Synthesis and antimicrobial evaluation of new 2-pyridinone and 2-iminochromene derivatives containing morpholine moiety

Article abstract of DOI:10.1002/jhet.4335

As trail to overcome on the antimicrobial drug-resistance problems, new functionalized 2-pyridinone and 2-iminochromene derivatives bearing morpholine moiety were designed and synthesized. The 2-pyridinone derivatives were obtained through the cyclization of cyanoacetohydrazone of 4-morpholinylacetophenone with 1,3-dicarbonyl compounds, α,β-unsaturated nitriles or 2-(arylidene)malononitriles. The 2-iminochromene derivatives were synthesized through the ring closure of cyanoacetohydrazonewith salicylaldehyde derivatives. The antibacterial and antifungal activities for the synthesized 2-pyridinone and 2-iminochromene derivatives were investigated. Most of the tested compounds showed moderate activity against P. vulgaris. Compounds 4a,b and 5a,b showed moderate activity against G ?ve bacteria. All iminochromene derivatives showed moderate activity against C. albicans. Compound 8c was the most active compound.

Full text of DOI:10.1002/jhet.4335

Received: 28 April 2021
DOI: 10.1002/jhet.4335
Revised: 20 June 2021
Accepted: 24 June 2021
A R T I C L E
Synthesis and antimicrobial evaluation of new 2-pyridinone
and 2-iminochromene derivatives containing morpholine
moiety
Mohamed A. Salem1,2
Abdullah Y. Alzahrani1
| Samir Y. Abbas3
| Mohamed H. Helal4
|
1Department of Chemistry, Faculty of
Science and Arts, King Khalid University,
Mohail, Saudi Arabia
2Chemistry Department, Faculty of
Science (Boys), Al-Azhar University, Nasr,
Egypt
3Department of Organometallic and
Organometalloid Chemistry, National
Research Centre, Cairo, Egypt
4Department of Chemistry, Faculty of Arts
and Science, Northern Border University,
Rafha, Saudi Arabia
Abstract
As trail to overcome on the antimicrobial drug-resistance problems, new
functionalized 2-pyridinone and 2-iminochromene derivatives bearing morpholine
moiety were designed and synthesized. The 2-pyridinone derivatives were obtained
through the cyclization of cyanoacetohydrazone of 4-morpholinylacetophenone
with 1,3-dicarbonyl compounds, α,β-unsaturated nitriles or 2-(arylidene)
malononitriles. The 2-iminochromene derivatives were synthesized through the
ring closure of cyanoacetohydrazonewith salicylaldehyde derivatives. The
antibacterial and antifungal activities for the synthesized 2-pyridinone and
2-iminochromene derivatives were investigated. Most of the tested compounds
showed moderate activity against P. vulgaris. Compounds 4a,b and 5a,b showed
moderate activity against G ꢀve bacteria. All iminochromene derivatives showed
moderate activity against C. albicans. Compound 8c was the most active
compound.
Correspondence
Samir Y. Abbas, Department of
Organometallic and Organometalloid
Chemistry, National Research Centre,
Dokki, Cairo 12622, Egypt.
Email: samiryoussef98@yahoo.com, sy.
abbas@nrc.sci.eg
Funding information
King Khalid University, Grant/Award
Number: R.G.P.1/231/41
1 | INTRODUCTION
which has great medicinal applications [11–13]. Many
morpholine derivatives possess diverse pharmacological
Due to the widespread use, inaccurate diagnosis and mis-
use of antimicrobial agents, many observation for drug-
resistant microbes have been reported [1,2]. For immuno-
compromised patients, treatment of drug-resistant
microbes represent major hindrance [3]. According to the
latest WHO's survey, about 500,000 people are antibiotic-
resistant among the total infected patients across 22 coun-
tries. To accomplish this problem, some strategies were
applied such as creation of novel pharmacophore. To get
powerful synergistic effect; researches were directed to
combine different pharmacophores in one structure [4–
10]. Morpholine moiety is a simple heterocyclic ring
activities. Morpholine derivatives have great attention to
design novel broad-spectra antimicrobial agents because
they have unique mechanism of action. Morpholine
nucleus is found in commercially available drugs. For
example, Linezolid as antibiotic is used to fight gram-
positive bacteria which are resistant to other drugs [14].
Amorolfine is used as antifungal drug for treatment of
the toe fungal infection and finger nails [15]. Also,
fenpropimorph is used in agriculture as fungicide. Large
numbers of compounds which contain pyridine moiety
are known in medicinal chemistry world as important
compounds. The cyanopyridone derivatives have shown
J Heterocyclic Chem. 2021;1–7.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

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SALEM ET AL.
to possess promising biological activities [16–20]. Pyri-
dine nucleus is found in commercially available antimi-
crobial drugs. For example, Isoniazid is used as a
tuberculostatic drug. Moreover, the ciclopiroxis a syn-
thetic antifungal drug that is used for treatment of skin
for superficial mycoses. It is especially effective in
treating Tinea versicolor. Chromene nucleus are of great
interest for their various biological and medicinal activi-
ties as well as their therapeutical applications [21–25].
Chromene nucleus is naturally occurring and they are
found in commercially available antimicrobial drugs. For
example, novobiocin is an antibiotic drug. Also,
clorobiocin is an aminocoumarin antibiotic.
signals at δ = 3.26 and 3.75 ppm formorpholine protons,
singlet signal at δ = 6.43 ppm for pyridine-H5. In addi-
tion, two doublet signals with two protons integral value
at δ = 7.03 and 7.90 ppm for phenylene AB protons
were assigned. One-pot multi-component reactions of
malononitrile, aliphatic aldehyde (namely, formalde-
hyde or acetaldehyde) and the derivative of
cyanoacetamide 3 in one molar ratio in ethanolic piperi-
dine under reflux condition afforded the 2-pyridinone
derivatives 5a and 5b, respectively.1H NMR spectrum of
pyridine-2-one derivative 5b showed at δ = 2.08 and
2.40 ppm two aliphatic singlet signals with three pro-
tons integral value assignable to two methyl protons.
Two singlet signals with four protons integral value
were displayed at δ = 3.22 and 3.75 ppm for morpholine
protons. The two doublet signals with two protons inte-
gral value at δ = 6.99 and 7.93 ppm for phenylene AB
protons were assigned. Broad exchangeable signal at
δ = 8.06 ppm was assigned for the amino protons. Simi-
larly, to the above reaction, one-pot, multi-component
reaction of malononitrile, aromatic aldehydes and
cyanoacetamide 3 in one molar ratio, in ethanolic piper-
idine gave the 1,2-dihydropyridine-2-one derivatives 6a-
d. Additionally, the 1,2-dihydropyridine-2-ones 6a-d can
be synthesized by heating cyanoacetamide 3 with the
corresponding 2-(arylidene)-malononitrile in ethanolic
Depending upon the above facts, it was aimed to syn-
thesize new 2-pyridinone and 2-iminochromene deriva-
tives containing morpholine moiety. These combination
was suggested; wish to discover new structures that may
have significant antimicrobial activity.
2 | RESULTS AND DISCUSSION
The cyanoacetohydrazone 3 as starting material was pre-
pared as illustrated in Scheme 1. At first,
4-morpholinylacetophenone 2 was prepared via the
nucleophilic replacement of fluorine atom at
1
4-fluoracetophenone
Cyanoacetohydrazone of 4-morpholinylacetophenone
was prepared through the condensation of
1
by morpholine ring [26].
piperidine under reflux. H NMR spectrum of pyridine-
2-one 6c, as representative example, showed at
δ = 3.24–3.31 and 3.70–3.80 ppm two multiplet signals
with four protons integral value for morpholine protons.
Two aliphatic signals at δ = 2.16 and 3.85 ppm with
three protons integral value were assigned to methyl
and methoxy protons, respectively. The four doublet sig-
nals with two protons integral value at δ = 7.04, 7.12,
7.52 and 7.97 ppm were assigned for two phenylene AB
protons. The broad exchangeable signal at δ = 8.14 ppm
was assigned for the amino protons. The creation of 6 is
proposed to create though the Michael addition of the
methyl function group of 3 to the activate olefinicbond
of 2-(arylidene)malononitrile to form Michael adduct
that was subjected to cyclize and loss of hydrogen mole-
cule to yield 6 (Scheme 2).
4-morpholinylacetophenone 2 with cyanoacetohydrazide.
It is well known that the reaction of cyanoacetamide
derivatives with either 1,3-dicarbonyl compounds or
α,β-unsaturated nitriles is easy and effective method for
creation derivatives of 2-pyridones [17,18]. Thus,
cyclocondensation of cyanoacetohydrazide 3 with acetyl
acetone or 1,3-diphenylpropane-1,3-dione under fusion
condition afforded the 2-pyridinone derivatives 4a,b
(Scheme 2). The structures of 2-pyridinones 4a,b were
proved by analytical and spectroscopic data. 1H NMR
spectrum of pyridinone 4a was characteristic by the
presence of three singlet signals at δ = 2.05, 2.21 and
2.37 ppm assignable for 3CH3 protons, two singlet
O
H
H3C
O
H3C
O
O
N
H3C
N
CN
N
H2N
CN
H
N
H
O
N
O
F
N
O
1
SCHEME 1 Synthesis of the starting
material cyanoacetohydrazide 3
2
3

SALEM ET AL.
3
O
N
R
CN
O
O
N
CN
CN
H3C
H3C
N
CN
N
H3C
N
R
CN
CN
O
O
O
H
N
R
R
R
H
R
H2N
piperidine, fusion
ethanol, piperidine,
reflux
N
4a, R = CH3
4b, R = Ph
N
N
5a, R = H
5b, R = CH3
O
O
O
3
O
N
CN
ethanol,
piperidine,
reflux
H3C
CN
CN
O
N
Ar
Ar
H
H2N
CN
NC
CN
or
N
6a, Ar = 4-F-C6H4
6b, Ar = 3-OCH3-C6H4
6c, Ar = 4-OCH3-C6H4
Ar
H
O
6d, Ar = 2,5-(OCH3)2-C6H3
6e
, Ar = N(CH3)2-C6H4
SCHEME 2 Synthesis of 2-pyridinone derivatives 4-6
SCHEME 3 Synthesis of
2-iminochromene derivatives
7 and 8a-e
O
O
H3C
N
CN
CHO
OH
N
N
H
O
N
N
H
CH3
ethanol, piperidine
reflux
O
NH
N
O
7
O
R
N
CHO
N
N
O
R
N
N
OH
N
N
H
CH3
ethanol, piperidine, reflux
O
NH
8d, R = 4-Br
8b, R = 4-F 8e, R = 3-CH3
8c,
8a, R = H
R = 3-Br
Here, the authors were aimed to synthesis chromene
scaffold bearing morpholine moiety hoping to add some
significant biological active compounds. Thus,
[27]. Thus, the present work was described the prepara-
tion of chromene nucleus containing aryldiazo group.
Thus, cyclization of cyanoacetamide 3 with 5-aryldiazo-
salicylaldehydes in the presence of piperidine afforded
5-aryldiazo-2-iminochromene derivatives 8a-d in reason-
ably good yields.
cyclocondensation
of
cyanoacetamide
3
by
salicylaldehyde afforded high yield of 2-iminochromene
1
7 as colored solid (Scheme 3). H NMR spectrum of imi-
nochromene derivative 7 was characteristic by found
three singlet signals at δ = 8.54, 9.22 and 13.42 ppm
assignable for chromene-H and 2NH protons,
respectively.
Several diazenyl derivatives have been synthesized
and evaluated for antimicrobial potentials. The majority
of them have shown promising antimicrobial activities
1H NMR spectrum of iminochromene derivative 8b
showed at δ = 3.20 and 3.75 ppm two singlet signals with
four protons integral value for morpholine protons. A
singlet signal at δ = 2.28 ppm with three protons integral
value was assigned for methyl group. Four signals with
two protons integral value were assigned at δ = 6.99,
7.45, 7.76 and 7.98 ppm for two phenylene AB protons.

4
SALEM ET AL.
The protons of benzopyran were assigned at δ = 7.48,
8.07 and 8.40 as doublet, doublet and singlet signals with
one proton integral value. Also, the singlet signal at
δ = 8.73 (one proton) was displayed for the chromene
proton. The imine protonsignals were assigned at
δ = 9.51 and 13.36 ppm as two exchangeable signals.
The newly synthesized pyridinone andchromen-
2-imine derivatives were screened for their expected anti-
fungal and antibacterial activities. Three microbial
groups were tested. Group one: G +ve bacteria; Bacillus
subtilis (RCMB 015) and Staphylococcus aureus (ATCC
25923). Group two: Gram-ve bacteria; Proteus vulgaris
(RCMB 004) and Escherichia coli (ATCC 25922). Group
three: (Fungi): Candida albicans (RCMB 005003) and
Aspergillus fumigatus (RCMB 002008). For probing the
antibacterial properties, diffusion agar technique [5] was
applied at 10 mg/mL concentration, well diameter
6.0 mm (100 μL). For comparison, gentamycin
(antibacterial agent) and ketoconazole (antifungal agent)
were chose as antimicrobial agents. The inhibition zone
diameters were depicted in Table 1.
All 2-iminochromene derivatives showed moderate activ-
ity against Candida albicans. Compound 8c was the most
active compound; it showed moderate activity against
four tested organisms. The major compounds displayed
no activities toward most of the tested microorganisms.
3 | CONCLUSION
Novel of nine 2-pyridinonesand six 2-iminochromenes
containing morpholine moiety were synthesized. The
2-pyridinone derivatives were obtained through the cycli-
zation
of
cyanoacetohydrazone
of
4-morpholi
nylacetophenone with 1,3-dicarbonyl compounds,
α,β-unsaturated nitriles or 2-(arylidene)malononitriles.
The 2-iminochromene derivatives were synthesized
through the ring closure of cyanoacetohydrazone with
salicylaldehyde derivatives. The antibacterial and anti-
fungal properties for the synthesized 2-pyridinone and
2-iminochromene derivatives were investigated. The
obtained results suggested that most of compounds do
not possess significant antimicrobial activity. Most of
tested compounds showed moderate activity against P.
vulgaris. Compounds 4a,b and 5a,b showed moderate
activity against G ꢀve bacteria. All iminochromene deriv-
atives showed moderate activity against C. albicans. Com-
pound 8c was the most active compound; it showed
Regarding the antimicrobial activity of 2-pyridinone
and 2-iminochromene derivatives, few compounds dis-
played weak activities toward some of the tested microor-
ganisms. Most of tested compounds showed moderate
activity against Proteus vulgaris. Compounds 4a,b and
5a,b showed moderate activity against G ꢀve bacteria.
TABLE 1 The mean results of
G +ve bacteria
S. a.
G ꢀve bacteria
E. c.
Fungi
inhibition zone in mm
Compd. No.
B. s.
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
10
P.v.
12
11
16
12
18
NA
10
15
16
15
16
10
NA
14
12
25
–
C. a.
NA
12
A. f.
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
18
4a
NA
NA
10
10
4b
5a
10
8
13
5b
6a
9
9
NA
NA
NA
NA
NA
NA
13
NA
NA
NA
NA
9
NA
NA
NA
NA
NA
NA
NA
NA
11
6b
6c
6d
6e
7
NA
NA
NA
NA
NA
NA
24
8a
15
8b
8c
12
13
8d
8e
NA
NA
26
NA
NA
30
10
NA
NA
–
11
Gent.
Ket.
–
–
–
–
20
17
Abbreviations: A. f., A. fumigates; B.s., B. subtilis; C. A., C. albicans; E. c., E. coli; Gent., Gentamycin; Ket.,
Ketoconazole; NA, no activity; P. V., P. vulgaris; S.a., S. aureus.

SALEM ET AL.
5
moderate activity against four tested organisms. The
major compounds displayed no activities toward most of
the tested microorganisms.
acetaldehyde) (0.015 mol), malononitrile (0.015 mol) and
three drops of piperidinein 40 mL ethanol was heated for
3 h under reflux conditions. The obtained products were
recrystallized from ethanol.
6-Amino-1-(1-(4-morpholinophenyl)ethylideneamino)-
2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (5a): Yield
65%; m.p. 223–225ꢁC; 1H NMR (400 MHz, DMSO):
δ = 2.27 (s, 3H, CH3), 3.19, 3.75 (2s, 8H, 4CH2), 6.71–7.13
(m, 3H, Ar-H), 7.36–8.20 (m, 4H, 2Ar-H and NH2); MS,
m/z (%): 362 (M+; 58.9); Anal. Calcd. for C19H18
N6O2(362.39): C, 62.97; H, 5.01; N, 23.19; Found: C,
63.11; H, 5.01; N, 23.20%.
4 | EXPERIMENTAL SECTION
The nuclear magnetic resonance were carried out in deu-
terated dimethylsulfoxide (DMSO-d6) by using Bruker
spectrometers (1H NMR 400 MHz; 13C NMR 101 MHz)
with chemical shift in δ from internal TMS.
6-Amino-4-methyl-1-(1-(4-morpholinophenyl)ethyl-
ideneamino)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
(5b): Yield 75%; m.p. 293–295ꢁC; 1H NMR (400 MHz,
DMSO): δ = 2.08, 2.40 (2s, 6H, 2CH3), 3.22, 3.75 (2s, 8H,
4CH2), 6.99, 7.93 (2d, 4H, J = 8.1 Hz, Ar-H, AB), 8.06 (br,
2H, NH2); 13C NMR (101 MHz, DMSO): 16.8 (CH3), 20.4
(CH3), 47.6 (2CH2), 48.6 (C), 66.3 (2CH2), 75.6, 88.0,
113.7, 115.1, 116.9, 125.1, 126.3, 130.1, 153.6, 154.08,
155.4, 158.5, 178.9 (C═O); MS, m/z (%): 376 (M+; 33.9);
Anal. Calcd. for C20H20N6O2(376.41): C, 63.82; H,
5.36; N, 22.33; Found: C, 63.76; H, 5.34; N, 22.30%.
4.1 | Synthesis of 4,6-disubstituted-
1-(1-(4-morpholinophenyl)
ethylideneamino)-2-oxo-
1,2-dihydropyridine-3-carbonitriles 4a,b
The mixture of cyanoacetohydrazone
3 (0.02 mol),
acetylacetone or benzoylacetone (0.02 mol), 1 mL of
piperidine was gently heated for 20 min at about 150ꢁC.
The products were triturated with ethanol and crystal-
lized from THF.
4,6-Dimethyl-1-(1-(4-morpholinophenyl)ethyl-
ideneamino)-2-oxo-1,2-dihydropyri-dine-3-carbonitrile (4a):
1
Yield 80%; m.p. 237–238ꢁC; H NMR (400 MHz, DMSO):
4.3 | Synthesis of 6-amino-
1-(1-(4-morpholinophenyl)
ethylideneamino)-2-oxo-4-aryl-
1,2-dihydropyridine-3,5-dicarbonitrile
(6a-d)
δ = 2.06 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.38 (s, 3H, CH3),
3.27 (s, 4H, 2CH2), 3.75 (s, 4H, 2CH2), 6.44 (s, 1H, pyridone-
H), 7.03 (d, 2H, J = 8.0 Hz, Ar-H), 7.90 (d, 9H, J = 7.9 Hz,
Ar-H); 13C NMR (101 MHz, DMSO): 16.4 (CH3), 19.6
(CH3), (CH3), 20.8 (CH3), 47.6 (2CH2), 66.3 (2CH2), 108.5
(C N), 114.1 (2CH), 116.6 (CH), 129.5 (2CH), 150.6 (C),
154.0 (C), 157.3 (C═O); MS, m/z (%): 350 (M+; 66.3); Anal.
Calcd. for C20H22N4O2 (350.41): C, 68.55; H, 6.33; N, 15.99;
Found: C, 68.42; H, 6.30; N, 16.13%.
Method A: The suspension of cyanoacetohydrazone
3
(0.015 mol), the appropriate aldehyde (namely,
4-fluorobenzaldehyde, m-anisaldehyde, p-anisaldehyde,
2,5-dimethoxybenzaldehyde, p-
1-(1-(4-Morpholinophenyl)ethylideneamino)-2-oxo-4,-
6-diphenyl-1,2-dihydropyri-dine-3-carbonitrile (4b): Yield
69%; m.p. 181–183ꢁC; 1H NMR (400 MHz, DMSO):
δ = 2.27 (s, 3H, CH3), 3.20, 3.75 (2s, 8H, 4CH2), 6.97 (s,
1H, pyridone-H5), 7.35–8.73 (m, 14H, Ar-H); MS, m/z
(%): 474 (M+; 28.8); Anal. Calcd. for C30H26N4O2
(474.55): C, 75.93; H, 5.52; N, 11.81; Found: C, 75.89; H,
5.49; N, 11.76%.
dimetylaminobenzaldehyde; 0.015 mol), malononitrile
(0.015 mol) and two drops of piperidine in 40 mL ethanol
was heated for 3 hours under reflux conditions. The
resulting products were separated by filtration and rec-
rystallized from ethanol.
Method B: The suspension of equimolar amounts
(0.015 mol) of cyanoacetohydrazone 3 and 2-(arylidene)
malononitrile
(2-(4-fluorobenzylidene)-malononitrile,
2-(3-methoxy-benzylidene)malononitrile, 2-(4-methoxy
benzylidene)malononitrile, 2,5-dimethoxybenzylidene-
4.2 | Synthesis of 6-amino-4-alkyl-
1-(1-(4-morpholinophenyl)
ethylideneamino)-2-oxo-
1,2-dihydropyridine-
malononitrile
and
p-dimetylaminobenzylidene-
malononitrile) in 40 mL ethanol containing two drops of
piperidine was heated for 3 h under reflux conditions.
6-Amino-4-(4-fluorophenyl)-1-(1-(4-morpholinophenyl)
ethylideneamino)-2-oxo-1,2-dihydropyridine-3,5-dicar
bonitrile (6a): Yield 75%; m.p. 271–272ꢁC; 1H NMR
(400 MHz, DMSO): δ = 2.15 (s, 3H, CH3), 3.22–3.31,
3.69–3.81 (2m, 8H, 4CH2), 7.05 (d, 2H, J = 8.9 Hz,
3,5-dicarbonitriles (5a,b)
The suspension of cyanoacetohydrazide 3 (0.015 mol),
the appropriate aldehyde (namely formaldehyde or

6
SALEM ET AL.
Ar-H, AB), 7.43 (m, 2H,Ar-H), 7.64 (m, 2H,Ar-H), 7.98
(d, 2H, J = 8.9 Hz, Ar-H, AB), 8.22 (br, 2H, NH2); MS,
m/z (%): 456 (M+; 28.3); Anal. Calcd. for C25H21FN6O2
(456.47): C, 65.78; H, 4.64; N, 18.41; Found: C,
65.82; H, 4.66; N, 18.38%.
6-Amino-4-(3-methoxyphenyl)-1-(1-(4-morpholinophenyl)
ethylideneamino)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
(6b): Yield 70%; m.p. >300ꢁC; 1H NMR (400 MHz, DMSO):
δ = 2.17 (s, 3H, CH3), 3.29, 3.72 (2m, 8H, 4CH2), 3.84 (s,
3H, OCH3), 7.05 (d, 2H, J = 9.0 Hz, Ar-H, AB), 7.12 (m,
2H,Ar-H), 7.38–7.62 (m, 2H,Ar-H), 8.00 (d, 2H, J = 9.0 Hz,
Ar-H, AB), 8.19 (br, 2H, NH2); MS, m/z (%): 468 (M+; 74.8);
Anal. Calcd. for C26H24N6O3 (468.51): C, 66.65; H, 5.16; N,
17.94; Found: C, 66.71; H, 5.14; N, 18.03%.
m.p. 219–220ꢁC; 1H NMR (400 MHz, DMSO): δ = 2.22 (s,
3H, CH3), 3.15, 3.71 (2s, 8H, 4CH2), 6.93–7.25 (m, 4H,
Ar-H), 7.71–7.76 (m, 4H, Ar-H), 8.54 (s, 1H, Chromen-
H), 9.22, 13.42 (2s, 2H, 2NH); 13C NMR (101 MHz,
DMSO): 16.8 (CH3), 47.6 (2CH2), 66.3 (2CH2), 113.7,
115.1, 116.9, 125.1, 126.3, 130.1, 153.6, 154.1, 155.4, 158.5,
178.9, (C═N); MS, m/z (%): 390 (M+; 47.4); Anal. Calcd.
for C22H22N4O3(390.44): C, 67.68; H, 5.68; N, 14.35;
Found: C, 67.73; H, 5.66; N, 14.31%.
4.5 | Synthesis of 2-imino-N0-
(1-(4-morpholinophenyl)ethylidene)-
6-(aryldiazenyl)-2H-chromene-
3-carbohydrazides 8a-e
6-Amino-4-(4-methoxyphenyl)-1-(1-(4-morpholinophenyl)
ethylideneamino)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
(6c): Yield 80%; m.p. >300ꢁC; 1H NMR (400 MHz, DMSO):
δ = 2.15 (s, 3H, CH3), 3.24–3.31, 3.70–3.80 (2m, 8H, 4CH2),
3.85 (s, 3H, OCH3), 7.04, 7.12 (2d, 4H, J = 8.7 Hz, Ar-H,
AB), 7.52 (d, 2H, J = 8.7 Hz, Ar-H, AB), 7.97 (d, 2H,
J = 9.0 Hz, Ar-H, AB), 8.14 (br, 2H, NH2); MS, m/z (%):
468 (M+; 64.1); Anal. Calcd. for C26H24N6O3 (468.51): C,
66.65; H, 5.16; N, 17.94; Found: C, 66.69; H, 5.13; N, 18.07%.
6-Amino-4-(2,5-dimethoxyphenyl)-1-(1-(4-morpholinophenyl)
ethylideneamino)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
The suspension of equimolar amounts (0.015 mol) of
cyanoacetohydrazide 3 and aryldiazosalicylaldehydes in
40 mL ethanol containing few drops of piperidine was
heated for 0.5 h under reflux conditions. The created
solid products were separated by filtration and crystal-
lized from dioxane to afford 8a-e.
2-Imino-N0-(1-(4-morpholinophenyl)ethylidene)-6-(phe-
nyldiazenyl)-2H-chromene-3-carbohydrazide (8a): Yield
85%; m.p. 221–222ꢁC; 1H NMR (400 MHz, DMSO):
δ = 2.28 (s, 3H, CH3), 3.21, 3.75 (2s, 8H, 4CH2), 6.99 (d,
2H, J = 7.9 Hz, Ar-H), 7.46 (d, 1H, J = 8.5 Hz, Ar-H),
7.61 (s, 2H, Ar-H), 7.77 (d, 2H, J = 7.8 Hz, Ar-H), 7.91 (d,
2H, J = 5.6 Hz, Ar-H), 8.09 (d, 1H, J = 7.1 Hz, Ar-H),
8.44 (s, 1H, Ar-H), 8.75 (s, 1H, Chromen-H), 9.52, 13.37
(2s, 2H, 2NH); MS, m/z (%): 494 (M+; 64.7); Anal. Calcd.
for C28H26N6O3 (494.54): C, 68.00; H, 5.30; N, 16.99;
Found: C, 68.07; H, 5.28; N, 17.08%.
1
(6d): Yield 85%; m.p. >300ꢁC; H NMR (400 MHz, DMSO):
δ=2.15(d, 3H, CH3), 3.28 (s, 4H, 2CH2), 3.77–3.81(m, 10H, 2CH2
and 2OCH3), 6.85–7.20 (m, 5H, Ar-H), 7.97 (d, 2H, J=8.6 Hz, Ar-
H), 8.15(br, 2H, NH2); 13C NMR (101 MHz, DMSO): 16.9 (CH3),
47.7 (2CH2), 48.5, 56.1 (OCH3), 56.7 (OCH3), 66.3 (2CH2), 66.5,
76.3,88.6,113.8,115.1,115.3,115.8,116.7,124.7,125.1,130.2,150.1,
153.3, 153.7, 154.1, 155.6, 157.6, 179.1 (C═O); MS, m/z (%):
498 (M+; 59.0); Anal. Calcd. for C27H26N6O4 (498.53): C, 65.05; H,
5.26;N,16.86;Found:C,64.96;H,5.23;N,16.90%.
6-((4-Fluorophenyl)diazenyl)-2-imino-N0-(1-(4-mor-
pholinophenyl)ethylidene)-2H-chromene-3-carbohydrazide
(8b): Yield 86%; m.p. 224–226ꢁC; 1H NMR (400 MHz,
DMSO): δ = 2.28 (s, 3H, CH3), 3.19, 3.75 (2s, 8H, 4CH2),
6.99 (d, 2H, J = 8.5 Hz, Ar-H), 7.43–7.48 (m, 3H, Ar-H),
7.76 (d, 2H, J = 8.4 Hz, Ar-H), 7.93–8.04 (m, 2H, Ar-
H), 8.07 (d, 1H, J = 8.7 Hz, Ar-H), 8.40 (s, 1H, Ar-H),
8.73 (s, 1H, Chromen-H), 9.51, 13.36 (2s, 2H, 2NH); MS,
m/z (%): 512 (M+; 47.1); Anal. Calcd. for C28H25FN6O3
(512.53): C, 65.61; H, 4.92; N, 16.40; Found: C, 65.56; H,
4.91; N, 16.36%.
6-Amino-4-(4-(dimethylamino)phenyl)-1-(1-(4-morpholinophenyl)
ethylideneamino)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
(6e):
Yield 68%; m.p. 243–245ꢁC; 1H NMR (400 MHz, DMSO):
δ = 2.27, 3.00, 3.08 (3s, 9H, 3CH3), 3.18–3.21, 3.73–3.75 (2m, 8H,
4CH2), 6.80–6.86 (m, 4H, Ar-H), 6.97, 7.36 (2d, 4H, J = 8.7 Hz, Ar-
H), 8.28 (br, 2H, NH2); MS, m/z (%): 481 (M+; 65.3); Anal. Calcd.
for C27H27N7O2 (481.55): C, 67.34; H, 5.65; N, 20.36; Found: C,
67.29; H, 5.61; N, 20.29%.
4.4 | Synthesis of 2-imino-N0-
6-((3-Bromophenyl)diazenyl)-2-imino-N0-(1-(4-mor-
(1-(4-morpholinophenyl)ethylidene)-2H-
chromene-3-carbohydrazide (7)
pholinophenyl)ethylidene)-2H-chromene-3-carbohydrazide
(8c): Yield 88%; m.p. 240–242ꢁC; 1H NMR (400 MHz, DMSO):
δ = 2.29 (s, 3H, CH3), 3.20, 3.76 (2s, 8H, 4CH2), 7.00 (m, 2H,
Ar-H), 7.59 (m, 2H, Ar-H), 7.78 (m, 2H, Ar-H), 8.02 (s, 1H,
Ar-H), 8.11 (d, 1H, Ar-H), 8.46 (s, 1H, Ar-H), 8.74 (s, 1H, Ar-
H), 9.53, 13.36 (2s, 2H, 2NH); MS, m/z (%): 573 (M+; 34.3);
Anal. Calcd. for C28H25BrN6O3 (573.44): C, 58.65; H, 4.39; N,
14.66; Found: C, 58.63; H, 4.38; N, 14.69%.
The suspension of equimolar amounts (0.015 mol) of
cyanoacetohydrazide 3 and salicyaldehyde in 40 mL etha-
nol containing two drops of piperidine was heated for 1 h
under reflux conditions. The solid product was filtrated
and recrystallized from dioxane to afford 7. Yield 75%;

SALEM ET AL.
7
6-((4-Bromophenyl)diazenyl)-2-imino-N0-(1-(4-mor-
[6] M. A. M. S. El-Sharief, S. Y. Abbas, M. A. Zahran, Y. A.
Mohamed, A. Ragab, Y. A. Ammar, Z. Naturforsch. B. 2016,
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Ammar, Med. Chem. Res. 2013, 22, 5598.
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Fouad, Y. A. Ammar, Med. Chem. Res. 2018, 27, 2287.
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Salem, A. Ragab, Eur. J. Chem. 2017, 8, 76.
[10] Z. Moussa, M. A. M. S. El-Sharief, S. Y. Abbas, Eur. J. Med.
Chem. 2016, 122, 419.
pholinophenyl)ethylidene)-2H-chromene-3-carbohydrazide
(8d): Yield 86%; m.p. 244–245ꢁC; 1H NMR (400 MHz,
DMSO): δ = 2.27 (s, 3H, CH3), 3.21, 3.75 (2s, 8H, 4CH2),
6.99 (d, 2H, J = 8.3 Hz, Ar-H), 7.45 (d, 1H, J = 9.1 Hz,
Ar-H), 7.76–7.84 (m, 4H, Ar-H), 8.08 (d, 1H, Ar-H),8.43
(s, 1H, Ar-H), 8.73 (s, 1H, Chromen-H), 9.53, 13.35 (2s,
2H, 2NH); MS, m/z (%): 573 (M+; 55.7); Anal. Calcd. for
C28H25BrN6O3 (573.44): C, 58.65; H, 4.39; N, 14.66;
Found: C, 58.68; H, 4.40; N, 14.70%.
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B. Xing, Z. Xu, Org. Biomol. Chem. 2016, 14, 10973.
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Shaquiquzzaman, Eur. J. Med. Chem 2019, 167, 324.
[14] C. Roger, J. A. Roberts, L. Muller, Clin. Pharmacokinet. 2018,
57, 559.
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Chem. Commun. 2014, 50, 978.
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2009, 62, 705.
2-Imino-N0-(1-(4-morpholinophenyl)ethylidene)-6-(m-
tolyldiazenyl)-2H-chromene-3-carbohydrazide (8e): Yield
86%; m.p. 238–240ꢁC; 1H NMR (400 MHz, DMSO):
δ = 2.26, 2.43 (2s, 6H, 2CH3), 3.20, 3.74 (2s, 8H, 4CH2),
6.97 (m, 2H, Ar-H), 7.38–7.57 (m, 3H, Ar-H), 7.67–7.86
(m, 4H, Ar-H), 8.07 (m, 1H, Ar-H), 8.38 (s, 1H, Ar-H),
8.70 (s, 1H, Chromen-H), 9.48, 13.37 (2s, 2H, 2NH); MS,
m/z (%): 508 (M+; 28.3); Anal. Calcd. for C29H28N6O3
(508.57): C, 68.49; H, 5.55; N, 16.52; Found: C, 68.53; H,
5.53; N, 16.47%.
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M. S. A. El-Gaby, S. Y. Abbas, Synth. Commun 2018, 48(13), 1534.
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Thabet, Y. A. Ammar, Croat. Chem. Acta 2016, 89(1), 91.
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J. Med. Chem. 2020, 207, 112832.
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ACKNOWLEDGMENT
The authors appreciated the Deanship of Scientific
Research at King Khalid University for funding this work
under grant number: R.G.P.1/231/41.
DATA AVAILABILITY STATEMENT
Data openly available in a public repository that issues
datasets with DOIs.
ORCID
Mohamed A. Salem https://orcid.org/0000-0003-4097-
0899
Samir Y. Abbas https://orcid.org/0000-0001-7584-5030
Mohamed H. Helal https://orcid.org/0000-0002-3769-
4670
Abdullah Y. Alzahrani https://orcid.org/0000-0003-
3195-8142
[26] M. H. M. Helal, M. A. Salem, M. S. A. El-Gaby, M. Aljahdali,
Eur. J. Med. Chem. 2013, 65, 517.
[27] H. Kaur, S. M. Lim, K. Ramasamy, M. Vasudevan, S. A. A.
Shah, B. Narasimhan, Arabian J. Chem. 2020, 13, 377.
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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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How to cite this article: M. A. Salem, S.
Y. Abbas, M. H. Helal, A. Y. Alzahrani,
J Heterocyclic Chem 2021, 1. https://doi.org/10.
1002/jhet.4335