mohamed Teleb,
A. E. M. Mekky, S. M. H. Sanad, J Heterocyclic
Chem 2021, 1. https://doi.org/10.1002/jhet.4313
[56] N. Bohm, U. Krasselt, S. Leistner, G. Wagner, Pharmazie 1992,
47, 897.